RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional application Ser. No.

62/313,583 entitled "Pediatric Population Pharmacokinetic Model Development", filed March 25, 2016, Cassella. The entire disclosure of which is hereby incorporated by reference. Any disclaimer that may have occurred during the prosecution of the above- referenced application is hereby expressly rescinded, and reconsideration of all relevant art is respectfully requested.

TECHNICAL FIELD

[0002] The present disclosure relates generally to population pharmacokinetic (PK) modeling and simulations of loxapine to establish parameters for the development of clinical study protocols, including dose selection, optimal sampling strategy, and sample size determination, for a pediatric PK study of loxapine in adolescent patients. The present disclosure teaches predictive measures employed for achieving target exposure and therapeutic effect.

BACKGROUND

[0003] Loxapine for inhalation is a drug-device combination product that delivers the antipsychotic loxapine by oral inhalation. Loxapine for inhalation has been approved for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

[0004] Loxapine is a dibenzoxazepine compound, a subclass of tricyclic antipsychotic agents, chemically distinct from the phenothiazines, butyrophenones, and thioxanthenes. It may reduce agitation via antagonism of central dopamine (Dl, D2, D3, and D4) receptors and serotonin 5-HT(2a) receptors. Loxapine for inhalation (Adasuve ^® ; Teva Select Brands, a division of Teva Pharmaceuticals USA, Horsham, PA) is a drug-device combination product that delivers the antipsychotic loxapine by oral inhalation. Loxapine is the first orally inhaled medication for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

[0005] This has prompted an evaluation of the safety, efficacy, and pharmacokinetics of loxapine for inhalation in children and adolescents. The pharmacokinetics of loxapine for inhalation have been described previously in healthy adult volunteers. Administration of loxapine for inhalation results in rapid absorption, with a median time to maximum plasma concentration (t _max ) of 2 minutes. Loxapine is metabolized extensively in the liver with multiple metabolites formed. The major metabolite, 8-OH-loxapine, is not pharmacologically active. Other metabolites include 7-OH-loxapine (active) and N-oxides of loxapine (inactive). A substantial proportion of loxapine and its metabolites is excreted within the first 24 hours after drug administration, mainly through the urine (56%-70%) and, to a lesser extent, via the feces (15%-22%). Loxapine pharmacokinetics are linear over the clinical dosing range. The mean terminal half-life (ti^) is approximately 6 hours, and the mean apparent clearance is 61.3 L/h.

[0006] A multicenter, randomized, placebo-controlled clinical trial has demonstrated that 5 mg and 10 mg of inhaled loxapine significantly reduced agitation in adult patients with bipolar I disorder compared with placebo, as measured by the Positive and Negative

Syndrome Scale-Excited Component score and the Clinical Global Impression-Improvement score. Overall, inhaled loxapine at doses of up to 10 mg was found to be safe and well tolerated. The most common adverse events (AEs) with loxapine treatment are dizziness, somnolence, and dysgeusia.

[0007] This disclosure teaches population pharmacokinetic (PK) modeling and simulations of loxapine to support the development of a clinical study protocol, including dose selection, optimal sampling strategy, and sample size determination, for a pediatric PK study of loxapine in adolescent patients.

Summary of the Embodiments

[0008] Accordingly, one aspect of the present disclosure teaches the application of population PK modeling and clinical trial simulation with the use of allometric scaling and realistic age-matched weight data specific to the targeted population. The pediatric loxapine population PK model includes an allometric component to take into account the effects of differences in body size on PK parameter estimates in the targeted pediatric patient population. Clinical trial simulations with the pediatric model are taught in the evaluation of to-be-expected distribution of loxapine exposures at different dose levels. This disclosure teaches these simulations as part of phase I study design. The disclosure teaches different dose levels to be considered. The disclosure teaches dependence on the targeted exposure using allometric scaling and realistic age-matched weight data specific to the targeted population resulting in drug exposures comparable to those observed in the adult patient studies.

[0009] One aspect of the present disclosure teaches performing clinical trial simulations to support dose selection, an optimal sampling strategy, and appropriate sample size for a phase I pediatric clinical pharmacokinetics study in children and adolescents. In addition, this disclosure teaches results of clinical studies in relation to predicted likelihood of achieving target exposure and therapeutic effect.

[0010] One aspect of the present disclosure provides a method of population PK modeling and clinical trial simulation with the use of allometric scaling and realistic age- matched weight data specific to the targeted population for use in a clinical trial.

[0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of certain embodiments, as claimed.

[0027] To achieve the foregoing objects, and in accordance with the invention as embodied and broadly described herein, a loxapine-containing dosage form is provided.

[0028] These and other objects and features of the invention will be more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1. A schematic representation of the structural pharmacokinetic model used in the population modeling. CL, apparent clearance of loxapine; Ka, rate constant of absorption of loxapine; Q2-3, apparent oral intercompartmental clearance; V2-4, apparent volume of distribution.

[0013] Figure 2. Age-matched body weight values for boys and girls aged 10-17 years, inclusive, from the CDC NHANES database. The external data from psychiatric patients (n=159; admission period, June-November 2013) and pediatric patients participating in the phase 1 loxapine pharmacokinetic study (n=30) are overlaid. CDC, Centers for Disease Control and Prevention; NHANES, National Health and Nutrition Examination Survey. [0014] Figure 3. Distribution of predicted AUCo-24h values at the 4 selected dose levels (panels D-G) compared with the adult reference values (panels A, B, and C). AUCo-24h, area under the concentration-time curve from 0 to 24 hours.

[0015] Figure 4. Predicted drug exposure (expressed as area under the curve [panel A] and

C _max [panel B]) in pediatric patients aged 10-17 years, inclusive, for loxapine compared with values in adult subjects. Trial simulation identified the pediatric doses that would result in comparable drug exposures as observed in adult studies. A virtual population of 8000 pediatric patients aged 10-17 years, inclusive, was randomly sampled from the CDC NHANES database. Red and green lines represent the 1st quartile, median, and 3rd quartile of the observations in the adult studies. AUCo-24h, area under the concentration-time curve from 0 to 24 hours; CDC, Centers for Disease Control and Prevention; C _max , maximum observed peak drug concentration; NHANES, National Health and Nutrition Examination Survey; Obs: observed exposure (AUCo-24h) and C _max level in the adult study at the dose level provided; Sim: simulated exposure (AUCo-24h) and C _max in the pediatric study at the dose level provided.

[0016] Figure 5a. Predicted AUC ₀ - _t values for Cohort 1 at dose levels 2.5 mg (<50 kg) and 5 mg (>50 kg; panel A) and for Cohort 2 at dose levels 5 mg (<50 kg) and 10 mg (>50 kg; panel B). The observations from the pediatric pharmacokinetic study are overlaid (blue circles). The solid lines present the upper and lower ranges as observed in the adult studies; dotted line represents mean. AUCo-t, area under the concentration vs time curve from time 0 to time t.

[0017] Figure 5b. Predicted AUC ₀ -2h values for Cohort 1 at dose levels 2.5 mg (<50 kg) and 5 mg (>50 kg; panel A) and for Cohort 2 at dose levels 5 mg (<50 kg) and 10 mg (>50 kg; panel B). The observations from the pediatric pharmacokinetic study are overlaid (blue circles). The solid lines present the upper and lower ranges as observed in the adult studies; dotted line represents mean. AUCo-2h, area under the concentration- time curve at 0-2 hours.

[0018] Figure 6. Observed (panel A) and predicted (panel B) C _max values for Cohort

1 at dose levels 2.5 mg (<50 kg) and 5 mg (>50 kg; panel A) and for Cohort 2 at dose levels 5 mg (<50 kg) and 10 mg (>50 kg; panel B). Observations from the pediatric PK study are overlaid (blue circles). The solid lines present the upper and lower ranges as observed in the adult studies; dotted line represents mean. Note: Y-axis as log scale. WT, weight.

[0019] Figure 7. Box-whisker plots representing post-hoc Bayesian estimates of individual clearance (CL/F; panel A) and volume of distribution (V2/F; panel B) of loxapine in pediatric patients participating in the phase I study compared with the model-based predictions.

[0020] Figure 8. Time after Dose Curves

[0021] Figure 9. Study design.

[0022] Figure 10. Mean plasma concentration versus time profile over (A) 0 to 2 hours and (B) 0 to 48 hours for loxapine by subgroup and dose on a semilogarithmic scale.

[0023] Figure 11. Mean plasma concentration versus time profile over (A) 0 to 2 hours and (B) 0 to 48 hours for 7-OH-loxapine by subgroup and dose on a semilogarithmic scale.

[0024] Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.

DESCRIPTION OF VARIOUS EMBODIMENTS

Definitions

[0025] "Drug" means any substance that is used in the prevention, diagnosis, alleviation, treatment or cure of a condition. The terms "drug", "compound", and

"medication" are used herein interchangeably. As described in throughout the specification, the term drug includes the following.

[0026] Any suitable drug compound may be used. Drugs that can be used include, for example but not limitation, drugs of one of the following classes: anesthetics,

anticonvulsants, antidepressants, antidiabetic agents, antidotes, antiemetics, antihistamines, anti-infective agents, antineoplastics, antiparkisonian drugs, antirheumatic agents, antipsychotics, anxiolytics, appetite stimulants and suppressants, blood modifiers, cardiovascular agents, central nervous system stimulants, drugs for Alzheimer's disease management, drugs for cystic fibrosis management, diagnostics, dietary supplements, drugs for erectile dysfunction, gastrointestinal agents, hormones, drugs for the treatment of alcoholism, drugs for the treatment of addiction, immunosuppressives, mast cell stabilizers, migraine preparations, motion sickness products, drugs for multiple sclerosis management, muscle relaxants, nonsteroidal anti-inflammatories, opioids, cannabinoids, other analgesics and stimulants, opthalmic preparations, osteoporosis preparations, prostaglandins, respiratory agents, sedatives and hypnotics, skin and mucous membrane agents, smoking cessation aids, Tourette's syndrome agents, urinary tract agents, and vertigo agents.

