Study on Sapropterin Dihydrochloride Oral Suspension in Healthy Subjects

A Pilot, Phase 1, Randomized, Open-Label, Single-Dose, Four-Way Crossover Study to Compare the Pharmacokinetics of Sapropterin Dihydrochloride 100 mg/mL Oral Suspension (Product Code: RLF-OD032) (Test) With Kuvan® (Sapropterin Dihydrochloride) 100 mg Powder for Oral Solution (Reference) and to Evaluate the Effect of Food and the Effect of Water on the Bioavailability of Sapropterin Dihydrochloride 100 mg/mL 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.

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Study Overview

• Status: Completed
• Conditions: Bioavailability
• Intervention / Treatment: Drug: RLF-OD032; Drug: Kuvan

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M1S3V6
      • Pharma Medica Research Inc. 4770 Sheppard Ave E,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Sequence DCAB; Where the Subject receives in this order D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions. A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions. B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.	Drug: RLF-OD032; 100 mg/mL oral suspension; Other Names: Sapropterin dihydrochloride; Drug: Kuvan; 100 mg powder for oral solution; Other Names: Sapropterin dihydrochloride
Other: Sequence ADBC; Where the Subject receives in this order A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions. D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions. C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.	Drug: RLF-OD032; 100 mg/mL oral suspension; Other Names: Sapropterin dihydrochloride; Drug: Kuvan; 100 mg powder for oral solution; Other Names: Sapropterin dihydrochloride
Other: Sequence BACD; Where the Subject receives in this order B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions. A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions. C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions. D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions	Drug: RLF-OD032; 100 mg/mL oral suspension; Other Names: Sapropterin dihydrochloride; Drug: Kuvan; 100 mg powder for oral solution; Other Names: Sapropterin dihydrochloride
Other: Sequence CBDA; Where the Subject receives in this order C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions. B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions. D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.	Drug: RLF-OD032; 100 mg/mL oral suspension; Other Names: Sapropterin dihydrochloride; Drug: Kuvan; 100 mg powder for oral solution; Other Names: Sapropterin dihydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uncorrected Sapropterin AUC0-t	Area under the concentration-time curve from time zero until the last observed concentration, as calculated by the linear up/log down variant of the trapezoidal method	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Baseline-corrected Sapropterin AUC0-t	Area under the concentration-time curve from time zero until the last observed concentration, as calculated by the linear up/log down variant of the trapezoidal method	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Uncorrected Sapropterin Cmax	Maximum observed concentration	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Baseline-corrected Sapropterin Cmax	Maximum observed concentration	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Uncorrected Sapropterin AUC0-inf	Area under the concentration-time curve from time zero to infinity (extrapolated)	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Baseline-corrected Sapropterin AUC0-inf	Area under the concentration-time curve from time zero to infinity (extrapolated)	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uncorrected and baseline-corrected sapropterin Tmax	Time when the maximal concentration is observed	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Uncorrected and baseline-corrected sapropterin Tlag	Time of observation prior to the first observation with a measurable (non-zero) concentration	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Uncorrected and baseline-corrected sapropterin T½ el	Terminal elimination half-life	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Uncorrected and baseline-corrected sapropterin Residual Area	Percentage of AUC0-inf due to extrapolation from the time of the last observed concentration to infinity, calculated as [1 - (AUC0-t/AUC0-inf)] x 100	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Uncorrected and baseline-corrected sapropterin Kel	Terminal elimination rate constant	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Uncorrected and baseline-corrected sapropterin Cl/F	Apparent clearance	Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Safety and Tolerability Analysis of sapropterin dihydrochloride when administered to healthy subjects.	Assessment of AEs. AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).	Safety monitored from the signature of the Informed Consent through study completion, approximately 24 days

Collaborators and Investigators

• Sponsor: APR Applied Pharma Research s.a.

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2024
• Primary Completion (Actual): August 31, 2024
• Study Completion (Actual): August 31, 2024

Study Registration Dates

• First Submitted: June 6, 2024
• First Submitted That Met QC Criteria: June 27, 2024
• First Posted (Actual): July 1, 2024

Study Record Updates

• Last Update Posted (Actual): June 12, 2025
• Last Update Submitted That Met QC Criteria: June 11, 2025
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Membrane Transport Modulators; Calcium Channel Blockers; Vasodilator Agents; Verapamil
• Other Study ID Numbers: 2023-5439

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes