Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics
Condition: HIV
Study type: Interventional

Summary: 
      1. To see how the liver breaks down efavirenz by an enzyme called CYP2B6. It is suggested
           that when Efavirenz is taken repeatedly it may increase the amount of CYP2B6 in your
           liver and thus speed up your liver's ability to get rid of efavirenz from your body.
           This may render efavirenz and other medications ineffective.

        2. To see how efavirenz interact with other drugs taken at the same time with it.

        3. To see if genetic differences can change the way how the liver breaks down efavirenz and
           its interactions with other co-administered drugs.
    

Detailed description: 
      The human hepatic cytochrome P450 2B6 (CYP2B6) is a key enzyme in the metabolism of a growing
      list of clinically important drugs, environmental chemicals (e.g. toxicants and carcinogens)
      and endogenous substances. The expression and activity of this enzyme varies widely among
      individuals, probably due to genetic polymorphisms in the CYP2B6 gene and drug interactions.
      This variability, in turn, likely contributes to variable response to those drugs primarily
      metabolized by CYP2B6. In deed, several drugs that are substrates of CYP2B6 exhibit large
      pharmacokinetic differences among individuals and their use is associated with unpredictable
      drug interactions. Therefore, identifying mechanisms and factors that might influence CYP2B6
      activity is important to the safe and effective use of its substrates. An important
      characteristic of several clinically important CYP2B6 substrate drugs that include efavirenz,
      nevirapine, cyclophosphamide, artemisinin and ifosfamide is their ability to enhance their
      own clearance upon repeated dosing, a process known as autoinduction of metabolism. Drugs
      that autoinduce metabolism also exhibit multiple interactions with drug metabolizing enzymes
      other than CYP2B6 (e.g. CYP3A, CYP2C9 and CYP2C19), and drug transporters (e.g.
      p-glycoprotein). As most of these medications are used in combination with other drugs, their
      potential to alter the pharmacokinetics of co-administered drugs is very high. We hypothesize
      that CYP2B6 genetic variants that influence constitutive CYP2B6 expression and activity
      contribute to interindividual variability in steady-state exposure of the autoinducer drugs
      and in the drug interactions that ensue. We will determine the impact of CYP2B6 genetic
      variants, typically the CYP2B6*6 allele, on the time-course and extent of autoinduction of
      metabolism and the consequences of differential autoinduction on drug interactions, using
      efavirenz (a known CYP2B6 substrate and an autoinducer) as a model drug. Thus, single (600 mg
      oral dose) and steady-state (600 mg/day) pharmacokinetics of efavirenz will be assessed in
      healthy subjects genotyped for the CYP2B6*6 allele. Trough concentrations of efavirenz and
      its metabolites will be collected during the course of efavirenz treatment. Efavirenz
      exposure will be compared between the genotypes after autoinduction. An autoinduction
      pharmacokinetic model will be developed to characterize the dynamics and time courses of
      autoinduction in the different genotypes. The potential impact of differences in efavirenz
      exposure on drug interactions will be determined by measuring the in vivo activity of
      selected CYP enzymes, using isoform specific substrate probes [omeprazole (CYP2C19),
      tolbutamide (CYP2C9), caffeine (CYP1A2) and midazolam (CYP3A)] at single and after multiple
      (steady-state) dosing with efavirenz.
    

Intervention name(s): Efavirenz
Intervention type(s): Drug
Intervention description(s): The metabolism and pharmacokinetics of efavirenz were assessed at a single 600 mg oral dose of efavirenz and after subjects took multiple doses of efavirenz (600 mg/day orally for 17 days).
Other intervention name(s): Sustiva
Intervention MeSH terms: Efavirenz
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: CYP2B6; Efavirenz; Pharmacokinetics; Pharmacogenetics; Drug-Interactions