Staccato Loxapine Single Dose PK

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.

Inclusion Criteria:

1. Male and female subjects between the ages of 18 to 55 years, inclusive.

2. Subjects with a body mass index (BMI) ≥21 and ≤30.

3. 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.

4. 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.

5. 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:

1. 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).

2. 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).

3. Subjects who have had an acute illness within 5 days of Visit 2 (Baseline).

4. 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).

5. Subjects who have smoked tobacco within the last year.

6. Subjects who have a history within the past 2 years of drug or alcohol dependence or
abuse as defined by DSM-4.

7. Subjects with a history of HIV positivity.

8. Subjects with a history of allergy or intolerance to dibenzoxazepines (amoxapine and
loxapine).

9. Subjects with a known history of contraindications to anticholinergics (bowel
obstructions, urinary retention, acute glaucoma).

10. Subjects with a history of pheochromocytoma, seizure disorder, Parkinson's disease, or
Restless Leg Syndrome (RLS).

11. Subjects who test positive for alcohol or have a positive urine drug screen at Visit 1
or Visit 2.

12. 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).

13. Subjects who have a clinically significant ECG abnormality.

14. 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.

15. Subjects who have a history of pulmonary disease that precludes administration of
Staccato Loxapine (asthma, bronchitis, bronchospasm, emphysema).

16. Subjects who have an FEV1 less than 80% of predicted values on spirometry assessments
at Visit 1.

17. Female subjects who are breastfeeding or have a positive pregnancy test at Visit 1 or
Visit 2.

18. 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.

19. 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.