Pharmacokinetics of multiple-dose darunavir in combination with low-dose ritonavir in individuals with mild-to-moderate hepatic impairment.
OBJECTIVE
The pharmacokinetics of some HIV protease inhibitors are altered in patients with hepatic impairment. The TMC114-C134 study assessed the pharmacokinetics and safety of darunavir/ritonavir 600 mg/100 mg twice daily in HIV-negative subjects with hepatic impairment (defined according to Child-Pugh classification A [mild] or B [moderate]) compared with matched, HIV-negative, healthy subjects.


METHODS
All subjects received darunavir/ritonavir 600 mg/100 mg twice daily for 6 days with a morning dose on day 7. Pharmacokinetic profiles were obtained up to 72 hours post-dose for darunavir and 12 hours post-dose for ritonavir on day 7. Safety and tolerability were also assessed.


RESULTS
Darunavir pharmacokinetics in subjects with mild (n = 8) and moderate (n = 8) hepatic impairment were comparable to those in matched healthy control subjects (n = 16). In those with mild hepatic impairment, the least square mean ratios relative to healthy subjects for darunavir exposure (the area under the plasma concentration-time curve from 0 to 12 hours) and for maximum and minimum plasma concentrations were 0.94 (90% CI 0.75, 1.17), 0.88 (90% CI 0.73, 1.07) and 0.83 (90% CI 0.63, 1.10), respectively. In those with moderate hepatic impairment, these values were 1.20 (90% CI 0.90, 1.60), 1.22 (90% CI 0.95, 1.56) and 1.27 (90% CI 0.87, 1.85), respectively. Ritonavir pharmacokinetics were comparable between healthy subjects and those with mild hepatic impairment, but mean exposure was 50% higher in subjects with moderate hepatic impairment. Darunavir/ritonavir was generally well tolerated, regardless of hepatic impairment. All adverse events were grade 1-2 in severity, except for a grade 3 increase in alanine aminotransferase reported in one subject with mild hepatic impairment. No adverse events led to discontinuation.


CONCLUSIONS
The results of this study show that the pharmacokinetics of darunavir/ritonavir 600 mg/100 mg are not affected by mild or moderate hepatic impairment. Therefore, it is recommended that dose adjustments of darunavir/ritonavir are not required in patients with mild or moderate hepatic impairment.
Sekar
Vanitha
V
Tibotec Inc., Yardley, Pennsylvania, USA. vsekar@tibus.jnj.com
Spinosa-Guzman
Sabrina
S
De Paepe
Els
E
Stevens
Tanja
T
Tomaka
Frank
F
De Pauw
Martine
M
Hoetelmans
Richard M W
RM
D000328:Adult; D000069454:Darunavir; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir
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