Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers

• Published in: British journal of clinical pharmacology Vol. 58; no. 6; pp. 632 - 640
• Main Authors: La Porte, C. J. L., De Graaff‐Teulen, M. J. A., Colbers, E. P. H., Voncken, D. S., Ibanez, S. Marco, Koopmans, P. P., Hekster, Y. A., Burger, D. M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-12-2004; Blackwell Science; Blackwell Science Inc
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Benzoxazines; Biological and medical sciences; Drug Combinations; Drug Interactions; efavirenz; Female; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - pharmacokinetics; Humans; Male; Medical sciences; Middle Aged; nelfinavir; Nelfinavir - administration & dosage; Nelfinavir - blood; Nelfinavir - pharmacokinetics; nucleoside‐sparing; once‐daily; Oxazines - blood; Oxazines - pharmacology; pharmacokinetics; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - blood; Reverse Transcriptase Inhibitors - pharmacology; ritonavir; Ritonavir - administration & dosage; Ritonavir - blood; Ritonavir - pharmacokinetics; Human; Drug combination; RNA-directed DNA polymerase; Acetylenic compound; Healthy subject; Enzyme; Ritonavir; Non nucleoside compound; Transferases; Enzyme inhibitor; Efavirenz; once-daily; Peptidases; Nucleotidyltransferases; Treatment; nucleoside- sparing; Reverse transcriptase inhibitor; Nelfinavir; Hydrolases; Antiviral; Drug interaction; Pharmacokinetics; Protease inhibitor
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2004.02214.x

Aims
A once‐daily (q.d.) nucleoside‐sparing regimen can prevent mitochondrial toxicity, overcome viral resistance and improve compliance. In the present study the effect of efavirenz on the pharmacokinetics and tolerability of once‐daily nelfinavir/ritonavir was evaluated in healthy subjects.
Methods
This was a multiple‐dose, open‐label, single‐group, two‐period study in 24 healthy subjects. Each received from days 1–10 (period 1): 1875 mg nelfinavir plus 200 mg ritonavir q.d. with a 300‐kcal snack. During days 11–20 (period 2) efavirenz 600 mg q.d. was added to the regimen. Blood samples were collected up to 24 h after dosing on days 10 (period 1) and 20 (period 2). High‐performance liquid chromatography methods were used for the determination of the concentrations of all compounds. The main pharmacokinetic parameters were calculated using noncompartmental methods.
Results
All subjects completed the study. After the first period mean nelfinavir AUC0−24 h, Cmax and C24 were 49.6 mg h−1 l−1, 5.0 mg l−1 and 0.37 mg l−1, and the sum of nelfinavir plus its active metabolite M8 C24 was 0.83 mg l−1. The relative bioavailability, expressed as a geometric mean ratio (90% confidence interval) for nelfinavir AUC0−24 h, Cmax and C24 of period 2 compared with period 1 was: 1.30 (1.21, 1.40), 1.29 (1.19, 1.40) and 1.48 (1.32, 1.66). The sum of nelfinavir and M8 C24 in period 2 was 0.99 mg l−1, an increase of 19%. No serious adverse events occurred.
Conclusions
The studied regimens were well tolerated. Nelfinavir/ritonavir given together with efavirenz resulted in a 48% higher mean C24 concentration for nelfinavir, and the sum of nelfinavir and M8 C24 concentrations was 0.99 mg l−1. Efavirenz exposure in this study was similar to that reported previously, and therefore can be used effectively in combination with ritonavir and nelfinavir.