Pharmacokinetic parameters of once―daily rilpivirine following administration of efavirenz in healthy subjects

• Published in: Antiviral therapy Vol. 17; no. 3; pp. 439 - 446
• Main Authors: CRAUWELS, Herta, VINGERHOETS, Johan, RYAN, Robert, WITEK, James, ANDERSON, David
• Format: Journal Article
• Language: English
• Published: London International Medical Press 01.01.2012
• Subjects: Adolescent; Adult; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Benzoxazines - administration & dosage; Biological and medical sciences; Female; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Seronegativity; HIV-1 - drug effects; Humans; Male; Medical sciences; Microbial Sensitivity Tests - methods; Middle Aged; Nitriles - administration & dosage; Nitriles - adverse effects; Nitriles - pharmacokinetics; Nitriles - pharmacology; Pharmacology. Drug treatments; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - pharmacokinetics; Reverse Transcriptase Inhibitors - pharmacology; Rilpivirine; Treatment Outcome; Young Adult; Human; Antiretroviral agent; Benzoxazine derivatives; RNA-directed DNA polymerase; Acetylenic compound; Healthy subject; Enzyme; Rilpivirine; Non nucleoside compound; Transferases; Enzyme inhibitor; Efavirenz; Allosteric inhibitor; Nucleotidyltransferases; Reverse transcriptase inhibitor; Antiviral; Single daily dose; Parameter; Pharmacokinetics
• ISSN: 1359-6535; 2040-2058
• DOI: 10.3851/IMP1959

Rilpivirine and efavirenz share metabolic pathways (CYP3A), potentially leading to drug-drug interactions. We report the pharmacokinetics, ex vivo antiviral activity and safety of rilpivirine, following efavirenz treatment. HIV-negative adults received in fixed sequence: treatment A (rilpivirine 25 mg once daily for 14 days, followed by a washout), treatment B (efavirenz 600 mg once daily for 14 days), immediately followed by treatment C (rilpivirine 25 mg once daily for 28 days). Rilpivirine pharmacokinetic profiles were determined on days 1 and 14 of treatment A and days 1, 14, 21 and 28 of treatment C. Ex vivo antiviral activity was measured in treatments A and C using an exploratory assay. Safety was evaluated throughout. From days 1 to 21, higher mean rilpivirine exposure was observed with treatment A compared with treatment C. The area under the concentration-time curve (AUC(24 h)) least squares (LS) means ratio (90% CI) for treatment C versus treatment A was 0.54 (0.46, 0.64; Day 1), 0.82 (0.75, 0.89; Day 14) and 0.84 (0.74, 0.94; Day 21). By day 28 of treatment C, the main rilpivirine pharmacokinetic parameters were similar to day 14 of treatment A (AUC(24 h) LS means ratio [90% CI], 0.91 [0.82, 1.01]), except for the minimum plasma concentration. At each time point in treatment C, samples of >80% of subjects demonstrated similar ex vivo antiviral activity compared with treatment A. All adverse events were grade 1 or 2. These results provide useful information supporting a clinical study evaluating HIV-1-positive subjects switching from efavirenz to rilpivirine.