Effects of hepatic impairment on the steady-state pharmacokinetics of etravirine 200 mg BID: An open-label, multiple-dose, controlled Phase I study in adults

• Published in: Clinical therapeutics Vol. 32; no. 2; pp. 328 - 337
• Main Authors: Schöller-Gyüre, Monika, MD, Kakuda, Thomas N., PharmD, Smedt, Goedele De, MD, Woodfall, Brian, MD, Berckmans, Cindy, MSc, Peeters, Monika, MSc, Hoetelmans, Richard M.W., PhD
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.02.2010; Elsevier; Elsevier Limited
• Subjects: Acquired immune deficiency syndrome; Administration, Oral; Adult; Aged; AIDS; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - pharmacokinetics; Antimicrobial agents; Biological and medical sciences; Chemotherapy; Cytochrome; Drug therapy; etravirine; Female; Gastroenterology. Liver. Pancreas. Abdomen; Germany; hepatic impairment; Hepatitis; HIV; Human immunodeficiency virus; Humans; Internal Medicine; Linear Models; Liver diseases; Liver Diseases - metabolism; Liver Diseases - physiopathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical Education; Medical sciences; Middle Aged; non-nucleoside reverse transcriptase inhibitor; Other diseases. Semiology; Pharmacokinetics; Pharmacology. Drug treatments; Pyridazines - administration & dosage; Pyridazines - adverse effects; Pyridazines - pharmacokinetics; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - pharmacokinetics; Severity of Illness Index; TMC125; Germany; Belgium; Mexico; hepatic impairment; etravirine; pharmacokinetics; TMC125; non-nucleoside reverse transcriptase inhibitor; Human; Antiretroviral agent; RNA-directed DNA polymerase; Enzyme; Transferases; Non nucleoside compound; Hepatic disease; Multiple dose; Nucleotidyltransferases; Liver failure; Treatment; Etravirine; Reverse transcriptase inhibitor; Phase I trial; Digestive diseases; Adult; Antiviral; Pharmacokinetics
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2010.02.013

Abstract Background: Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against both wild-type HIV and viruses harboring NNRTI resistance. Etravirine is mainly eliminated via the hepatobiliary route. Objectives: This study in HIV− patients with mild or moderate hepatic impairment and healthy matched controls was conducted to explore the effects of mild and moderate hepatic impairment on the steady-state pharmacokinetics of etravirine and to provide guidance for the treatment of HIV+ patients with hepatic impairment. Methods: This open-label, multiple-dose study enrolled HIV− patients aged 18 to 65 years with mild or moderate hepatic impairment (Child-Pugh score, 5–6 or 7–9, respectively) and healthy volunteers matched for age, sex, race, and body mass index (BMI). All subjects received etravirine 200 mg BID with food for 7 days and a morning dose on day 8. Etravirine pharmacokinetics over a period of 12 hours on days 1 and 8 were determined using noncompartmental methods and analyzed using linear mixed-effects modeling. Tolerability of etravirine was assessed based on the reported adverse events, laboratory investigations, ECG, and physical examination. Results: Each group comprised 8 subjects (mild hepatic impairment patients: 5 men, 3 women; median age, 57 years [range, 41–65 years]; BMI, 26 kg/m2 [range, 20–32 kg/m2 ]; moderate hepatic impairment patients: 6 men, 2 women; age, 54 years [range, 44–64 years]; BMI, 26 kg/m2 [range, 22–32 kg/m2 ]). All patients were white and light smokers. On day 8, the least squares mean ratios (90% CIs) of the logtransformed pharmacokinetic properties in patients with mild and moderate hepatic impairment were, respectively: Cmin , 0.87 (0.65–1.17) and 0.98 (0.68–1.42) μg/mL; Cmax , 0.79 (0.63–1.00) and 0.72 (0.54–0.96) ug/mL; and AUC0–12 , 0.87 (0.69–1.09) and 0.82 (0.60–1.11) μg/mL/h. All treatment-emergent adverse events were considered mild to moderate; the most common were headache (50% in healthy controls) and fatigue and nausea (both 25% in patients with mild hepatic impairment). No clinically significant changes in laboratory parameters, physical examination including vital signs, or ECG were observed. One serious adverse event was reported during the follow-up period in a patient with moderate hepatic impairment due to hepatic cirrhosis secondary to alcoholism. This patient presented at screening with dilated cardiomyopathy and cardiac arrhythmia. Conclusions: In this Phase I pharmacokinetic study, no clinically relevant differences were observed between patients with mild or moderate hepatic impairment and healthy matched subjects with regard to the pharmacokinetics of etravirine. Based on these findings in these HIV− volunteers, no dose adjustment of etravirine appears to be necessary in patients with mild or moderate hepatic impairment. Etravirine was generally well tolerated.