title: Model-based approach to characterize efavirenz autoinduction and concurrent enzyme induction with carbamazepine.
abstract: Characterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.
authors.affiliation: Research and Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kaul
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
authors.forename: Marc
authors.initials: M
authors.lastname: Pfister
mesh_terms: D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D002220:Carbamazepine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz