Bioequivalence Study of Two Oral Haloperidol Tablets Formulations in Healthy Subjects Under Fed Conditions

The specific aim was to conduct a single dose, open-label, randomized, two period crossover pivotal study to determine the bioequivalence of two formulations containing haloperidol 2 mg in healthy males and females under fed conditions.

A total of 32 healthy female and male volunteers (age 18 to 55 years old) were entered into the study. Volunteers were determined to be free of significant medical conditions as assessed by medical history, physical examination, and blood and urine tests. Volunteers were randomly allocated to a treatment sequence, before administration of investigational medicinal product (IMP) under fed conditions.

A wash-out period of at least 14 calendar days (minimum number of days based on half-life of the analyte) between consecutive administrations of the IMP was maintained.

Blood samples were collected at at pre-dose (0 hours), at 30 minutes, at 1 hour,

1 hour 30 minutes, 2 hours, 2 hours 30 minutes, 3 hours, 3 hours 30 minutes, 4 hours, 4 hours 30 minutes, 5 hours, 5 hours 30 minutes, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours and 192 hours post-dose (total: 26 samples per treatment period).

• Haloperidol Tablets, Mylan Pharmaceuticals Inc. (Drug), also known as Benztropine Mesylate Tablets: single dose, 2 mg Haloperidol tablet
• Haloperidol Tablets, Cycle Pharmaceuticals Ltd (Drug), also known as Benztropine Mesylate Tablets: single dose, 2 mg Haloperidol tablet

Primary outcomes

• Concentration Maximum (Cmax) [pre-dose (0 hours), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144, 168, 192 hours post dose]: The maximum observed concentration of haloperidol as measured by bioanalysis of the blood plasma is referred to as the Cmax.
• Area Under the Curve (0-t) (AUC(0-t)) [pre-dose (0 hours), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144, 168, 192 hours post dose]: Area under the plasma concentration versus time curve from time zero to t, where t is the time of the timepoint of the last quantifiable concentration of haloperidol in the blood plasma. The curve is constructed by plotting the concentration of haloperidol in the blood plasma against the time for each blood sample.
• Area Under the Curve(0-∞) (AUC(0-∞)) [pre-dose (0 hours), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144, 168, 192 hours post dose]: Area under the plasma concentration versus time curve from time zero to ∞, where ∞ is the timepoint of the last quantifiable concentration of haloperidol in the blood plasma, plus it's elimination rate constant. AUC(0-∞) = AUC(0-t) + AUC(t-∞).

Secondary outcomes

• Time to Maximum Concentration (Tmax) [pre-dose (0 hours), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144, 168, 192 hours post dose]: The timepoint at which the maximum concentration of haloperidol as measured by bioanalysis of the blood plasma is observed.
• Terminal Elimination Rate Constant (λz) [pre-dose (0 hours), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144, 168, 192 hours post dose]: Terminal elimination rate constant (λz) is a mathematical estimate calculated using log-linear regression of the terminal portions of a blood plasma concentration against time curve.
• Terminal Elimination Half-life (t½) [pre-dose (0 hours), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, 24, 30, 36, 48, 72, 96, 120, 144, 168, 192 hours post dose]: The apparent terminal elimination half-life (t½) is defined as the time necessary for the concentration of a drug to decrease by one-half in the terminal phase.

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

* Body mass index (BMI) between 18.5 and 30 kg/m\^2 (both inclusive).
* Body mass not less than 50 kg.
* Medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations must be clinically acceptable or within laboratory reference ranges for the relevant laboratory tests, unless the investigator considers the deviation to be irrelevant for the purpose of the study.
* Non-smokers.
* Females, if:
* Not of childbearing potential, e.g., has been surgically sterilized, undergone a hysterectomy, amenorrhea for ≥ 12 months and considered post-menopausal, Note: In post-menopausal women, the value of the serum pregnancy test may be slightly increased. This test will be repeated to confirm the results. If there is no increase indicative of pregnancy, the female will be included in the study.
* Of childbearing potential, the following conditions are to be met:
* Negative pregnancy test If this test is positive, the subject will be excluded from the study. In the rare circumstance that a pregnancy is discovered after the subject received IMP, every attempt must be made to follow her to term.
* Not lactating
* Abstaining from sexual activity (if this is the usual lifestyle of the subject) or must agree to use an accepted method of contraception, and agree to continue with the same method throughout the study An example of a reliable method of contraception is a non-hormonal intrauterine device. In this study the concomitant use of hormonal contraceptives is NOT allowed. Other methods, if considered by the investigator as reliable, will be accepted.
* Written consent given for participation in the study.
* Written consent given for participation in the genetic component of the study (if performed based on Food and Drug Administration (FDA) feedback). If the subject declines participation in the genetic component, the subject will not be allowed to participate in the study.

