title: 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.
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.
  
  
  OBJECTIVE
  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/m(2) [range, 20-32 kg/m(2)]; moderate hepatic impairment patients: 6 men, 2 women; age, 54 years [range, 44-64 years]; BMI, 26 kg/m(2) [range, 22-32 kg/m(2)]). All patients were white and light smokers. On day 8, the least squares mean ratios (90% CIs) of the log transformed pharmacokinetic properties in patients with mild and moderate hepatic impairment were, respectively: C(min), 0.87 (0.65-1.17) and 0.98 (0.68-1.42) microg/mL; C(max), 0.79 (0.63-1.00) and 0.72 (0.54-0.96) ug/mL; and AUC(0-12), 0.87 (0.69-1.09) and 0.82 (0.60-1.11) microg/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.
authors.affiliation: Tibotec BVBA, Mechelen, Belgium. mscholle@its.jnj.com
authors.forename: Monika
authors.initials: M
authors.lastname: Schöller-Gyüre
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Kakuda
authors.forename: Goedele
authors.initials: G
authors.lastname: De Smedt
authors.forename: Brian
authors.initials: B
authors.lastname: Woodfall
authors.forename: Cindy
authors.initials: C
authors.lastname: Berckmans
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D005858:Germany; D006801:Humans; D016014:Linear Models; D008107:Liver Diseases / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine