Study on Sapropterin Dihydrochloride Oral Suspension in Healthy Subjects

This is a single center, Phase 1, randomized, open-label, single-dose, 4 treatment, 4-period, 4-sequence, crossover study designed to compare the pharmacokinetics (PK) of sapropterin from the Test and Reference products, and to evaluate the effect of food and the effect of water administration on the bioavailability of sapropterin from the Test product in healthy subjects.

.

In each period, subjects will receive a single 10 mg/kg dose of sapropterin dihydrochloride on Day 1, under fasting or fed conditions, and with or without water, followed by 24 hours of PK sampling. The study will include a screening visit from Day -30 to Day -1. In each period, eligible subjects will be admitted to the clinical site on Day -1 and will be confined until completion of the assessments on Day 2. There will be a washout period of at least 7 days between doses.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female, light smoker (no more than 10 cigarettes daily) or non smoker, ≥18 and ≤50 years of age, with body mass index (BMI) ≥18.5 and ≤30.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females.
2. Healthy as defined by:

   1. the absence of clinically significant illness and surgery within 30 days prior to dosing.
   2. the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.
3. Female subjects of non-childbearing potential must be:

   1. post-menopausal (no menstrual period at least 12 consecutive months without any other medical cause and FSH and LH values consistent with being menopausal); or
   2. surgically sterile (bilateral oophorectomy, bilateral salpingectomy, hysterectomy or tubal ligation) at least 3 months prior to dosing.
4. Sexually active female subjects of childbearing potential must be willing to use an acceptable contraceptive method throughout the study as detailed in the protocol.
5. Willing to take off dentures or mouth piercing at the time of dosing.
6. Able to understand the study procedures and provide signed informed consent to participate in the study.

Exclusion Criteria:

1. Any clinically significant abnormal finding at physical examination at screening.
2. Clinically significant abnormal laboratory test results (may be repeated up to two times) or positive serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV)-1 and HIV-2 antibodies at screening.
3. Positive pregnancy test or lactating female subject.
4. Positive urine drug screen.
5. Known allergic reactions to sapropterin dihydrochloride or other related drugs, or to any excipient in the formulation.
6. Clinically significant ECG abnormalities or vital signs abnormalities (systolic blood pressure lower than 90 or over 150 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or pulse rate less than 50 or over 100 bpm) at screening. ECG and vitals signs may be repeated up to two times, to determine if the values are significantly abnormal.
7. Recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine \[PCP\], crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months prior to screening.
8. History of alcohol addiction requiring treatment.
9. History of abuse of medicinal product or drugs within the last 3 years.
10. History or presence of alcoholism within the last 3 years. (\>40 g ethanol/day or more than 10 units per week \[1 unit =150 mL of wine, or 360 mL of beer, or 45 mL of 45% alcohol\]).
11. Use of medications within the timeframes specified in the protocol
12. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to dosing, administration of a biological product in the context of a clinical research study within 90 days prior to dosing, or concomitant participation in an investigational study involving no drug or device administration.
13. Known predisposition to seizures.
14. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to dosing.
15. Presence of orthodontic braces or orthodontic retention wires, or any physical findings in the mouth or tongue that would be likely to interfere with successful completion of the dosing procedure.
16. Females who:

    1. Have discontinued or changed the use of implanted, intrauterine, intravaginal, or injected hormonal contraceptives within 6 months prior to study treatment administration.
    2. Have discontinued or changed the use of oral or patch hormonal contraceptives within 1 month prior to study treatment administration.
17. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.