Exclusion Criteria:

* Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements.
* Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol per week for females (1 unit is equal to approximately 330 mL of beer, one small glass \[200 mL\] of wine, or one measure \[25 mL\] of spirits).
* Regular exposure to substances of abuse (other than alcohol) within the past year.
* Use of any medication, prescribed or over-the-counter or herbal remedies, within 2 weeks before the first administration of IMP except if this will not affect the outcome of the study in the opinion of the investigator. In this study the concomitant use of hormonal contraceptives is NOT allowed.
* Participation in another study with an experimental drug, where the last administration of the previous IMP was within 8 weeks (or within 5 elimination half-lives for chemical entities or 2 elimination half-lives for antibodies or insulin, whichever is the longer) before administration of IMP in this study, at the discretion of the investigator.
* Treatment within the previous 3 months before the first administration of IMP with any drug with a well-defined potential for adversely affecting a major organ or system.
* A major illness during the 3 months before commencement of the screening period.
* History of hypersensitivity or allergy to the IMP or its excipients or any related medication.
* History of hypersensitivity or allergy to the pre-medication or its excipients or any related medication.
* History of hypersensitivity or allergy to the rescue medication or its excipients or any related medication.
* History of bronchial asthma or any other bronchospastic disease.
* History of convulsions.
* History of porphyria.
* History of cardiac arrhythmias.
* History of sudden cardiac death in the family or history of familial long QT syndrome.
* Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to influence study outcome.
* Cytochrome P450 (CYP) 2D6 poor metabolizers (if warranted by the FDA).
* Hypomagnesemia.
* Hypothyroidism or hyperthyroidism.
* Hypokalemia.
* Subjects with narrow-angle glaucoma.
* Subjects with stenosing peptic ulcers.
* Subjects who have pyloroduodenal obstruction.
* Subjects who have symptomatic prostatic hypertrophy or bladder-neck obstruction.
* Known or previous dystonia or dyskinesia.
* Subjects with severe toxic central nervous system depression or who have experienced comatose states from any cause.
* Subjects who have Parkinson's disease.
* Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the first administration of IMP.
* Diagnosis of hypotension made during the screening period.
* Diagnosis of hypertension made during the screening period or current diagnosis of hypertension.
* Resting pulse of > 100 beats per minute or < 40 beats per minute during the screening period, either supine or standing.
* Positive testing for human immunodeficiency virus (HIV), hepatitis B and hepatitis C.
* Positive urine screen for drugs of abuse. In case of a positive result the urine screen for drugs of abuse may be repeated once at the discretion of the investigator.
* Positive pregnancy test (female subjects).
* Hemoglobin count deviating more than 10% of the lower limit of normal.
* Veins unsuitable for venous blood collection.
* Difficulty in swallowing.
* Any specific IMP safety concern.
* Vulnerable subjects, e.g., persons in detention.
* Employees or close relatives of the contract research organization, the sponsor, 3rd party vendors or affiliates of the above mentioned parties.

Participant flow

Outcome results

• Concentration Maximum (Cmax) (Primary), Mean, ng/ml: Reference Product (Treatment A) 1.326 +/- 0.4338; Test Product (Treatment B) 1.293 +/- 0.3919
• Area Under the Curve (0-t) (AUC(0-t)) (Primary), Mean, h*ng/ml: Reference Product (Treatment A) 27.75 +/- 10.19; Test Product (Treatment B) 28.46 +/- 11.78
• Area Under the Curve(0-∞) (AUC(0-∞)) (Primary), Mean, h*ng/ml: Reference Product (Treatment A) 30.61 +/- 11.29; Test Product (Treatment B) 31.34 +/- 12.06
• Time to Maximum Concentration (Tmax) (Secondary), Mean, Hours: Reference Product (Treatment A) 4.871 +/- 3.750; Test Product (Treatment B) 3.839 +/- 1.274
• Terminal Elimination Rate Constant (λz) (Secondary), Mean, 1/h: Reference Product (Treatment A) 0.01114 +/- 0.003451; Test Product (Treatment B) 0.01152 +/- 0.004028
• Terminal Elimination Half-life (t½) (Secondary), Mean, Hours: Reference Product (Treatment A) 69.12 +/- 26.40; Test Product (Treatment B) 70.19 +/- 35.25

Adverse events

Time frame: Adverse events data was collected for the duration of the study (24 days).

Other adverse events by term

• Study Protocol (PDF, 2019-09-25)
• Statistical Analysis Plan (PDF, 2020-01-09)