Study of Excretion Balance and Pharmacokinetics of [14C]-Sodium Valproate (3.7 MBq) in Healthy Postmenopausal or Permanently Sterile Female Subjects

An Open-label Study of Excretion Balance and Pharmacokinetics Following a Single Oral Dose of [14C]-Sodium Valproate (3.7 MBq) in Healthy Postmenopausal or Permanently Sterile Female Subjects

Primary Objectives:

• To determine the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-sodium valproate (VPA) .
• To determine the pharmacokinetics of sodium VPA and metabolite(s) and its contribution to the overall exposure of radioactivity.
• To collect samples in order to determine the metabolic pathways of sodium VPA and identify the chemical structures and main excretion route of the main metabolites.

Secondary Objective:

To assess the clinical and biological tolerability of oral solution of sodium VPA.

Study Overview

• Status: Completed
• Conditions: Epilepsy
• Intervention / Treatment: Drug: sodium valproate

Detailed Description

Total study duration is 3 to 10 weeks, including a screening period of 8 to 28 days, treatment period of up to 15 days and a follow-up and end of study of up to 4 weeks.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom
    • Investigational Site Number

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion criteria :

• Female subjects, between 30 and 60 years of age, inclusive.
• Body weight between 40.0 and 90.0 kg, inclusive, body mass index between 18.0 and 30.0 kg/m2, inclusive.
• Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
• Normal vital signs after 10 minutes resting in supine position: 95 mmHg < systolic blood pressure (SBP) <140 mmHg or, for subjects over 45 years of age, <150 mmHg, 45 mmHg < diastolic blood pressure (DBP) <90 mmHg, 40 bpm < heart rate (HR) <100 bpm
• Standard 12-lead electrocardiogram (ECG) parameters after 10 minutes resting in supine position in the following ranges; 120 ms<PR<220 ms, QRS<120 ms, QTc≤450 ms and normal ECG tracing unless the Investigator considers an ECG tracing abnormality to be not clinically relevant, or for subjects over 45 years of age, standard 12-lead ECG without clinically significant abnormality, in the judgment of the Investigator, with QTc≤470 ms.
• Laboratory parameters within the normal range (or defined screening threshold for the Investigator site), unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects; however, serum creatinine, alkaline phosphatase, hepatic enzymes (aspartate aminotransferase, alanine aminotransferase), and total bilirubin (unless the subject has documented Gilbert syndrome) should not exceed the upper laboratory norm.
• Surgically and permanently sterile (hysterectomy, bilateral salpingectomy or bilateral salpingo-oophorectomy) at least 3 months earlier or postmenopausal. Menopause is defined as being amenorrheic for at least 2 years with plasma FSH level > 30 UI/L. No additional contraception is required.
• Having given written informed consent prior to undertaking any study-related procedure.
• Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research.
• Not under any administrative or legal supervision.
• Normal renal function as expressed by a creatinine clearance > 80 mL/min as calculated by the Cockroft and Gault formula

Exclusion criteria:

• Any subject with specific dietary habits, such as vegan.
• Any subject with irregular bowel habits (more than 3 bowel movements/day or less than 1 every 2 days).
• Any subject undergoing dental care or presenting with dental caries.
• Any subject who is occupationally exposed to radiation as defined in the Ionising Radiations Regulations 2017.
• Participation in a trial with 14C-radiolabelled medication in the 12 months preceding the study.
• Radiation exposure, including that from the present study and radiopharmaceuticals or radionuclides in therapeutic or diagnostic procedures, but excluding background radiation, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years.
• Poor metabolizer status for CYP2C9, CYP2C19, CYP2D6 (by genotyping).
• Any consumption of citrus (grapefruit, orange, etc) or their juices within 5 days before inclusion.
• Any contra-indications to sodium VPA according to the applicable labeling (including personal or family history of severe hepatic dysfunction, urea cycle disorders, porphyria, hypersensitivity to valproate, active liver disease, pregnancy, child bearing potential) and patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase γ (POLG, e.g. Alpers-Huttenlocher Syndrome).

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sodium valproate; Single oral dose of sodium valproate containing [14C]-sodium VPA	Drug: sodium valproate; Pharmaceutical form:Powder for oral solution reconstituted with water Route of administration: Oral; Other Names: LA40220

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of radioactive dose excreted in urine and feces	Fractional and cumulative percentage of radioactive dose excreted in urine and feces	Day 1 to Day 43
Assessment of key metabolite(s) of sodium valproate	key metabolite(s) of sodium valproate will be assessed in plasma, urine and feces.	Day 1 to Day 43
Assessment of PK parameters: Cmax	Maximum plasma or blood concentration observed	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43
Assessment of PK parameters: tmax	Time to reach Cmax (tmax)	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43
Assessment of PK parameters: AUClast	Area under the plasma concentration versus time curve calculated from time zero to the real time, tlast (time corresponding to the last concentration above the limit of quantification, Clast (AUClast)	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43
Assessment of PK parameters: AUC	Area under the plasma concentration versus time curve extrapolated to infinity (AUC)	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43
Assessment of PK parameters: t1/2z	Terminal half-life associated with the terminal slope (λz) (t1/2z) in plasma, blood radioactivity and plasma VPA	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43
Assessment of PK parameters: B/P (blood/plasma radioactivity ratio)	Blood to plasma radioactivity ratio calculated at each time point	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43
Assessment of PK parameters: RCmax (VPA to radioactivity ratio for plasma Cmax)	RCmax is calculated as Cmax(VPA)/Cmax (radioactivity)	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43
Assessment of PK parameters: RAUC (VPA to radioactivity ratio for plasma AUC)	RAUC is calculated as AUC(VPA)/AUC (radioactivity)	Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety- Adverse Events	Adverse events, spontaneously reported by the subject or observed by the Investigator from day -1 to day 43	From day -1 to 43

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2018
• Primary Completion (Actual): April 11, 2019
• Study Completion (Actual): April 11, 2019

Study Registration Dates

• First Submitted: September 14, 2018
• First Submitted That Met QC Criteria: September 20, 2018
• First Posted (Actual): September 21, 2018

Study Record Updates

• Last Update Posted (Actual): April 25, 2022
• Last Update Submitted That Met QC Criteria: April 21, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: BEX15316; 2017-004987-36 (EudraCT Number); U1111-1205-1651 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No