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Effect of co‐administration of efavirenz and nelfinavir on the pharmacokinetics of indinavir
Author(s) -
Labbeé L.,
Morse G.,
Fischl M. A.,
Feinberg J.,
Collier A.,
DiCenzo R.,
Sheiner L. B.
Publication year - 2005
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.2004.12.199
Subject(s) - pharmacokinetics , nelfinavir , efavirenz , indinavir , population , pharmacology , nonmem , medicine , human immunodeficiency virus (hiv) , viral load , antiretroviral therapy , virology , environmental health
Background/Aims Indinavir (IDV) is metabolized mainly by hepatic CYP450, primarily CYP3A4. It has been reported that efavirenz (EFV) induces CYP3A4, while nelfinavir (NFV) inhibits its activity. Therefore, pharmacokinetic (PK) interactions between IDV and EFV / NFV are expected. The goal of this PK analysis was to explore the differences observed in IDV PK among treatment arms (ARM 1: IDV alone; ARM 2: IDV+ EFV; ARM3: IDV+ NFV) in clinical trial ACTG 388. Methods Three hundred fifty‐two patients provided a total of 987 IDV concentration measurements. These were drawn at week 2 (12 (8) h PK study for ARM3 (1), approximately 10 (8) samples/study; 18 patients) and at week 40 (12h PK study for arm 3, approximately 10 samples/study; 7 patients). An additional random (“population”) sample was drawn at one or more follow‐up visits in 347 patients. A two‐compartment PK disposition model with first order absorption and “well stirred” hepatic elimination was fit to the concentration data. Results The oral clearance (CL/F) of IDV was 49.9 L/h. IDV CL/F was significantly increased with co‐administration of EFV (45%), while NFV reduced IDV CL/F by 26%. Patient weight was associated with a marginal increase of IDV CL/F (5% higher CL/F/10 Kg; p<0.05). Neither gender, age, race, nor height were correlated with IDV CL/F. Conclusion These data extend our previous population analysis and show that IDV CL/F is higher and lower when combined with EFV and NFV, respectively. Clinical Pharmacology & Therapeutics (2005) 77 , P80–P80; doi: 10.1016/j.clpt.2004.12.199