Interaction of CYP2B6 Genotype and Efavirenz With Methadone and Tizanidine PK

Conditions

• Drug-Drug Interaction

Eligibility Criteria

Sex

ALL

Age

18 Years - 65 Years

Healthy Volunteers

Accepted

Interventions

• Methadone and Tizanidine — DRUG
  Each CYP2B6 genotype predicted phenotypes will receive methadone (10 mg) and tizanidine (4 mg) by mouth at baseline (control)
• Efavirenz, Methadone and Tizanidine — DRUG
  Each CYP2B6 genotype predicted phenotypes will receive methadone (10 mg) and tizanidine (4 mg) by mouth after pretreatment with efavirenz (600 mg PO for 16 days)

Study Details

The main goal of this clinical study is to test how CYP2B6 genetic variations and efavirenz (cornerstone in HIV-1 therapy) dictate the disposition (PK) of CYP2B6 substrate (methadone) and PK and effect (PD) of CYP1A2 substrate (tizanidine). Specifically, the investigators will test whether efavirenz produces CYP2B6 genotype dependent unanticipated DDIs with CYP2B6 (methadone) and CYP1A2 (tizanidine), leading to lack of efficacy or increased toxicity. Healthy volunteers genotyped for CYP2B6\*6 and \*18 alleles will be grouped in to three genotype predicted phenotype groups: 20 normal metabolizer (NM) (CYP2B6\*1/\*1); 20 intermediate metabolizer (IM) (\*1/\*6, or \*1/\*18); and 20 poor metabolizer (PM) (\*6/\*6, \*6/\*18 or \*18/\*18). Each phenotype group will receive methadone and tizanidine (separated by a washout period) on two occasions: at baseline (control) and after treatment with efavirenz (600 mg/day for 17 days).

Key Dates

Start date

Oct 6, 2023

Status verified

May 2026

Primary completion

Aug 15, 2026

Completion

Dec 31, 2026

Study Design

Enrollment

60 participants (estimated)

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

BASIC_SCIENCE

Arms

• Experimental: Baseline (control)
  Each CYP2B6 normal metabolizer (NM) (\*1/\*1), intermediate metabolizer (IM) (\*1/\*6), and poor metabolizer (PM) (\*6/\*6, \*6/\*18, or \*18/\*18) group will receive a single dose of methadone (10 mg) and a single dose of tizanidine (4 mg) orally simultaneously at baseline (control).
• Experimental: Efavirenz (treatment)
  Each CYP2B6 normal metabolizer (NM) (\*1/\*1), intermediate metabolizer (IM) (\*1/\*6), and poor metabolizer (PM) (\*6/\*6, \*6/\*18, or \*18/\*18) group will be administered a single dose of methadone (10 mg) and a single dose of tizanidine (4 mg) orally simultaneously after 16-day oral treatment with 600 mg/day efavirenz

Primary Outcome Measure

Magnitude of effects of CYP2B6 genotype and multiple doses of efavirenz on the: 1) stereoselective disposition of methadone; and 2) disposition and pharmacodynamics of tizanidine [ Time Frame: Methadone and tizanidine plasma concentrations (0-72 hours) will be determined before (control) and after pretreatment with efavirenz (600 mg/day) for 16 days and AUC0-∞ will be estimated. ]

Central Contacts

• Zeruesenay Desta, PhD
  3172742823
  [email protected]
• Abi Colwell
  317-274-2715
  [email protected]

Locations (1)

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