[0027] Typically, where the drug is an anesthetic, it is selected from one of the following compounds: ketamine and lidocaine.

[0028] Typically, where the drug is an anticonvulsant, it is selected from one of the following classes: GABA analogs, tiagabine, vigabatrin; barbiturates such as pentobarbital; benzodiazepines such as clonazepam; hydantoins such as phenytoin; phenyltriazines such as lamotrigine; miscellaneous anticonvulsants such as carbamazepine, topiramate, valproic acid, and zonisamide.

[0029] Typically, where the drug is an antidepressant, it is selected from one of the following compounds: amitriptyline, amoxapine, benmoxine, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, kitanserin, lofepramine, medifoxamine, mianserin, maprotoline, mirtazapine, nortriptyline, protriptyline, trimipramine, venlafaxine, viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine, acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine, iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine, selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil, amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone, gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone, nomifensine, ritanserin, roxindole, S-adenosylmethionine, escitalopram, tofenacin, trazodone, tryptophan, and zalospirone.

[0030] Typically, where the drug is an antidiabetic agent, it is selected from one of the following compounds: pioglitazone, rosiglitazone, and troglitazone.

[0031] Typically, where the drug is an antidote, it is selected from one of the following compounds: edrophonium chloride, flumazenil, deferoxamine, nalmefene, naloxone, and naltrexone.

[0032] Typically, where the drug is an antiemetic, it is selected from one of the following compounds: alizapride, azasetron, benzquinamide, bromopride, buclizine, chlorpromazine, cinnarizine, clebopride, cyclizine, diphenhydramine, diphenidol, dolasetron, droperidol, granisetron, hyoscine, lorazepam, dronabinol, metoclopramide, metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, triethylperazine, trifluoperazine, triflupromazine, trimethobenzamide, tropisetron, domperidone, and palonosetron.

[0033] Typically, where the drug is an antihistamine, it is selected from one of the following compounds: astemizole, azatadine, brompheniramine, carbinoxamine, cetrizine, chlorpheniramine, cinnarizine, clemastine, cyproheptadine, dexmedetomidine,

diphenhydramine, doxylamine, fexofenadine, hydroxyzine, loratidine, promethazine, pyrilamine and terfenidine.

[0034] Typically, where the drug is an anti-infective agent, it is selected from one of the following classes: antivirals such as efavirenz; AIDS adjunct agents such as dapsone; aminoglycosides such as tobramycin; antifungals such as fluconazole; antimalarial agents such as quinine; antituberculosis agents such as ethambutol; β-lactams such as cefmetazole, cefazolin, cephalexin, cefoperazone, cefoxitin, cephacetrile, cephaloglycin, cephaloridine; cephalosporins, such as cephalosporin C, cephalothin; cephamycins such as cephamycin A, cephamycin B, and cephamycin C, cephapirin, cephradine; leprostatics such as clofazimine; penicillins such as ampicillin, amoxicillin, hetacillin, carfecillin, carindacillin, carbeniciUin, amylpenicillin, azidocillin, benzylpenicillin, clometocillin, cloxacillin, cyclacillin, methicillin, nafcillin, 2-pentenylpenicillin, penicillin N, penicillin O, penicillin S, penicillin V, dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin; quinolones such as ciprofloxacin, clinafloxacin, difloxacin, grepafloxacin, norfloxacin, ofloxacine, temafloxacin; tetracyclines such as doxycycline and oxy tetracycline; miscellaneous anti-infectives such as linezolide, trimethoprim and sulfamethoxazole.

[0035] Typically, where the drug is an anti-neoplastic agent, it is selected from one of the following compounds: droloxifene, tamoxifen, and toremifene.

[0036] Typically, where the drug is an antiparkisonian drug, it is selected from one of the following compounds: amantadine, baclofen, biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa, carbidopa, andropinirole, apomorphine, benserazide, bromocriptine, budipine, cabergoline, eliprodil, eptastigmine, ergoline, galanthamine, lazabemide, lisuride, mazindol, memantine, mofegiline, pergolide, piribedil, pramipexole, propentofylline, rasagiline, remacemide, ropinerole, selegiline, spheramine, terguride, entacapone, and tolcapone.

[0037] Typically, where the drug is an antirheumatic agent, it is selected from one of the following compounds: diclofenac, hydroxychloroquine and methotrexate. [0038] Typically, where the drug is an antipsychotic, it is selected from one of the following compounds: acetophenazine, alizapride, amisulpride, amoxapine, amperozide, aripiprazole, benperidol, benzquinamide, bromperidol, buramate, butaclamol, butaperazine, carphenazine, carpipramine, chlorpromazine, chlorprothixene, clocapramine, clomacran, clopenthixol, clospirazine, clothiapine, clozapine, cyamemazine, droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, loxapine, melperone, mesoridazine, metofenazate, molindrone, olanzapine, penfluridol, pericyazine, perphenazine, pimozide, pipamerone, piperacetazine, pipotiazine, prochlorperazine, promazine, quetiapine, remoxipride, risperidone, sertindole, spiperone, sulpiride, thioridazine, thiothixene, trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine, and zuclopenthixol.

[0039] Typically, where the drug is an anxiolytic, it is selected from one of the following compounds: alprazolam, bromazepam, oxazepam, buspirone, hydroxyzine, mecloqualone, medetomidine, metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol, bromisovalum, captodiamine, capuride, carbcloral, carbromal, chloral betaine, enciprazine, flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon, propanolol, tandospirone, trazadone, zopiclone, and Zolpidem.

[0040] Typically, where the drug is an appetite stimulant, it is dronabinol.

[0041] Typically, where the drug is an appetite suppressant, it is selected from one of the following compounds: fenfluramine, phentermine and sibutramine.

[0042] Typically, where the drug is a blood modifier, it is selected from one of the following compounds: cilostazol and dipyridamol.

[0043] Typically, where the drug is a cardiovascular agent, it is selected from one of the following compounds: benazepril, captopril, enalapril, quinapril, ramipril, doxazosin, prazosin, clonidine, labetolol, candesartan, irbesartan, losartan, telmisartan, valsartan, disopyramide, flecanide, mexiletine, procainamide, propafenone, quinidine, tocainide, amiodarone, dofetilide, ibutilide, adenosine, gemfibrozil, lovastatin, acebutalol, atenolol, bisoprolol, esmolol, metoprolol, nadolol, pindolol, propranolol, sotalol, diltiazem, nifedipine, verapamil, spironolactone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, triamterene, and metolazone.

[0044] Typically, where the drug is a central nervous system stimulant, it is selected from one of the following compounds: amphetamine, brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindol, methyphenidate, pemoline, phentermine, sibutramine, and modafinil.

[0045] Typically, where the drug is a drug for Alzheimer's disease management, it is selected from one of the following compounds: donepezil, galanthamine and tacrin.

[0046] Typically, where the drug is a drug for cystic fibrosis management, it is selected from one of the following compounds: CPX, IB MX, XAC and analogues; 4- phenylbutyric acid; genistein and analogous isoflavones; and milrinone.

[0047] Typically, where the drug is a diagnostic agent, it is selected from one of the following compounds: adenosine and aminohippuric acid.

[0048] Typically, where the drug is a dietary supplement, it is selected from one of the following compounds: melatonin and vitamin-E.

[0049] Typically, where the drug is a drug for erectile dysfunction, it is selected from one of the following compounds: tadalafil, sildenafil, vardenafil, apomorphine, apomorphine diacetate, phentolamine, and yohimbine.

[0050] Typically, where the drug is a gastrointestinal agent, it is selected from one of the following compounds: loperamide, atropine, hyoscyamine, famotidine, lansoprazole, omeprazole, and rebeprazole.

[0051] Typically, where the drug is a hormone, it is selected from one of the following compounds: testosterone, estradiol, and cortisone.

[0052] Typically, where the drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone, and disulfiram.

[0053] Typically, where the drug is a drug for the treatment of addiction it is buprenorphine.

[0054] Typically, where the drug is an immunosupressive, it is selected from one of the following compounds: mycophenolic acid, cyclosporin, azathioprine, tacrolimus, and rapamycin.

[0055] Typically, where the drug is a mast cell stabilizer, it is selected from one of the following compounds: cromolyn, pemirolast, and nedocromil.

[0056] Typically, where the drug is a drug for migraine headache, it is selected from one of the following compounds: almotriptan, alperopride, codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometheptene, lidocaine, lisuride, metoclopramide, naratriptan, oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol, nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol, protriptyline, sertraline, timolol, and verapamil.

[0057] Typically, where the drug is a motion sickness product, it is selected from one of the following compounds: diphenhydramine, promethazine, and scopolamine.

[0058] Typically, where the drug is a drug for multiple sclerosis management, it is selected from one of the following compounds: bencyclane, methylprednisolone,

mitoxantrone, and prednisolone.

[0059] Typically, where the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, chlorzoxazone, cyclobenzaprine, methocarbamol, orphenadrine, quinine, and tizanidine.

