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PII‐40
Author(s) -
Zhu M.,
Nandy P.,
Kaul S.,
Grasela D.,
Pfister M.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.165
Subject(s) - efavirenz , nonmem , reverse transcriptase inhibitor , pharmacokinetics , human immunodeficiency virus (hiv) , dosing , chemistry , pharmacology , medicine , antiretroviral therapy , viral load , immunology
BACKGROUND Drug metabolising enzymes can be self‐induced or co‐drug induced leading to lower systemic exposures and reduced accumulation upon repeated dosing. The study was aimed at developing a generic model to characterize the dynamics of the auto‐induction (AI) with efavirenz (EFV) as a model drug. EFV is a non‐nucleoside reverse transcriptase inhibitor for the treatment of HIV. It is primarily metabolised by CYP3A4 and 2B6 and exhibits AI. METHODS Analysis was performed with data from a single dose (600 mg, n=21) and a multiple dose study (600 mg daily × 14 days, n=14) in healthy subjects using NONMEM. A Well‐Stirred model served as the base model, where total clearance was expressed as intrinsic hepatic clearance (CLi). In the final model, AI of EFV was estimated by changes in CLi: CLi=CLi_ day1 +CLi max ·time/(T 50 +time), where CLi max was the maximal change of CLi from baseline (CLi_ day1 ) and T 50 was the time to achieve 50% of CLi max . RESULTS EFV PK estimates were similar to literature values. Adding time‐dependent AI term improved the model and quantified the AI effect on CLi. The mean CLi_ day1 , CLi max and T 50 were estimated to be 6.54 L/h, 9.13 L/h and 270h, respectively. The mean CL/F was 5.78 L/h on day 1, and 80% of steady state (SS) CL/F was achieved by day 15. CONCLUSIONS The model quantified the AI dynamics, time to achieve SS of AI and magnitude of changes in EFV PK. It confirmed near SS conditions of EFV with 14 day dosing. Similar modeling approaches may permit differentiation of AI and co‐drug related induction. Clinical Pharmacology & Therapeutics (2005) 79 , P46–P46; doi: 10.1016/j.clpt.2005.12.165