NCT03103568

A Study to Investigate the Potential Influence of Nitisinone on the Metabolism and the Transport of Other Drugs in Healthy Volunteers

An Open-label, Non-randomized, 2-arm, 2-period Fixed Sequence Phase 1 Study to Evaluate the Potential Inhibition of Nitisinone on Cytochrome P450 2C9, 2D6, and 2E1 and the Organic Anion Transporters OAT1 and OAT3 in Healthy Volunteers

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 36 (actual)
• Sponsor: Swedish Orphan Biovitrum · Industry
• Sex: All
• Age: 18 Years – 55 Years
• Healthy volunteers: Accepted

Summary

An open-label, non-randomized, 2-arm, 2-period fixed sequence phase 1 study to evaluate the potential inhibition of nitisinone on cytochrome P450 2C9, 2D6, and 2E1 and the organic anion transporters OAT1 and OAT3 in healthy volunteers

Detailed description

This is an open-label, non-randomized, 2-arm, 2-period fixed-sequence drug-drug interaction study in a total of 36 (18 in each arm) male and female healthy volunteers. The study consists of: Screening, Period 1 (substrates only), Period 2 (substrates + nitisinone) and Follow-up. In the screening period, subjects will be assessed for eligibility. Eligible subjects will be assigned to one of two treatment arms. In Arm A, the potential inhibition of nitisinone on CYP2C9, CYP2D6, and CYP2E1 will be investigated. In Arm B, the possible combined effect of nitisinone on the renal transporters OAT1 and OAT3 will be investigated. In Period 1, the subjects will receive a single dose of a CYP cocktail of 3 substrates (Arm A) or an OAT1/OAT3 substrate (Arm B). Substrate plasma concentrations will be measured for determination of substrate PK; for up to 48 hours in Arm A and for 8 hours in Arm B. During Period 2, the treatment and assessments will vary slightly between the 2 treatment arms. Nitisinone will be administered for 14 days, without co-administration of any substrate, in order to reach steady state and the recommended target plasma concentration, before the interaction with the substrates is studied. In Arm A, Period 2, subjects will receive nitisinone for 16 consecutive days (14 days on nitisinone only and two days on nitisinone + substrate). Nitisinone steady state PK will be determined based on plasma and urine samples collected during one dosage interval at steady state, on the day before co-administration of the substrates. Nitisinone will then be administered together with the CYP substrates, and plasma samples for determination of their PK will be collected as in Period 1. There will be a final nitisinone dose on the day after substrate administration in order to maintain therapeutic levels throughout the 48-hour sampling period. In Arm B, Period 2, subjects will receive nitisinone for 15 consecutive days (14 days on nitisinone only and one day on nitisinone + substrate). No nitisinone steady state PK characterization will be conducted in this arm. On the last treatment day, the subjects will receive nitisinone together with the OAT1/OAT3 substrate. This will be followed by 8 hours of blood sampling for determination of substrate PK.

Conditions

• Drug Drug Interaction

Interventions

Type	Name	Description
DRUG	Nitisinone in Arm A	4 capsules of 20 mg nitisinone (80 mg) is given once daily for 17 days.
DRUG	Tolbutamide	A 500 mg tablet is given as single oral dose 2 weeks apart.
DRUG	Metoprolol	A 50 mg tablet of metoprolol tartrate is given as single oral dose 2 weeks apart.
DRUG	Chlorzoxazone	A 250 mg tablet is given as single oral dose 2 weeks apart.
DRUG	Furosemide	A single intravenous dose of 20 mg administered as an i.v. infusion is given 2 weeks apart.
DRUG	Nitisinone in Arm B	4 capsules of 20 mg nitisinone (80 mg) is given once daily for 16 days.

Timeline

• Start date: 2017-03-28
• Primary completion: 2017-06-10
• Completion: 2017-07-24
• First posted: 2017-04-06
• Last updated: 2017-08-10

Locations

1 site across 1 country: Germany