[0060] Typically, where the drug is a nonsteroidal anti-inflammatory, it is selected from one of the following compounds: aceclofenac, acetaminophen, alminoprofen, amfenac, aminopropylon, amixetrine, aspirin, benoxaprofen, bromfenac, bufexamac, carprofen, celecoxib, choline, salicylate, cinchophen, cinmetacin, clopriac, clometacin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, mazipredone, meclofenamate, nabumetone, naproxen, parecoxib, piroxicam, pirprofen, rofecoxib, sulindac, tolfenamate, tolmetin, and valdecoxib.

[0061] Typically, where the drug is an opioid, it is selected from one of the following compounds: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, carbiphene, cipramadol, clonitazene, codeine, dextromoramide, dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate, dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol, lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon, morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine, pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

[0062] Typically, where the drug is another analgesic it is selected from one of the following compounds: apazone, benzpiperylon, benzydramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine, propacetamol, and propoxyphene.

[0063] Typically, where the drug is an opthalmic preparation, it is selected from one of the following compounds: ketotifen and betaxolol.

[0064] Typically, where the drug is an osteoporosis preparation, it is selected from one of the following compounds: alendronate, estradiol, estropitate, risedronate and raloxifene. [0065] Typically, where the drug is a prostaglandin, it is selected from one of the following compounds: epoprostanol, dinoprostone, misoprostol, and alprostadil.

[0066] Typically, where the drug is a respiratory agent, it is selected from one of the following compounds: albuterol, ephedrine, epinephrine, fomoterol, metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, ipratropium bromide, pseudoephedrine, theophylline, montelukast, zafirlukast, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pirfenidone

[0067] Typically, where the drug is a sedative and hypnotic, it is selected from one of the following compounds: butalbital, chlordiazepoxide, diazepam, estazolam, flunitrazepam, flurazepam, lorazepam, midazolam, temazepam, triazolam, zaleplon, Zolpidem, and zopiclone.

[0068] Typically, where the drug is a skin and mucous membrane agent, it is selected from one of the following compounds: isotretinoin, bergapten and methoxsalen.

[0069] Typically, where the drug is a smoking cessation aid, it is selected from one of the following compounds: nicotine and varenicline.

[0070] Typically, where the drug is a Tourette's syndrome agent, it is pimozide.

[0071] Typically, where the drug is a urinary tract agent, it is selected from one of the following compounds: tolteridine, darifenicin, propantheline bromide, and oxybutynin.

[0072] Typically, where the drug is a vertigo agent, it is selected from one of the following compounds: betahistine and meclizine.

[0073] "Drug composition" refers to a composition that comprises only pure drug, two or more drugs in combination, or one or more drugs in combination with additional components. Additional components can include, for example, pharmaceutically acceptable excipients, carriers, and surfactants.

[0074] "Drug degradation product" or "thermal degradation product" are used interchangeably and means any byproduct, which results from heating the drug(s) and is not responsible for producing a therapeutic effect.

[0075] "Drug supply article" or "drug supply unit" are used interchangeably and refers to a substrate with at least a portion of its surface coated with one or more drug compositions. Drug supply articles of the invention may also include additional elements such as, for example, but not limitation, a heating element. [0076] "Fraction drug degradation product" refers to the quantity of drug degradation products present in the aerosol particles divided by the quantity of drug plus drug degradation product present in the aerosol, i.e. (sum of quantities of all drug degradation products present in the aerosol)/( (quantity of drug(s) present in the aerosol) + (sum of quantities of all drug degradation products present in the aerosol)). The term "percent drug degradation product" as used herein refers to the fraction drug degradation product multiplied by 100%, whereas "purity" of the aerosol refers to 100% minus the percent drug degradation products.

[0077] "Purity" as used herein, with respect to the aerosol purity, means the fraction of drug composition in the aerosol/ the fraction of drug composition in the aerosol plus drug degradation products. Thus purity is relative with regard to the purity of the starting material. For example, when the starting drug or drug composition used for substrate coating contained detectable impurities, the reported purity of the aerosol does not include those impurities present in the starting material that were also found in the aerosol, e.g., in certain cases if the starting material contained a 1 % impurity and the aerosol was found to contain the identical 1% impurity, the aerosol purity may nevertheless be reported as >99 % pure, reflecting the fact that the detectable 1% purity was not produced during the vaporization-condensation aerosol generation process.

[0078] "Substantially free of means that the material, compound, aerosol, etc., being described is at least 95% free of the other component from which it is substantially free.

[0079] "Therapeutically effective amount" means the amount required to achieve a therapeutic effect. The therapeutic effect could be any therapeutic effect ranging from prevention, symptom amelioration, symptom treatment, to disease termination or cure.

[0080] This disclosure teaches the application of population PK modeling and clinical trial simulation with the use of allometric scaling and realistic age-matched weight data specific to the targeted population. The pediatric population PK model includes an allometric component to take into account the effects of differences in body size on PK parameter estimates in the targeted pediatric patient population. The clinical trial simulations with the pediatric model are instrumental in the evaluation of to-be-expected distribution of drug exposures at different dose levels as part of the phase I study design. With regard to loxapine, different dose levels were considered (1.25, 2.5, 5, and 10 mg), and, depending on the targeted exposure (associated with 5 mg or 10 mg loxapine as observed in the adult studies), a loxapine dose of 2.5 mg or 5 mg in patients weighing 20-50 kg and a loxapine dose of 5 mg or 10 mg in patients weighing 50-215 kg would result in drug exposures comparable to those observed in the adult patient studies.

[0081] An optimal sampling strategy is developed to minimize the number of blood samples collected while maximizing the robustness of PK parameters in pediatric patients in clinical trials. A sampling strategy involving <7 blood samples over 48 hours in <20 pediatric patients was found to be required for precise estimation of loxapine clearance. The adequacy of this design was subsequently confirmed by the findings from the phase I PK study of children and adolescents aged 10-17 years, inclusive. The PK parameters in the modeling were precise and unbiased. The total drug exposure of inhaled loxapine in the phase I pediatric study was slightly lower but within a range similar to that observed in the adult studies. The estimates for loxapine clearance and volume of distribution in the pediatric study patients were higher than predicted in the simulations. This result is partially based on differences in the total amount of loxapine delivered to the lungs, in the younger patients. Drug delivery to the lungs can be reduced in younger patients as a result of physiological differences and less-well-developed coordination. Despite the differences in PK parameter estimates, loxapine peak concentrations (C _max ) and early and overall exposures (expressed as AUCo-2h and AUCo-24h) in this pediatric study group were all well within the ranges observed in the adult studies. This disclosure teaches the predictive value by the simulations to be used to further the design of future drug studies in children.

Pediatric Population PK Model Development

[0082] As the first step, a population PK model was constructed in healthy adults on the basis of loxapine concentration data obtained after administration of loxapine for inhalation as part of 2 phase I studies conducted by sponsor (ref). A total of 884 plasma concentration samples collected from 71 healthy adult subjects were available for population PK modeling. Plasma samples were collected at multiple time points over 24 hours and were assayed for loxapine and its metabolites using a validated liquid chromatography tandem mass spectrometry assay. Population PK analysis was conducted by nonlinear mixed effects modeling with NONMEM software, version 7.2.0 (ICON pic, Ellicott City, MD) with an Intel ⁴ Fortran Compiler version 12.0 (Intel Corporation, Santa Clara, CA). The first-order conditional estimation with interaction (FOCE-I) method in NONMEM was employed for all model development runs. The shrinkage for inter-individual variability (IIV) and residual errors was calculated for diagnostic assessment. Visualization of NONMEM output was implemented by Xpose4 package in R (v 3.0.3).

[0083] The IIV model was described as: θ _{ί =} θ _τν - εχρ(η _ί ) (2) where represents the value of the PK parameter Θ for the ι subject; θχγ is the population mean of parameter Θ in the structural model. The deviation of Θ from the mean Ojy was approximated with //,-, which was assumed to follow a normal distribution with a mean of 0 and a variance of ω ² (ie, ,

~N[0, ω ² ]).

[0084] The RV was described by a combined additive and proportional model, but other residual error models, such as exponential, additive, or proportional, were also examined. The combined additive and proportional residual model was described as:

where C, represents the f ^h observed concentration in the i' ^h individual, , is the f ^h model predicted concentration in the i' ^h individual, and e _pij and e _aij are the proportional and additive residual random errors, respectively. ¾ and ¾ are assumed to be independently normally distributed with a mean of 0 and a variance of σ ² (ie, ¾·~Ν[0, σ _ρ ² ] and ~N[0, o _a ² ]).

[0085] A variety of possibly compartmental PK models was explored to describe the

Staccato Loxapine concentration-time data. Model selection was based on various goodness- of-fit indicators, including visual inspection of diagnostic scatter plots, comparisons based on the minimum objective function value (OFV), and evaluation of the estimates of population fixed and random effect parameters. The population PK model was validated using bootstrapping and visual predictive check analyses.

[0086] Demographic data including age, body weight, height, sex, race, body mass index, body surface area, and smoking status were evaluated as part of the covariate analysis, which used the stepwise forward addition and backward elimination approach. The difference in the OFVs from nested models is assumed to be χ2 distributed. A drop in OFV of more than >3.84 (JkO.05) in the forward selection and >6.63 (P<0.0\) in the backward elimination were used as selection criteria.

[0087] To account for growth effects, body weight (WT) was included in the pediatric model, which used an allometric scaling component on clearance (CL) and volume of distribution (V), with respective power coefficients of 0.75 and l.O. ¹³ ' ¹⁴ This methodology has a strong theoretical and empirical basis and is increasingly being used in pediatric PK studies, as presented below.

