Indiana University
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).
This is an open-label, two period, fixed sequence study in healthy volunteers genotyped for CYP2B6 allele (\*6 and \*18) investigating the metabolism, pharmacokinetics (PK) and pharmacodynamics (PD) of a single oral dose of tizanidine and methadone before and after oral pre-treatment with 600 mg/day efavirenz for 16 days. Enrollment targets will be normal metabolizers (N=20, CYP2B6\*1/\*1), intermediate metabolizers (N=20, CYP2B6\*1/\*6 and \*1/\*18) and poor metabolizers (N=20, CYP2B6\*6/\*6; \*18/\*18, and \*6/\*18). Schedule of assessment: A. PHASE 1 (CONTROL PHASE): Tizanidine and methad…
Inclusion Criteria: Subjects will be included in the study if participants: * 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 st…
Each CYP2B6 genotype predicted phenotypes will receive methadone (10 mg) and tizanidine (4 mg) by mouth at baseline (control)
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)
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