Interaction of CYP2B6 Genotype and Efavirenz With Methadone and Tizanidine PK

ConditionDrug-Drug Interaction

Trial statusRecruiting

Trial phaseEarly Phase 1

Trial typeInterventional

Biological sexAll

Age18-65

SponsorIndiana University

About this trial

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).

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

are male and female (approximately 1:1) volunteers between the age of 18 and 65 years old

are judged healthy without any significant medical condition as determined by and decided from a pre-enrollment screening session that include medical history, laboratory tests such as blood and urine tests, vital signs, and an electrical tracing of the heartbeat (electrocardiogram, EKG). The pre-enrollment screening will be done no more than six weeks before the start of the study.

are able and willing to adhere to the study medication restrictions two weeks before initiating the study and during the conduct of the entire study. These will include refraining from taking any prescriptions medications, over-the-counter medications, and herbal, dietary, and alternative supplements that may interact with the metabolism of those study drugs at least 2 weeks prior to the start of the study and until study completion.

are nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at least two weeks prior to and until the completion of the study.

Disqualifiers

are underweight (weigh less than 50 kg or 110 lb.) or overweight [BMI greater than 32]. Body mass index is calculated using height and weight to estimate how much body fat subjects have.

have laboratory results that do not fall in a healthy range

have an electrical tracing (baseline EKG readings) that are abnormal as decided by the study physician (medical doctor).

have history of intolerance, allergic reactions (e.g., rash) or other forms of hypersensitivities to any of the study medications (efavirenz, tizanidine or methadone).

Trial design

Design model

Sequential

Treatments tested in this trial

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)

Treatment groups

60 Participants

are divided into 2 treatment groups

Group A: Baseline (control)Experimental treatment 1 intervention

Group B: Efavirenz (treatment)Experimental treatment 1 intervention

Trial outcomes

Primary outcomes

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

1. The primary PK interaction magnitude with R- and S-methadone will be quantified using the treatment:control \[+efavirenz:-efavirenz (baseline)\] ratios of the area under the time concentration curve to infinity (AUC0-∞) of S- and R-methadone. 2. The primary PK interaction magnitude with tizanidine will be quantified using the treatment:control \[+efavirenz:-efavirenz (baseline)\] ratios of the area under the time concentration curve to infinity (AUC0-∞) 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.

Sponsors and contacts

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Indiana University

Lead sponsor

National Institute of General Medical Sciences (NIGMS)

Collaborator

Source ClinicalTrials.gov

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