[0088]

* (-

^^pediatric— ^^adult V ) ^v pediatric— ^v adult V ^{y i} )1.0

[0089] As this study was performed in children aged >10 years, maturation of metabolism was assumed to be complete. Model Validation

[0090] Non-parametric bootstrap analysis was performed with 1000 resampled datasets, and the estimated medians and 95% confidence intervals (CIs) of parameter estimates were compared with the final model estimates. Models with a >10% difference in the estimated medians or with a 95% CI containing zero were rejected. The final model was also evaluated by prediction-corrected visual predictive check (pcVPC), where the final model was used to simulate 1000 datasets and the real data observations were compared with the distribution of the simulated concentrations.

Clinical Trial Simulations

[0091] Loxapine pharmacokinetics were evaluated at different dose levels (1.25, 2.5, 5, and

10 mg) in a virtual pediatric population. Because sex, age, and weight are known to be highly correlated in pediatric patients, realistic demographic data were used as part of the simulations. A total of 8000 pediatric patients aged 10-17 years, inclusive, were randomly sampled from the US Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (CDC NHANES) database (ie, 2000 patients for 4 age groups). External data that were not part of the database (kindly provided by the Division of Child Psychiatry at Cincinnati Children' s Hospital Medical Center) were plotted alongside the model predictions to assess validity of the external data source. For the simulations in pediatric patients, an exposure-response relationship similar to that observed in adults was assumed. Loxapine exposure targets were defined based on the observed peak concentration (C _max ) and area under the concentration-time curve (AUC) data at 0-2 hours (AUCo-2h) and 0-24 hours (AUCo-24h) after a single dose as observed in the adult studies with the 5 mg and 10 mg loxapine doses. These exposure targets were chosen because of their association with good efficacy and minimal AEs at the 5 mg and 10 mg dose levels in the adult studies. Descriptive statistics of loxapine PK parameters (ie, C _max , AUCo-2h, and AUCo-24h) for relevant dose levels were derived for each predefined age and body weight cohort. Four- year age cohorts were used for summary purposes covering the age range of 10-17 years, inclusive. Twelve body weight cohorts (10-kg weight increase per group) were defined to cover the range of 20-130 kg, with the last group covering 130-215 kg.

[0092] AUCo-2h and AUCo-24h were calculated based on the trapezoidal rule for each- individual with the R package metrumrg. ¹⁷ The distributions of AUCo-2h, UCo-24h and C _max values were compared with the exposures associated with loxapine efficacy and safety in adult patients. The reference PK parameters observed in the adult studies are summarized in the supplemental materials. The percentage of predicted AUC levels above the maximum referenced AUCs (ie, AUCo-2h of 55 ng*h/mL for the 5 mg dose, AUCo-2h of 110 ng*h/mL for the 10 mg dose, AUCo-24h of 144 ng*h/mL for the 5 mg dose, and AUCo-24h of 288 ng*h/mL for the 10 mg dose) was minimized, and the percentage of exposures within the minimum- maximum AUC reference ranges (ie, AUCo-2h within 7.1-55 ng*h/mL for the 5 mg dose, AUCo-2h within 14.2-110 ng-h/mL for the 10 mg dose, AUC ₀ -24h within 33-144 ng-h/mL for the 5 mg dose, and AUCo-24h within 67-288 ng-h/mL for the 10 mg dose) was maximized. For each age and body weight cohort, a value of >2% of patients with exposures above the maximum AUC levels and peak concentration (Cma _X ) was considered not acceptable. In addition, >95% of patients in each cohort were targeted to have exposures falling within the minimum and maximum AUC ranges.

Optimal Study Design and Sample Size

[0093] To identify the optimal sampling times and number of samples required to robustly estimate individual PK parameters and total hydroxyurea exposure (AUC), a D-optimal design analysis was performed using WinPOPT. ¹⁸ Sampling windows between 0-24 and 0-48 hours were subsequently evaluated. Feasibility of the time points for sampling was evaluated with input from the clinical team

[0094] A power analysis was performed to determine the appropriate number of patients required for this pediatric PK study. ¹⁹ We used the recently proposed 80% power criterion of being able to estimate the 95% CI within 60% and 140% of the geometric mean estimates of the PK parameters of interest (clearance and volume of distribution) in pediatric patients. In addition, a model-based approach was used with scaling for size differences to allow continuous data analysis and evaluation across the entire age range, obviating the need for subgroup analysis. To satisfy the quality criterion, different candidate sample-size scenarios were tested using a simulation and fitting approach after the appropriate dose and optimal PK sampling schedule were identified. Five hundred replicate trials in pediatric subjects were simulated using the proposed design and candidate sample- size scenarios. Simulated plasma concentration profiles were fit using the FOCE-I method in NONMEM 7.2, and the 95% CIs for the oral clearance (CL/F) were obtained using the standard error estimates from iterations with successful covariance steps for each replicate. The power was calculated as the proportion of replicates with a 95% CI that did not fall outside the referenced 60% and 140% of the mean estimates.

Analysis of the Pediatric Phase I Clinical Trial Data

[0095] Pharmacokinetic data of the phase I study in pediatric patients

(ClinicalTrials.org registration number NCT02184767) were analyzed with NONMEM, as described below under Model Development. A total of 300 plasma concentrations from 30 pediatric patients were available for analysis. The pediatric PK parameter estimates (CL/F, V/F) were evaluated and compared with the PK parameters observed in the adult studies.

[0096] To evaluate the performance of the clinical trial simulations, the observed PK parameters, including AUC ₀ .2h> AUC ₀ . _t (where t=48h), and C _max estimates, were superimposed and compared with the projected PK parameter distributions predicted by the simulations.

Model Development

[0097] A 3-compartment model with first-order absorption best described the adult data.

Adding a lag time to the absorption phase did not significantly improve the model fit. Since no intravenous data were available, the absolute oral bioavailability (F) of loxapine was not defined and the model was parameterized as apparent oral clearance (CL/F), apparent oral intercompartment clearance (Q2/F, Q3/F), and apparent oral volume of distribution (V2/F, V3/F, V4/F) with a first- order absorption rate-constant Ka. Of the covariate factors tested (age, body weight, height, sex, race, body mass index, body surface area, and smoking status), none significantly decreased variability in CL/F and V2/F. To address differences in body size, loxapine clearance and volume of distribution were allometrically scaled to body weight with fixed exponents of 0.75 and 1.0, respectively.

Goodness-of-fit criteria revealed that the final model provided a good description of the loxapine PK data. Model validation results further demonstrated that the final model adequately described the observed data without any bias. The performance results of the population PK model are presented. Observed concentrations versus population predicted concentrations (DV vs. PRED) and individual predicted concentrations (DV vs. IPRED) were tightly grouped along the identity line. Conditional weighted residuals (CWRES) were homogeneously distributed around the zero line with only one concentration that had a ICWRESI > 4. The final population PK parameters of loxapine in adult patients are presented in Table 1.

Table 1. Loxapine population pharmacokinetic parameter estimates in adult patients

Bootstrap analysis

Parameter Estimate RSE (%) Mean Bias 95% CI

CL/F (L/h/70 kg) 54.1 4.1 % 54.0 0.1 % 50.3-58.0

V ₂ /F (L/70 kg) 83.1 1 1 .6% 81 .2 2.3% 63.8-102.4

Q ₃ /F (L/h/70 kg) 703 8% 716.2 1.9% 571 .3 834.5

V ₃ /F (L/kg) 149 5% 150.5 1.0% 132.5-165.5

Q ₄ /F (L/h/70 kg) 27.6 4.9% 27.8 0.8% 24.8-30.4

V ₄ /F (L/70 kg) 335 10.1 % 341 .2 1.8% 264.4-405.6

Ka (hr-1 ) 58.2 12.7% 57.5 1.2% 43.5-72.9 Between-subject variability

0.026 - u cL 0.053 1 1 .8% 0.053 0.4%

0.080

2

ω V ₂ 0.992 8.8% 0.994 0.3% 0.662 - 1 .32

2 0.287 - ω Ka 0.631 12.6% 0.626 0.8%

0.975

Residual error

2

σ _o Prop 0.105 6.4% 0.105 0.1 % 0.09 - 0.12

CI, confidence interval; CL/F, apparent oral clearance of loxapine; Ka, rate constant of absorption of loxapine; Q ₃ . ₄ /F, apparent oral intercompartmental clearance; prop, proportion; RSE, residual error; V ₂ - ₄ /F, apparent volume of distribution.

Clinical Trial Simulations

[0098] The NHANES pediatric age -body weight distribution used for the clinical trial simulations in the virtual pediatric population are shown. To verify the age-matched body weight distribution for this group of patients aged 10-17 years, inclusive, we compared the NHANES data with age-weight pairs obtained from 159 psychiatric inpatients at our institution.

[0099] Predicted loxapine exposures were evaluated across the 10-17 year, inclusive, age groups, with respective body weight ranges of 20-215 kg. The predictions of Cma _X ,

AUCo-2h, and AUCo-24h and their association with age and weight were evaluated. C _max was not well predicted by age or weight (R ² < 0.10), whereas AUCo-2h and AUCo-24h were best predicted by body weig ht (R ² of 0.19 and 0.21 vs. R ² of 0.46 and 0.51, respectively). Body weight, therefore, was chosen as the primary metric in the simulations to define loxapine dose requirements. In patients weighing <50 kg, the predicted drug exposure after a 2.5-mg dose was comparable with that observed in adults after a 5-mg loxapine dose. The predicted drug exposure after a 5-mg dose was comparable with that observed in adults after a 10-mg loxapine dose. In both scenarios, >95% of patients had predicted drug exposures within the defined target AUC range, with <0.1% of the children having predicted exposures above the maximum AUC values. In patients weighing >50 kg, the 5-mg and 10-mg doses provided loxapine exposures comparable with those observed in the adult studies after 5-mg and 10- mg doses (>95% of the patients had predicted AUC levels within the AUC reference ranges). The distribution of predicted AUCo-24h values at the 4 selected dose levels compared with the adult reference values. The reference AUCo-24h levels overlap with the AUCo-24h in the 2.5-mg and 5-mg dose groups. The predicted AUCo-24h with the 1.25-mg dose was mostly below the reference ranges, whereas the 10-mg loxapine dose led to higher-than-desired predicted AUCo-24h levels in patients weighing <50 kg. The results for the prediction of the AUCo-2h estimates are summarized.

[00100] Based on predicted safe and effective loxapine exposures, a loxapine dose of 2.5 mg or 5 mg is suggested for patients with a body weight in the range of 20-50 kg, depending on the targeted exposure. A dose of 5 mg or 10 mg is suggested for patients weighing >50 kg, depending on the targeted exposure. Based on these results, patients were enrolled into 2 subgroups on the basis of total body weight:

[00101] Subgroup 1 : patients weighing <50 kg

a. Loxapine for inhalation 2.5 mg (Cohort 1; n=6) followed by loxapine for inhalation 5 mg (Cohort 2)

[00102] Subgroup 2: patients weighing >50 kg

a. Loxapine for inhalation 5 mg (Cohort 1; n=6) followed by loxapine for inhalation 10 mg (Cohort 2)

[00103] The results of the clinical trial simulations of loxapine exposure (expressed as AUCo-24h and Cma _X ) using the proposed doses in pediatric patients compared with the observations in adult subjects are summarized.

Optimal Study Design and Sample Size

[00104] Different time periods for PK sampling were evaluated: all samplings to be collected within 12 hours after drug administration, and samplings on day 1 collected 8-10 hours after drug administration with additional samples drawn 24 and/or 48 hours postdose. Taking feasibility into consideration, the proposed sampling schedule was 1-3, 10, and 40 minutes and 4, 8, 24, and 48 hours postdose. Power analysis suggested that enrollment of at least 20 pediatric patients would result in CL/F estimation with >80% power. A larger number of patients (>100) would be required to achieve these precision criteria for estimation of volume of distribution (Vc/F) unless additional early samples were to be obtained. Given that total drug exposure (AUC) is determined in large part by clearance, sample size justification in the proposed design was based primarily on estimation of clearance. [00105] A sampling strategy with at least 7 samples at time points 1-3, 10, and 40 minutes and 4, 8, 24, and 48 hours postdose in 20 pediatric patients would result in a robust estimation of loxapine clearance.

[00106] Based on these results, the clinical protocol was projected to enroll up to 30 patients with the intent that at least 20 patients would complete the study. Blood samples for pharmacokinetic analysis were obtained approximately 30 minutes before administration of inhaled loxapine, and 2 minutes, 5 minutes (+1 minute), 15 minutes (+1 minute), 45 minutes (+1 minute), 2 hours (+2 minutes), 4 hours (+5 minutes), 8 hours (+5 minutes), 24 hours (+30 minutes), and 48 hours (+60 minutes) after administration of loxapine for inhalation. Because robust estimation of early drug exposure, as characterized by C _max and AUCo-2h, was considered an important metric, additional samples were included at time points 5 minutes, 15 minutes, 45 minutes, and 2 hours.

[00107] A total of 30 pediatric patients were enrolled in the multicenter, phase 1 study to assess the safety and pharmacokinetics of loxapine for inhalation. The median age was 13 years (range, 10-17 years), and mean body weight was 50.2 kg (Table 2). The distribution of the age-weight data of the pediatric patients enrolled in the study is presented in Figure 2 along with the data used in the clinical trial simulations in support of the study design. Study patients comprised 17 females (43.3%) and 13 males (56.7%), and the majority were black (63.3%) and white (33.3%). Each cohort consisted of 15 patients who received a loxapine for inhalation dose of 2.5 mg, 5 mg, or 10 mg, depending on body weight. Prior medications most frequently used included risperidone (12 [40%] patients), aripiprazole (6 [20.0%] patients), and clonidine (4 [13.3%] patients).

Loxapine Pharmacokinetics in Pediatric Patients

[00108] Table 2. Demographics of pediatric patients participating in the loxapine phase I pharmacokinetic study

N = 30

Age, median, yr (range) 13 (10-17)

Weight, median, kg (range) 50.2 (33.3-86.9)

Height, median, m (range) 1 .60 (1 .44-1 .79)

BMI, median, kg/m ² (range) 19.6 (14.8-30.4)

Sex, n (%)

Male 13 (43.3)

Female 17 (56.7)

Race, n (%)

White 10 (33.3) Black 19 (63.3)

Native American 1 (3.3)

Ethnicity, n (%)

Non-Hispanic 25 (83.3)

Hispanic 5 (16.7)

BMI, body mass index.

[00109] The data were well described by a three-compartment model with first-order absorption. Of the covariate factors tested, none significantly decreased variability in clearance (CL/F) and/or volume of distribution (V2/F). Goodness-of-fit criteria revealed that the final model provided a good description of the loxapine PK data (Table 3). The performance of the population PK model is presented. Observed concentrations versus population predicted concentrations (DV vs. PRED) and individual predicted concentrations (DV vs. IPRED) were tightly grouped along the line of identity. Conditional weighted residuals were homogeneously distributed around the zero line with only one concentration that had a ICWRESI >4. The final population PK parameter estimates of loxapine in pediatric patients are presented in Table 3.

[00110] Table 3. Final population pharmacokinetic parameter estimates in pediatric patients (aged 10-17 years)

Bootstrap

Parameters Estimates RSE (%) Mean Bias 95% CI

CL/F (L/h/70 kg) 78.0 4.6% 78.0 0.0%

V ₂ /F (1/70 kg) 195.0 19.1 % 203.0 4.1 % A

Q ₃ /F (L/h/70 kg) 878.0 8.1 % 795.0 9.5% 91

V ₃ /F (1/70 kg) 214.0 1 1 .3% 220.0 2.8% 9

Q ₄ /F (L/h/70 kg) 39.1 16.5% 39.2 0.3% 5.7

V ₄ /F (1/70 kg) 866.0 10.2% 894.0 3.2% 64

Ka (hf ¹ ) 58.0 - - - -

Fixed

Between-patient variability

ω CL/F 0.032 14.7% 0.031 3.1 % 0.013- ^■ 0.051 ω V2/F 0.981 9.6% 0.893 9.0% 0.593- ^■ 1 .368

Residual error

2

σ Prop 0.083 14.7% 0.080 3.6% 0.065- ^■ 0.102 CI, confidence interval; CL/F, apparent oral clearance of loxapine; Ka, rate constant of absorption of loxapine; Q3-4/F, apparent oral intercompartmental clearance; prop, proportion; RSE, residual error; V2-4/F, apparent volume of distribution.

[00111] Median values and 95% CIs from the bootstrap analysis are listed in Table 3. All model parameter estimates are within the 95% CIs and deviate <10% from the median value obtained by the bootstrap analysis, indicating the stability of the model. Model validation results, including the visual predictive check, showed good agreement between the 95% prediction intervals and the observed data. This indicated that the final model appropriately described the observed data and that no bias remained.

[00112] In both lower-dose groups (Cohort 1), several patients had AUCo-2h, AUCo-t, and C _max values slightly lower than the target ranges as observed in the adult studies.

However, most of the values were in good agreement with model predictions. In both higher- dose groups (Cohort 2), nearly all patients had AUCo-2h, AUCo-t, and C _max values within the adult target range and coincided with the model predictions. Overall, both cohorts had loxapine exposures around the lower range of the observed values in the adult studies. The population estimate of loxapine clearance (CL/F) in the pediatric study was 78.0 L/h 70 kg and was significantly higher than that observed in the adult studies and in the pediatric simulations (54.1 L/h/70 kg; <0.01 ;). The population estimate of volume of distribution (V2/F) in pediatric patients was also significantly higher compared with results in the adult studies and pediatric simulations (195.0 L/70 kg vs. 83.1 L/70 kg; <0.01).

[00113] Retrospective power analysis showed that the data collected in 30 pediatric patients participating in this phase I trial resulted in precise estimation of CL/F and V2/F, as indicated by respective power estimates of 100% and 78%. These parameter estimates, which largely determine total systemic exposure (AUC), exceeded or were in line with the precision criterion of 80% suggested by the regulatory agency.

Example

[00114] Objective: This open-label, phase 1 study was designed to characterize the pharmacokinetics and safety of single doses of inhaled loxapine in children and adolescents with any condition warranting chronic use of antipsychotics.

[00115] Method: Subjects aged 10 to 17 years were enrolled into 2 subgroups by weight, <50 kg and >50 kg, and received 2.5 mg or 5 mg, respectively, of inhaled loxapine via the single-use, handheld drug-device combination Adasuve ^® . Dose escalation in each subgroup to 5 mg and 10 mg, respectively, was dependent on review of safety and pharmacokinetic data from 6 subjects in the first dose group. Blood samples were collected for pharmacokinetic analysis of loxapine and its metabolites for 48 hours after drug administration. Safety was monitored continuously.

