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Pharmacokinetics of Single‐Dose Dolutegravir in HIV‐Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls
Author(s) -
Song Ivy H.,
Borland Julie,
Savina Paul M.,
Chen Shuguang,
Patel Parul,
Wajima Toshihiro,
Peppercorn Amanda F.,
Piscitelli Stephen C.
Publication year - 2013
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.55
Subject(s) - dolutegravir , medicine , pharmacokinetics , dosing , gastroenterology , adverse effect , confidence interval , urology , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load , immunology
This study evaluated dolutegravir pharmacokinetics (PK) in subjects with moderate hepatic impairment compared to matched, healthy controls. In this open‐label, parallel‐group study, eight adult subjects with moderate hepatic impairment (Child‐Pugh Score 7–9) and eight healthy subjects matched for gender, age, and body mass index received a single dolutegravir 50‐mg dose. Following dosing, 72‐hour PK sampling was performed to determine total and unbound dolutegravir concentrations. PK parameters were calculated using non‐compartmental analysis. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CIs) in subjects with hepatic impairment versus healthy subjects were generated by analysis of variance. Results showed that PK parameters of total plasma dolutegravir were similar between subject groups. The unbound fraction was higher in subjects with moderate hepatic impairment than in healthy subjects with GMR (90% CI) of 2.20 (1.62, 2.99) for unbound fraction at 3 hours post‐dose and 1.76 (1.23, 2.51) for unbound fraction at 24 hours post‐dose; this correlated with lower serum albumin concentrations and was not considered clinically significant. Dolutegravir was well tolerated in both groups; all adverse events were reported as minor. Although free fraction was increased, no dose adjustment is required for patients treated with dolutegravir who have mild to moderate hepatic impairment.