1388. Pharmacokinetics of Cabotegravir in Subjects with Moderate Hepatic Impairment
Session: Poster Abstract Session: HIV: Antiretroviral Therapy
Friday, October 6, 2017
Room: Poster Hall CD
  • IDWeek 2017_Shaik et al.pdf (232.7 kB)
  • Background: Cabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes hepatic metabolism primarily via UGT1A1; thus hepatic impairment has the potential to affect CAB exposure.

    Methods: This was a multi-center, single-dose, open-label, parallel group study to evaluate the effect of moderate hepatic impairment on the pharmacokinetics (PK) and safety of CAB. Adults with moderate hepatic impairment as determined by Child-Pugh classification score of 7-9 (n=8) and matched healthy control subjects (n=8) were enrolled. Control subjects were matched for gender, age (±10 years), and body mass index (BMI) (±25%). Subjects received oral CAB 30 mg as a single dose in the fasted state followed by serial PK sampling for 168 hours. CAB unbound concentrations at 2 and 24 hours after dosing were determined by equilibrium dialysis. Non-compartmental PK analysis was performed; geometric least squares (GLS) mean ratios (hepatic impaired group/control group) and 90% confidence intervals (CI) were generated.

    Results: Sixteen subjects completed study; 12 (75%) male, mean age 59 years (range: 51-67), mean BMI 29 kg/m2 (range: 21-37), and total Child Pugh score in range of 7-9. CAB PK parameters were similar between subjects with moderate hepatic impairment and matched healthy subjects. The GLS mean ratios (90% CI) for AUC(0-∞), Cmax, C24, CL/F, and t1/2 were 0.73 (0.50, 1.06), 0.69 (0.51, 0.93), 0.73 (0.53, 1.02), 1.38 (0.95, 2.01), and 0.82 (0.65, 1.04), respectively. Although highly protein bound, the unbound fraction of CAB was increased in subjects with moderate hepatic impairment relative to healthy subjects with GLS mean ratio (90%CI) of 2.14 (1.57, 2.90) at 2 hours post dose and 1.90 (1.14, 3.18) at 24 hours post dose; this was associated with lower serum albumin concentrations and was not considered clinically significant. All adverse events (AE) were reported as mild (Grade 1) to moderate (Grade 2) in severity and no serious AEs were reported.

    Conclusion: Plasma exposures of CAB in subjects with moderate hepatic impairment were similar to those in healthy subjects. No dose adjustment of CAB is required for subjects with mild to moderate hepatic impairment.

    Jafar Sadik Shaik, PhD1, Susan Ford, PharmD2, Yu Lou, MS3, Zhiping Zhang, PhD2, Kalpana Bakshi, MS4, Allan Tenorio, MD4, Christine Trezza, PharmD4, William Spreen, PharmD4 and Parul Patel, PharmD4, (1)GlaxoSmithKline, Upper Merion, PA, (2)PAREXEL International, Durham, NC, (3)Clinical Statistics, PAREXEL International, Research Triangle Park, NC, (4)ViiV Healthcare, Research Triangle Park, NC


    J. S. Shaik, GlaxoSmithKline: Employee and Shareholder , Salary

    S. Ford, PAREXEL International: Employee , Salary

    Y. Lou, PAREXEL International: Employee , Salary

    Z. Zhang, PAREXEL International: Employee , Salary

    K. Bakshi, GlaxoSmithKline: Employee and Shareholder , Salary

    A. Tenorio, ViiV Healthcare: Employee and Shareholder , Salary

    C. Trezza, ViiV Healthcare: Employee and Shareholder , Salary

    W. Spreen, ViiV Healthcare: Employee and Shareholder , Salary

    P. Patel, ViiV Healthcare: Employee and Shareholder , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.