Staccato Loxapine Single Dose PK

Study Overview
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Brief Summary
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The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single inhaled dose of (administered in 1 or 2 puffs) Staccato Loxapine in healthy volunteers.

Detailed Description
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Safety and pharmacokinetic data obtained from 50 subjects (between the ages of 18 to 55 years) entered into this randomized, placebo-controlled study. To obtain 50 enrolled subjects, screening procedures and inclusion/exclusion criteria were evaluated for 126 subjects during a variable screening period of up to 21 days. Once enrolled, subjects were randomized to either Staccato Loxapine or Staccato placebo. Plasma samples for pharmacokinetic analysis were collected beginning on Day 0, pre-dose and continuing for 24 hr post dose. Blood samples for the PK analysis of loxapine and its metabolites (8-OH loxapine, 7-OH loxapine and amoxapine) were obtained at time 0 (immediately before dosing), at 30 sec, 1, 2, 3, 5, 10, 30, 45 min, 1, 2, 4, 6, 12, 24 hr after dosing. Plasma concentrations of loxapine and metabolites were used to estimate the following PK parameters for loxapine and its metabolites: area under the plasma concentration time curve from time 0 extrapolated to infinity (AUCinf), AUC from time 0 to time tlast, the last quantifiable concentration (AUClast), maximum observed plasma concentration (Cmax), observed time of Cmax (tmax), terminal phase elimination rate constant (ke), apparent terminal elimination half life calculated from ke (T½ ), apparent total body clearance / fraction absorbed calculated from AUCinf and dose (CL/F) (for loxapine and the metabolites where permitted by measurable concentrations). Safety was evaluated by the incidence of adverse events, clinical laboratory testing (blood chemistry, hematology, and urinalysis), physical examination, vital signs, pulse oximetry, postural vital signs, 12-lead electrocardiogram, pulmonary function tests, continuous 12-lead Holter monitoring, sedation assessments, akathisia assessments.

Official Title
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Safety, Tolerability, and Pharmacokinetics of a Single Dose of Staccato™ Loxapine for Inhalation in Normal, Healthy Volunteers

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: inhaled Loxapine 0.625 mg
* Drug: inhaled Loxapine 1.25 mg
* Drug: inhaled Loxapine 2.5 mg
* Drug: inhaled Loxapine 5 mg
* Drug: inhaled Loxapine 10 mg
* Drug: inhaled Placebo (0 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between the ages of 18 to 55 years, inclusive. Subjects with a body mass index (BMI) ≥21 and ≤30. Subjects who speak, read, and understand English and are willing and able to provide written informed consent on an IRB-approved form prior to the initiation of any study procedures. Subjects who are willing and able to be confined to the Clinical Research Unit (CRU) for approximately 2 days and comply with the study schedule and study requirements. Subjects who are in good general health as determined by a complete medical history, physical examination, 12-lead ECG, spirometry, blood chemistry profile, hematology, and urinalysis. Exclusion Criteria: Subjects who regularly consume large amounts of xanthine-containing substances (i.e., more than 5 cups of coffee or equivalent amounts of xanthine-containing substances per day). Subjects who have taken prescription or nonprescription medication (with the exception of vitamins and acetaminophen if medically necessary) within 5 days of Visit 2 (Baseline). Subjects who have had an acute illness within 5 days of Visit 2 (Baseline). Subjects who have received an investigational drug within 30 days (or within 5 half lives of the investigational drug, if >30 days) prior to Visit 2 (Baseline). Subjects who have smoked tobacco within the last year. Subjects who have a history within the past 2 years of drug or alcohol dependence or abuse as defined by DSM-4. Subjects with a history of HIV positivity. Subjects with a history of allergy or intolerance to dibenzoxazepines (amoxapine and loxapine). Subjects with a known history of contraindications to anticholinergics (bowel obstructions, urinary retention, acute glaucoma). Subjects with a history of pheochromocytoma, seizure disorder, Parkinson's disease, or Restless Leg Syndrome (RLS). Subjects who test positive for alcohol or have a positive urine drug screen at Visit 1 or Visit 2. Subjects who have hypotension (systolic blood pressure ≤90 mmHg, diastolic blood pressure ≤50 mmHg), or hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg). Subjects who have a clinically significant ECG abnormality. Subjects with a history of unstable angina, syncope, coronary artery disease, myocardial infarction, congestive heart failure (CHF), stroke, transient ischemic attack (TIA), or a neurological disorder. Subjects who have a history of pulmonary disease that precludes administration of Staccato Loxapine (asthma, bronchitis, bronchospasm, emphysema). Subjects who have an FEV1 less than 80% of predicted values on spirometry assessments at Visit 1. Female subjects who are breastfeeding or have a positive pregnancy test at Visit 1 or Visit 2. Female participants of child-bearing potential or within 1 year of menopause, and sexually active are excluded unless they use a medically acceptable and effective birth control method throughout the study and for 1 week following the end of the study. Medically acceptable methods of contraception include abstinence, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization, and birth control pills. Unacceptable methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone. Subjects who have any other disease or condition, by history, physical examination, or laboratory abnormalities that in the investigator's opinion, would present undue risk to the subject, or may confound the interpretation of study results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Inhaled Loxapine 0.625 mg or Placebo<br>Single 0.625 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine | Drug: inhaled Loxapine 0.625 mg<br>* Single 0.625 mg (lowest) dose of inhaled loxapine<br>* Other names: ADASUVE;Drug: inhaled Placebo (0 mg)<br>* Single placebo dose of inhaled loxapine<br>* Other names: PLACEBO;|
| Experimental: Cohort B: Inhaled Loxapine 1.25 mg or Placebo<br>Single 1.25 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine | Drug: inhaled Loxapine 1.25 mg<br>* Single 1.25 mg (2nd) dose of inhaled loxapine<br>* Other names: ADASUVE;Drug: inhaled Placebo (0 mg)<br>* Single placebo dose of inhaled loxapine<br>* Other names: PLACEBO;|
| Experimental: Cohort C: Inhaled Loxapine 2.5 mg or Placebo<br>Single 2.5 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine | Drug: inhaled Loxapine 2.5 mg<br>* Single 2.5 mg (3rd) dose of inhaled loxapine<br>* Other names: ADASUVE;Drug: inhaled Placebo (0 mg)<br>* Single placebo dose of inhaled loxapine<br>* Other names: PLACEBO;|
| Experimental: Cohort D: Inhaled Loxapine 5 mg or Placebo<br>Single 5 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine | Drug: inhaled Loxapine 5 mg<br>* Single 5 mg (4th) dose of inhaled loxapine<br>* Other names: ADASUVE;Drug: inhaled Placebo (0 mg)<br>* Single placebo dose of inhaled loxapine<br>* Other names: PLACEBO;|
| Experimental: Cohort E: Inhaled Loxapine 10 mg or Placebo<br>Single 10 mg dose of inhaled loxapine or Single Placebo dose of inhaled loxapine | Drug: inhaled Loxapine 10 mg<br>* Single 10 mg (5th) dose of inhaled loxapine<br>* Other names: ADASUVE;Drug: inhaled Placebo (0 mg)<br>* Single placebo dose of inhaled loxapine<br>* Other names: PLACEBO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax | Tmax = time from inhalation to to maximum observed loxapine concentration | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | 
| Half-life | Half-life of the terminal elimination phase of loxapine concentrations | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | 
| ke | elimination rate constant | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | 
| Clearance | clearance (CL/F) of lozxapine | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | 
| Cmax | maximum concentration of loxapine observed | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | 
| Dose Proportionality (AUCinf) by Power Analysis | Dose proportionality by power analysis examines the linear regression of the log-AUC versus log-Dose on a by-patient basis across all doses administered. The slope and 90% confidence interval (CI) provide a clear, quantitative (best practices) assessment of the relationship of drug delivered to dose administered. The units on such analyses are generally those of slope (rise over run), with 1.000 being perfect. Although any positive slope might be considered clinically useful, a 90% CI within the criteria of 0.800-1.250 may be considered a delivery system which is as good as it gets. | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Staccato Loxapine