Assessment of Intra-subject Variability in the Bioavailability of Chlorpromazine Hydrochloride
Condition: Anti-Psychotic; Management of Manifestations of Psychotic Disorders; Treatment of Schizophrenia; Control Nausea and Vomiting; Relief of Restlessness and Apprehension Before Surgery; Acute Intermittent Porphyria; Adjunct in the Treatment of Tetanus; Control Manifestations of the Manic Type of Mani-depressive Illness; Relief of Intractable Hiccups
MeSH terms: Porphyria, Acute Intermittent; Psychomotor Agitation; Porphyrias; Vomiting; Schizophrenia; Mental Disorders; Psychotic Disorders
Intervention: Chlorpromazine Hydrochloride
Intervention description: Chlorpromazine Hydrochloride (25 mg Tablet) - Generic US Applicant holder is USL Pharma Inc.
Intervention MeSH terms: Chlorpromazine
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Chlorpromazine; Hydrochloride; Chlorpromazine Hydrochloride; Bioavailability; Variability; Variable; Absorption; USL Pharma; USL; Healthy; South Africa; Cycle; Anti-Psychotic

Summary:

      Cycle Pharmaceuticals Ltd. (Cycle) is developing an oral tablet formulation of Chlorpromazine
      Hydrochloride and intends to conduct bioequivalence trials to demonstrate its similarity to
      the RLD.

      The aim of this pilot study is to investigate intrasubject variability in the bioavailability
      of Chlorpromazine Hydrochloride 25 mg sugar coated tablets.

      Cycle aims to demonstrate that Chlorpromazine Hydrochloride has a shallow dose response curve
      and a wide safety margin. This will then allow for the modification of bioequivalence
      acceptance criteria in future pivotal studies which will reduce the number of participants
      required whilst still maintaining assurance of safety and efficacy.

      Pilot Subjects (n): 20 Periods: 2 (2xR) Dosing: Single-dose Strength: 25 mg Test Product: N/A
      Reference: USL PHARMA Chlorpromazine Hydrochloride Analytes (in plasma): Chlorpromazine;
      7-Hydroxychlorpromazine Bioequivalence based on 90% CI (Cmax, AUC): Standard; 80.00 - 125.00%
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy males and females, 18 to 65 years (both inclusive) at signing of informed
             consent.

          2. Body Mass Index (BMI) between 18.5 and 30 kg/m2 (both inclusive).

          3. Body mass not less than 50 kg.

          4. 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.

          5. Non-smokers.

          6. 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
                  postmenopausal 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.

             OR

               -  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. Examples of reliable methods of
                  contraception include non-hormonal intrauterine device, and barrier methods
                  combined with an additional contraceptive method.

             In this study the concomitant use of hormonal contraceptives is NOT allowed. Other
             methods, if considered by the investigator as reliable, will be accepted.

          7. Written consent given for participation in the study.

        Exclusion Criteria:

          1. 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.

          2. Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol
             per week for females.

          3. Consumption of more than 5 cups of coffee (or equivalent amounts of caffeine) per day.

          4. Regular exposure to substances of abuse (other than alcohol) within the past year.

          5. 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.

          6. Participation in another study with an experimental drug, where the last
             administration of the previous IMP was within 8 weeks (or within 10 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.

          7. 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.

          8. A major illness during the 3 months before commencement of the screening period.

          9. History of hypersensitivity or allergy to the IMP or its excipients or any related
             medication including phenothiazines or other anti-psychotics or anti-emetics.

         10. History of extrapyramidal symptoms.

         11. History of liver or renal dysfunction, epilepsy, Parkinson's disease, hypothyroidism,
             cardiac failure, phaeochromocytoma, myasthenia gravis, prostate hypertrophy.

         12. Familial history of deep vein thrombosis.

         13. Hereditary problems of galactose intolerance, Lapp lactase deficiency.

         14. History of QT prolongation or signs of QT prolongation on ECG.

         15. History of bronchial asthma or any other bronchospastic disease.

         16. History of convulsions.

         17. History of porphyria.

         18. Relevant history or laboratory or clinical findings indicative of acute or chronic
             disease, likely to influence study outcome.

         19. Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the
             first administration of IMP.

         20. Diagnosis of hypotension made during the screening period.

         21. Diagnosis of hypertension made during the screening period or current diagnosis of
             hypertension.

         22. Resting pulse of > 100 beats per minute or < 40 beats per minute during the screening
             period, either supine or standing.

         23. Positive testing for HIV and Hepatitis B and Hepatitis C.

         24. 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.

         25. Positive urine screen for tobacco use.

         26. Female subjects that are pregnant (positive pregnancy test) or breastfeeding.

         27. Difficulty in swallowing.

         28. Any specific investigational product safety concern.

         29. Vulnerable subjects, e.g., persons in detention.