Model-based approach to characterize efavirenz autoinduction and concurrent enzyme induction with carbamazepine.
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.
Zhu
Min
M
Research and Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543-4000, USA.
Kaul
Sanjeev
S
Nandy
Partha
P
Grasela
Dennis M
DM
Pfister
Marc
M
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
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