[00116] Results: Loxapine plasma concentrations peaked by 2 to 5 minutes in most subjects, and systemic exposure increased with dose in both weight subgroups. The terminal half-life of loxapine was approximately 13 to 17 hours. Inhaled loxapine was well tolerated in nonagitated pediatric subjects, and the most common adverse events were sedation and dysgeusia. No serious adverse events or withdrawals due to adverse events were reported, and there were no reports of bronchospasm.

[00117] Conclusions: Inhaled loxapine provides very rapid and safe administration of loxapine in pediatric subjects. Results of this single-dose study are consistent with prior experience with inhaled loxapine in adults, and no new safety signals were observed

[00118] This was an open-label, phase I pharmacokinetic and safety study of a single dose (2.5, 5, or 10 mg) of inhaled loxapine in children and adolescents. Enrollment began on August 11, 2014, and the last subject completed the study on March 11, 2015. Subjects were enrolled into 2 subgroups based on total body weight. Those weighing <50 kg (subgroup 1) received inhaled loxapine 2.5 mg (cohort 1) followed by 5 mg (cohort 2). Subjects weighing >50 kg (subgroup 2) received inhaled loxapine 5 mg (cohort 1) followed by 10 mg (cohort 2). Dose escalation in each subgroup from cohort 1 to cohort 2 was dependent on review of safety and pharmacokinetic data from cohort 1 and occurred only after 6 subjects had been dosed in the first cohort.

[00119] Doses were selected on the basis of pharmacokinetic modeling and simulations that suggested that the corresponding loxapine exposure in children and adolescents would be within a range previously demonstrated as safe and effective in adults. This study was conducted in full accordance with the International Conference on

Harmonisation Good Clinical Practice guidelines, and all subjects and their parents/guardians provided written informed consent.

Subjects

[00120] The study population included up to 30 boys and girls aged 10 to 17 years with any condition warranting chronic use of an antipsychotic medication. Subjects were required to be within the 2.5 and 97.5 percentile for body mass index on the basis of age and sex, and within the weight range of >27 kg to 127 kg for boys and >27 kg to 111 kg for girls. Subjects receiving treatment for any condition had to be on a stable regimen for at least 28 days before study administration of inhaled loxapine; however, long-acting intramuscular antipsychotics were not permitted within 7 days of inhaled loxapine administration. Study enrollment criteria also included having negative alcohol and urine drug tests, with exceptions allowed for an appropriate medical explanation (eg, prescribed amphetamines) or low and consistent presence of tetrahydrocannabinol after discussion with the sponsor.

[00121] Subjects were excluded for any clinically significant uncontrolled medical condition or signs/symptoms of ill health; current diagnosis or history of asthma, chronic obstructive pulmonary disease, bronchiolitis, chronic bronchitis, emphysema, or other lung disease with bronchospasm; acute respiratory signs or symptoms (including forced expiratory volume in 1 second [FEVi] <80% of predicted value on spirometry); pregnancy or lactation; or fever. Subjects who received any investigational drug within 30 days, medications for airway disease, loxapine or amoxapine within 30 days, or had excessive caffeine

consumption (>600 mg per day) were also excluded.

Study drug

[00122] All subjects received a single 2.5-, 5-, or 10-mg dose of inhaled loxapine via the single-use, handheld, drug-device combination product Adasuve. This product provides rapid, systemic delivery of a thermally generated aerosol of loxapine for inhalation. Study drug was administered to subjects approximately 2 hours after a standard light breakfast, and subjects were required to fast for at least 2 hours after dose administration.

Assessments

Pharmacokinetic analysis

[00123] Blood samples were obtained predose and 2, 5, 15, and 45 minutes and 2, 4, 8, 24, and 48 hours after administration of inhaled loxapine. Plasma concentrations of loxapine and its metabolites (8-OH-loxapine, 7-OH-loxapine, loxapine N-oxide, and amoxapine) were determined using a validated high-performance liquid chromatography with tandem mass spectrometric detection method. The lower limit of quantitation was 0.050 ng/mL for loxapine and all analytes.

[00124] Pharmacokinetic analyses were performed using noncompartmental methods with extravascular input via Phoenix WinNonlin ^® Professional Version 6.3 or higher (Pharsight Corp., Mountain View, CA). Data from subjects with missing concentration values (missed blood draws, lost samples, samples unable to be quantitated) could be used if the pharmacokinetic parameters could be estimated using the remaining data points.

Pharmacokinetic parameters

[00125] The following pharmacokinetic parameters were calculated for loxapine and, if possible, the metabolites: area under the plasma concentration-time curve from 0 to 2 hours postdose (AUC ₀ -2) calculated by the linear trapezoidal linear interpolation method; AUCo- _t (where t is the last measurable concentration); AUC from time 0 to infinity (AUCo- _∞ ) calculated as the sum of the AUCo- _t plus Ci _ast divided by the terminal elimination rate constant (λ _ζ ); percentage of the area that is extrapolated in the estimation of AUCo- _∞ , calculated as 100 - [(AUCo- _∞ - AUCo- _t )/ AUCo- _∞ ] ; maximum observed plasma drug concentration (C _max ); time to maximum plasma concentration (t _max ); λ _ζ estimated by linear regression on the terminal phase of the semilogarithmic plasma concentration versus time curve; elimination half-life calculated as 0.693/λ _ζ ; apparent clearance calculated as dose/AUCo- _∞ ; and apparent volume of distribution calculated as dose/(AUCo- _∞ x λ _Ζ ).

Safety assessments

[00126] Following administration of inhaled loxapine, subjects were monitored for signs and symptoms of bronchospasm. Safety was monitored throughout the study by evaluating adverse events, serious adverse events, clinical laboratory test results, vital sign measurements, pulse oximetry, chest auscultation findings, physical examination, neurological examination, 12-lead electrocardiogram (ECG), and concomitant medications. Suicidality assessments were performed at screening, before administration and discharge, and at the final assessment using the Columbia-Suicide Severity Rating Scale

[Baseline/Screening for Phase I Study version and Since Last Visit version]). The Barnes Akathisia Rating Scale (BARS) and Simpson- Angus Scale (SAS) were used to evaluate extrapyramidal symptoms before and 1 hour after administration of inhaled loxapine. A sedation visual analog scale (VAS) assessment (0 = extremely sleepy, 100 = wide awake) was performed before and 15 minutes, 1, 2, 4, and 24 hours after inhalation of loxapine. Spirometry and serology were evaluated at screening only.

Other [00127] Palatability of inhaled loxapine was assessed using a 100-mm VAS. At least 30 minutes before administration of inhaled loxapine, subjects received placebo and, within 5 minutes, they placed a perpendicular line on the VAS corresponding to the taste in their mouth. Following administration of inhaled loxapine, the VAS assessment was completed in a similar manner within 5 and 30 minutes.

Statistical analysis

[00128] A sample size of 20 evaluable subjects would provide 80% power to ensure that the 95% confidence intervals (CI) of the geometric mean of clearance would fall between 60% and 140% based on population pharmacokinetic modeling and simulation of adult pharmacokinetic data. All data were processed and summarized using S AS ^® Version 9.1.2 (SAS Institute Inc., Cary, NC).

[00129] Before dosing in cohort 2 could be initiated, an interim analysis of the 6 dosed subjects in cohort 1 from each subgroup was completed. A safety review committee evaluated safety data, including adverse events (especially bronchospasm and sedation level) and pharmacokinetic data focused on C _max and AUCo-2- Escalation to the cohort 2 dose in each subgroup could occur only after the safety review committee determined that the previously administered dose was well tolerated with no safety concerns and systemic exposure was consistent with or less than what would be expected.

[00130] For the final analyses, the pharmacokinetic analysis set consisted of all subjects who received inhaled loxapine and for whom at least one pharmacokinetic parameter could be measured. The safety analysis set included all subjects who received the dose of inhaled loxapine. Subject demographics were summarized by weight group and dose.

Summary statistics included number of subjects (n), mean, standard deviation (SD), standard error (SE), median, minimum, and maximum. Plasma concentrations of loxapine and its metabolites were summarized using arithmetic mean, SD, coefficient of variation (CV), median, minimum, and maximum; values below the lower limit of quantification (BLQ) were set to zero. Pharmacokinetic parameters were calculated using arithmetic and geometric means, SD, 90% CI, minimum, maximum, median, and CV by analyte, subgroup, and dose. Descriptive statistics were used to summarize the incidence of adverse events and changes in other safety assessments from baseline to endpoint.

Results Subject disposition

[00131] A total of 38 subjects were screened; 30 subjects met entry criteria and were enrolled into the study. All 30 subjects received study drug and completed the study. In those weighing <50 kg, 6 received 2.5 mg and 9 received 5 mg of inhaled loxapine. In those weighing >50 kg, 6 received 5 mg and 9 received 10 mg of inhaled loxapine.

Subject demographics

[00132] Overall, the mean subject age was 13.6 years, and girls comprised 57% of the study population The majority of subjects were black (63%), with similar proportions of subjects by race in each dose group. Overall, 20 subjects received concomitant medications during the study, including 12 receiving risperidone, 6 receiving aripiprazole, and 1 each receiving asenapine, lorazepam, olanzapine, or temazepam.

Table 4. Subject Demographics

Subjects weighing <50 kg Subjects weighing >50 kg Overall

Inhaled Inhaled Inhaled Inhaled Inhaled

loxapine loxapine loxapine loxapine loxapine

2.5 mg 5 mg 5 mg 10 mg 5 mg Total

Characteristic (n=6) (n=9) (n=6) (n=9) (n=15) (N=30)

Age, y, mean 12.8 (2.6) 12.9 (1.5) 14.8 (1.9) 13.9 (2.2) 13.7 (1.9) 13.6 (2.1) (SD)

Female, n (%) 4 (67%) 5 (56%) 4 (67%) 4 (44%) 9 (60%) 17 (57%)

Race, n (%)

Black 4 (67%) 5 (56%) 3 (50%) 7 (78%) 8 (53%) 19 (63%)

White 2 (33%) 4 (44%) 2 (33%) 2 (22%) 6 (40%) 10 (33%)

American 0 0 1 (17%) 0 1 (7%) 1 (3%) Indian or

Alaskan

Native

Weight, kg, 41.9 (5.7) 43.5 (4.1) 67.7 (10.1) 59.2 (4.7) 53.2 (14.1) 52.7 (12.0) mean (SD)

BMI, kg/m ² , 17.4 (1.8) 17.7 (1.1) 25.3 (4.2) 22.0 (2.3) 20.8 (4.7) 20.5 (3.9) mean (SD)

[00133] BMI = body mass index; SD = standard deviation.

Pharmacokinetics Loxapine

[00134] Loxapine concentrations were quantifiable in all subjects in all groups by the first measured time point, 2 minutes after inhalation. Peak plasma concentrations of loxapine were achieved in 2 to 5 minutes in 26 (87%) subjects; in the remaining 4 subjects, loxapine concentrations peaked by 0.25 to 2 hours. Loxapine concentrations decreased in a multiphasic manner until the last measurement at 48 hours in all subjects. Plasma concentrations of loxapine were lowest in subjects receiving 2.5 mg and increased in each group as dose increased up to 10 mg.

[00135] Pharmacokinetic parameters for loxapine and its metabolites are shown in Table 5. Systemic exposure to loxapine increased as dose increased. In subjects weighing <50 kg, the geometric means of C _max , AUC0-2, AUCo-t, and AUCo-∞ increased by

approximately 10%, 35%, 54%, and 47%, respectively, as the dose doubled from 2.5 mg to 5 mg. In subjects weighing >50 kg, C _max decreased by 13%, while AUC0-2, AUCo-t, and AUCo- _∞ increased by 73%, 101%, and 93%, respectively, as dose increased from 5 mg to 10 mg. Comparing all subjects who received 5 mg of inhaled loxapine, C _max increased approximately 3-fold for those weighing >50 kg compared with those weighing <50 kg, while AUC values between the subgroups were comparable. The elimination half-life of loxapine ranged from 12.9 to 16.9 hours across subgroups and doses and did not appear to be related to weight or dose. Apparent clearance and apparent volume of distribution appeared dose related in the <50 kg subjects, while values were more similar in those weighing >50 kg receiving 5 mg or 10 mg.

Table 5. Plasma Pharmacokinetic Parameters for Loxapine and Its Metabolites by Subgroup and Dose of Inhaled Loxapine

Subjects weighing <50 kg Subjects weighing >50 kg

Pharmacokinetic

Inhaled loxapine Inhaled loxapine Inhaled loxapine Inhaled loxapine Parameter"

2.5 mg (n=6) 5 mg (n=9) 5 mg (11=6 ) 10 mg (n=9)

C _ma x, ng mL

Loxapine 167 (5.2, 49.4) 18.4 (8.4, 58.9) 59.9 (17.5, 94.2) 51.9 (21.9, 156.0)

8-OH-loxapine 1.2 (0.5, 1.9) 2.3 (1.0, 3.9) 1.7 (0.7, 2.9) 4.1 (2.3, 7.2)

7-OH-loxapine 0.3 (0.1, 0.7) 0.8 (0.6, 1.7) 0.5 (0.2, 1.0) 1.0 (0.5, 1.8) Loxapine N-oxide 1.2 (0.8, 2.1) 2.2 (1.3, 3.8) 1.4 (0.9, 2.3) 3.2 (2.1, 4.6)

Amoxapine 0.1 (0.1, 0.4) 0.2 (0.1, 0.6) 0.2 (0.0, 0.5) 0.3 (0.1, 0.5)

AUCo hr-ng mL

Loxapine 15.5 (8.6, 32.0) 20.8 (14.0, 36.0) 23.6 (11.9, 37.1) 41.0 (31.6, 53.4)

8-OH-loxapine 1.2 (0.4, 2.8) 2.2 (0.5, 5.1) 2.2 (0.8, 4.2) 3.2 (1.9, 6.5)

7-OH-loxapine 0.4 (0.1, 1.0) 0.9 (0.5, 2.2) 0.6 (0.3, 1.3) 1.0 (0.6, 2.4)

Loxapine N-oxide 1.6 (0.8, 3.1) 2.9 (1.3, 5.2) 2.2 (1.2, 3.7) 4.2 (2.6, 5.8)

Amoxapine 0.2 (0.0, 0.4) 0.2 (0.0, 0.6) 0.2 (0.0, 0.8) 0.2 (0.0, 0.5)

AUC hi-ng mL

Loxapine 52.6 (38.2, 81.9) 80.9 (53.0, 115.2) 70.2 (36.8, 90.4) 141.3 (119.2,

184.7)

8-OH-loxapine 22.1 (7.4, 40.0) 43.3 (22.8, 68.5) 33.9 (15.0, 49.6) 90.0 (55.1, 179.5)

7-OH-loxapine 2.6 (0.2, 5.7) 12.6 (5.8, 28.1) 6.0 (3.5, 11.8) 15.9 (10.0, 31.8)

Loxapine N-oxide 6.8 (4.0, 16.4) 18.5 (9.1, 30.0) 10.4 (4.8, 17.3) 29.5 (20.2, 44.5)

Amoxapine 1.9 (0.3, 5.4) 4.1 (0.8, 10.7) 1.5 (0.0, 8.6) 5.2 (0.7, 15.3)

AUCo hr-ng mL

Loxapine 58.5 (39.2, 85.4) 86.0 (56.9, 119.4) 78.0 (41.9, 107.1) 150.9 (125.6,

190.5)

8-OH-loxapine 37.8 (31.3, 48.5) 55.3 (29.6, 80.3) 42.6 (18.0, 61.8) 108.7 (84.0, 148.9)

7-OH-loxapine 5.8 (5.3, 6.4) 12.9 (6.5, 29.7) 7.2 (5.6, 12.7) 16.0 (11.1, 23.3)

Loxapine N-oxide 12.1 (8.5, 17.1) 19.6 (10.3, 31.3) 15.7 (12.8, 18.5) 31.1 (21.0, 48.2)

Amoxapine 4.9 (4.0, 5.9) 8.3 (4.3, 12.8) 10.0 (10.0, 10.0) 10.5 (5.6, 16.1) hr, median

Loxapine 0.06 (0.03, 2.0) 0.08 (0.03, 0.3) 0.03 (0.03, 0.03) 0.03 (0.03, 0.8)

8-OH-loxapine 3 (0.8, 4.0) 2.0 (0.8, 8.0) 1.4 (0.8, 4.0) 4 (2.0, 8.0)

7-OH-loxapine 3 (0.8, 4.0) 2 (0.8, 8.0) 0.8 (0.8, 4.0) 4 (0.8, 8.0)

Loxapine N-oxide 2 (0.8, 2.0) 2 (2.0, 4.0) 2 (0.8, 3.9) 2 (0.8, 2.0)

Amoxapine 6 (2.0, 24.3) 4 (2.0, 8.0) 2 (0.8, 8.0) 4 (2.0, 8.0) hr Loxapine 12.9 (10.0, 17.9) 13.7 (10.5, 16.6) 16.9 (10.8, 27.5) 13.9 (10.2, 19.8)

8-OH-loxapine 15.4 (13.4, 18.7) 17.2 (13.8, 22.7) 20.2 (16.9, 31.1) 19.3 (16.1, 22.0)

7-OH-loxapine 7.6 (7.5, 7.7) 10.2 (7.0, 15.6) 10.1 (7.5, 12.2) 11.3 (6.5, 15.7)

Loxapine N-oxide 4.4 (3.2, 5.2) 8.1 (5.3, 13.6) 8.9 (5.0, 13.6) 10.0 (5.0, 15.3)

Amoxapine 18.3 (15.4, 21.7) 15.3 (12.7, 18.5) 17.3 (17.3, 17.3) 19.4 (16.9, 20.7)

CL/F, L/hr ^b

Loxapine 42.7 (29.3, 63.8) 58.1 (41.9, 87.9) 64.1 (46.7, 119.2) 66.3 (52.5, 79.6) jF, L ^b

Loxapine 797.4 (538.3, 1148.0 (644.9, 1567.5 (1050.1, 1329.5 (772.3,

977.0) 1947.5) 3227.2) 1521.0)Values presented as geometric mean or, for t _max , median (minimum, maximum).

bCalculated for parent loxapine only.

Cmax - maximum plasma concentration; AUC ₀ -2 = area under the plasma concentration-time curve from time 0 to 2 hours; AUC ₀ - _t = area under the plasma drug concentration-time curve from time 0 to the time of the last measurable drug concentration; AUC ₀ - _∞ = area under the plasma concentration-time curve from time 0 to infinity; CL/F = apparent clearance calculated as dose/AUC ₀ - _∞ ; CV = coefficient of variability; hr = hour; t _max = time to C _max ; t _½ = elimination half-life; V _z /F = apparent volume of distribution calculated by dose/AUC ₀ - _∞ x λ _ζ (terminal elimination rate constant).

8-OH-loxapine

[00136] Plasma concentrations of 8-OH-loxapine became quantifiable in most subjects in all groups by 15 minutes and peaked by 2 to 4 hours in all but 8 subjects. In those 8 subjects, peak levels were observed by 0.75 or 8 hours. After reaching maximum levels, 8- OH-loxapine concentrations decreased in a biphasic manner through 48 hours. All subjects had quantifiable levels of 8-OH-loxapine through 48 hours.

[00137] Formation of 8-OH-loxapine began immediately upon absorption with a median time to peak formation of approximately 2 to 4 hours and did not appear to be dose or weight related (Table 5). 8-OH-loxapine was a major metabolite of inhaled loxapine, with an AUC of approximately 8% to 10% that of the parent compound at 2 hours and 40% to 70% that of the parent compound by 48 hours. Systemic exposure to 8-OH-loxapine increased as the dose increased. The elimination half-life of 8-OH-loxapine was greater than that of the parent compound for each weight and dose group.

7-OH-loxapine [00138] The mean plasma concentration-time profile of 7-OH-loxapine was similar to that of 8-OH-loxapine. Concentrations of 7-OH-loxapine were quantifiable in most subjects in most groups by 15 minutes after inhalation of loxapine, and peak concentrations occurred by 2 to 4 hours in most subjects. In the remaining subjects, plasma concentrations peaked by 0.75 or 8 hours. Following peak concentrations, 7-OH-loxapine concentrations decreased in a generally biphasic manner until 4 to 24 hours in the 2.5 mg group and 24 to 48 hours in the other dose groups.

[00139] Similar to 8-OH-loxapine, 7-OH-loxapine formation began immediately upon absorption and did not appear to be related to weight or dose. In contrast, the 7-OH metabolite was a minor metabolite with systemic exposure of approximately 5% to 15% that of the parent compound through 48 hours. The elimination half-life of 7-OH-loxapine ranged from 7.6 to 11.3 hours and was shorter than that of the parent compound.

Loxapine N-oxide

[00140] Plasma concentrations of loxapine N-oxide became quantifiable from 2 to 15 minutes in subjects receiving 2.5 mg of inhaled loxapine and from 2 to 5 minutes in subjects receiving 5 to 10 mg. Overall concentrations responded in a dose-dependent manner with 4 subjects achieving peak loxapine N-oxide concentrations at 0.75 hours and the remaining subjects achieving peak at 2 hours. Loxapine N-oxide concentrations decreased in a multiphasic manner through 48 hours, with plasma concentrations quantifiable through 24 hours in 10 subjects and 48 hours in the remaining subjects.

[00141] Loxapine N-oxide was formed immediately upon absorption with a median time to peak of 2 hours and was not related to weight or dose. At 2 hours postdose, systemic exposure of loxapine N-oxide was 9% to 14% that of the parent compound, and by 48 hours, it was 13% to 23% that of the parent compound, making loxapine N-oxide a significant metabolite. The elimination half-life of loxapine N-oxide ranged from 4.4 to 10 hours and was shorter than that of the parent compound.

Amoxapine

[00142] Amoxapine concentrations became quantifiable in most subjects in all groups by 0.75 hours after inhalation of loxapine. Peak concentrations of amoxapine were observed from 2 to 8 hours in all but 2 subjects; in the remaining subjects, peak levels occurred at 0.75 and 24 hours. After reaching maximum levels, amoxapine concentrations decreased in a mono- or biphasic manner until the time of the last quantifiable sample, which was at 8 hours for 6 subjects, 24 hours for 13 subjects, and 48 hours for 9 subjects, with no relationship to dose.

[00143] Similar to the other metabolites, formation of amoxapine began immediately upon absorption with a median peak time of 2 to 6 hours and was not related to weight or dose. Amoxapine was a minor metabolite with systemic exposure of approximately 2% to 5% that of the parent compound by 48 hours. The elimination half-life of amoxapine ranged from 15.3 to 19.4 hours but was calculable from only 11 subjects.

Safety

[00144] Overall, 29 (97%) subjects had at least 1 adverse event: 5 (83%) subjects receiving 2.5 mg, 9 (100%) subjects weighing <50 kg receiving 5 mg, 6 (100%) subjects weighing >50 kg receiving 5 mg, and 9 (100%) subjects receiving 10 mg. All adverse events were considered to be related to treatment with inhaled loxapine. Most adverse events were mild or moderate in intensity in both subgroups; 2 (7%) subjects reported severe sedation. None of the subjects withdrew from the study because of adverse events. The most frequently occurring adverse events were sedation (n=27, 90%) and dysgeusia (n=21, 70%); the only other adverse events experienced during the study were anxiety, logorrhea, and hiccups, occurring in 1 subject each (3%). No respiratory adverse events were reported. No serious adverse events occurred during the study.

[00145] There were no clinically meaningful trends in mean changes from baseline for clinical chemistry, hematology, urinalysis, vital signs, or ECG findings, including no QTc interval prolongations of >450 msec (by either Bazett or Fridericia correction) at any time point. Isolated findings included the following: 1 subject with blood pressure decrease to 97/44 mmHg at 1 hour after dosing that increased at all subsequent assessments; 1 subject with decreased neutrophils (1.7 x 10 ³ /μί); and a new finding of sinus rhythm with Mobitz type II second-degree atrioventricular block on ECG. The latter 2 abnormalities were not considered clinically significant by the investigator.

[00146] There were no newly diagnosed physical examination findings for any subject. No abnormalities in pulse oximetry, chest auscultation, brief neurologic examinations, or BARS scores were observed. A few abnormalities were seen on SAS scores, but there were no shifts in SAS measures from baseline to 1 hour postbaseline in more than 1 subject. No subject responded "yes" to any question on suicidal ideation, intensity of ideation, or behavior during the study.

[00147] An initial decrease in mean sedation VAS scores, indicating a more sedated state, compared with baseline was observed in all treatment groups within 1 hour postdose. VAS scores recovered to baseline or greater than baseline levels through 24 hours in a dose- dependent manner. In subjects <50 kg receiving 2.5 mg, sedation VAS scores were unaffected at 15 minutes postdose, decreased to below baseline at 1 hour, and increased above baseline at 24 hours. Subjects in the same weight group who received 5 mg and those in the >50-kg weight groups who received 5 mg and 10 mg of inhaled loxapine reported decreased sedation VAS scores (ie, more sedation) at 15 minutes after dosing followed by a return to baseline or greater at 24 hours postdose.

[00148] Although scores varied considerably between individual subjects and between weight and dose groups, the majority of subjects rated inhaled loxapine as less palatable than placebo.

Table 6 Drug dosage and Staccato Platform

Drug Typical Preferred Film Calculated Slope of Line on

Dose Thickness (μιη) Substrate Surface aerosol purity vs.

(mg) Area (cm ² ) thickness plot (% purity/micron)

Albuterol 0.2 0.1 - 10 0.2 - 20 -0.64 (Fig. 23)

Alprazolam 0.25 0.1 - 10 0.25 - 25 -0.44 (Fig. 21)

Amoxapine 25 2 - 20 12.5 - 125

Atropine 0.4 0.1 - 10 0.4 - 40 -0.93 (Fig. 6)

Bumetanide 0.5 0.1 - 5 1 - 50

Buprenorphine 0.3 0.05 - 10 0.3 - 60 -0.63 (Fig. 9)

Butorphanol 1 0.1 - 10 1 - 100

Clomipramine 50 1 - 8 62 - 500 -1.0 (Fig. 10)

Donepezil 5 1 - 10 5 - 50 -0.38 (Fig. 7)

Hydromorphone 2 0.05 - 10 2 - 400 -0.55 (Fig. 8)

Loxapine 10 1 - 20 5 - 100

Midazolam 1 0.05 - 20 0.5 - 200 -0.083 (Fig. 12)

Morphine 5 0.2 - 10 5 - 250 Nalbuphine 5 0.2-5 10-250 -1.12 (Fig.13)

Naratriptan 1 0.2-5 2-50 -1.42 (Fig.14)

Olanzapine 10 1-20 5-100 -0.16 (Fig.15)

Paroxetine 20 1-20 10 - 200

Prochlorperazine 5 0.1-20 2.5 - 500 -0.11 (Fig.18)

Quetiapine 50 1-20 25 - 500 -0.18 (Fig.16)

Rizatriptan 3 0.2 - 20 1.5-150

Sertraline 25 1-20 12.5-250

Sibutramine 10 0.5-2 50 - 200

Sildenafil 6 0.2-3 20 - 300 -3.76 (Fig.22)

Sumatriptan 3 0.2-6 5-150

Tadalafil 3 0.2-5 6-150 -1.52 (Fig.17)

Testosterone 3 0.2 - 20 1.5-150

Vardenafil 3 0.1-2 15 - 300

Venlafaxine 50 2-20 25 - 250

Zolpidem 5 0.1-10 5-500 -0.88 (Fig.19)

Apomorphine 2 0.1-5 4-200

HC1

Celecoxib 50 2-20 25 - 250

Ciclesonide 0.2 0.05 - 5 0.4 - 40 -1.70 (Fig.11)

Fentanyl 0.05 0.05 - 5 0.1 - 10

Eletriptan 3 0.2 - 20 1.5-150

Parecoxib 10 0.5-2 50 - 200

Valdecoxib 10 0.5 - 10 10 - 200

Many drugs are specified in US Patent Number 9211382. The entirety of which is hereby incorporated by reference.

[00149] The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or limiting of the invention to the form disclosed. The scope of the present invention is limited only by the scope of the following claims. Many modifications and variations will be apparent to those of ordinary skill in the art. The modeling encompasses loxapine or other drug. The embodiment described and shown in the figures was chosen and described in order to best explain the principles of the invention, the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications suited to the particular use contemplated.