A Phase 1 Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Patients With Hepatic Impairment and Healthy Matched Controls

Jafar Sadik B Shaik, Susan L Ford, Yu Lou, Zhiping Zhang, Kalpana K Bakshi, Allan R Tenorio, Christine Trezza, William R Spreen, Parul Patel, Jafar Sadik B Shaik, Susan L Ford, Yu Lou, Zhiping Zhang, Kalpana K Bakshi, Allan R Tenorio, Christine Trezza, William R Spreen, Parul Patel

Abstract

Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre-exposure prophylaxis of HIV-1 infection. Liver disease is a major cause of morbidity and mortality in HIV-infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30-mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations. Calculated geometric least-squares mean ratios (90% confidence intervals) for individuals with hepatic impairment versus healthy controls were 0.73 (0.50-1.06) for AUC0-∞ , 0.69 (0.51-0.93) for Cmax , 1.40 (0.80-2.46) for unbound concentration (CU) 2 hours postdose, 1.55 (0.82-2.94) for CU at 24 hours, 2.14 (1.57-2.90) for unbound fraction (FU) at 2 hours, and 1.90 (1.14-3.18) for FU at 24 hours. Adverse events (AEs) occurred in 2 individuals with hepatic impairment and 3 healthy controls and were grade 1/2 in severity. No participant discontinued because of AEs. Increased FU resulted in a modest decrease in total plasma exposure not considered clinically relevant. We conclude that cabotegravir may be administered without dose adjustment in patients with mild to moderate hepatic impairment.

Keywords: cabotegravir; hepatic impairment; pharmacokinetics; protein binding.

Conflict of interest statement

J.S.B.S., S.L.F., and K.K.B. are currently employed by GlaxoSmithKline. Y.L. and Z.Z. are employees of PAREXEL International. Z.Z. received grant support from ViiV Healthcare for statistical analysis. A.R.T., C.T., W.R.S., and P.P. are currently employed by ViiV Healthcare and are shareholders in GlaxoSmithKline.

© 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean ± standard deviation of (A) total cabotegravir plasma concentrations from 0 to 180 hours after dosing and inset, highlighting 0 to 24 hours, and (B) mean unbound cabotegravir plasma concentrations 2 and 24 hours after dosing.
Figure 2
Figure 2
Scatterplot of unbound plasma cabotegravir fraction versus serum albumin concentration at 2 and 24 hours.

References

    1. Margolis DA, Brinson CC, Smith GH, et al; LAI116482 study team . Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral‐naive adults with HIV‐1 infection (LATTE): a randomised, phase 2b, dose‐ranging trial. Lancet Infect Dis. 2015;15(10):1145–1155.
    1. Margolis DA, Gonzalez‐Garcia J, Stellbrink HJ, et al. Long‐acting intramuscular cabotegravir and rilpivirine in adults with HIV‐1 infection (LATTE‐2): 96‐week results of a randomised, open‐label, phase 2b, non‐inferiority trial. Lancet. 2017;390(10101):1499–1510.
    1. Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long‐acting cabotegravir injections in HIV‐uninfected men (ECLAIR): a multicentre, double‐blind, randomised, placebo‐controlled, phase 2a trial. Lancet HIV. 2017;4(8):e331–e340.
    1. Spreen W, Ford SL, Chen S, et al. GSK1265744 pharmacokinetics in plasma and tissue after single‐dose long‐acting injectable administration in healthy subjects. J Acquir Immune Defic Syndr. 2014;67(5):481–486.
    1. Ford SL, Sutton K, Lou Y, et al. Effect of rifampin on the single‐dose pharmacokinetics of oral cabotegravir in healthy subjects. Antimicrob Agents Chemother. 2017;61(10):e00487–17.
    1. Spreen W, Min S, Ford SL, et al. Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin Trials. 2013;14(5):192–203.
    1. Bowers GD, Culp A, Reese MJ, et al. Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans. Xenobiotica. 2016;46(2):147–162.
    1. World Health Organization . Global hepatitis report, 2017. . Accessed August 2, 2018.
    1. Price JC, Thio CL. Liver disease in the HIV‐infected individual. Clin Gastroenterol Hepatol. 2010;8(12):1002–1012.
    1. Podany AT, Scarsi KK, Fletcher CV. Comparative clinical pharmacokinetics and pharmacodynamics of HIV‐1 integrase strand transfer inhibitors. Clin Pharmacokinet. 2017;56(1):25–40.
    1. Margolis DA, Boffito M. Long‐acting antiviral agents for HIV treatment. Curr Opin HIV AIDS. 2015;10(4):246–252.
    1. Arroyo V, Garcia‐Martinez R, Salvatella X. Human serum albumin, systemic inflammation, and cirrhosis. J Hepatol. 2014;61(2):396–407.
    1. Greenblatt DJ, Sellers EM, Koch‐Weser J. Importance of protein binding for the interpretation of serum or plasma drug concentrations. J Clin Pharmacol. 1982;22(5‐6):259–263.
    1. Easterbrook P, Johnson C, Figueroa C, Baggaley R. HIV and hepatitis testing: global progress, challenges, and future directions. AIDS Rev. 2016;18(1):3–14.
    1. Tafesh ZH, Verna EC. Managing nonalcoholic fatty liver disease in patients living with HIV. Curr Opin Infect Dis. 2017;30(1):12–20.
    1. Furlan V, Demirdjian S, Bourdon O, Magdalou J, Taburet AM. Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther. 1999;289(2):1169–1175.
    1. Bernardi M, Maggioli C, Zaccherini G. Human albumin in the management of complications of liver cirrhosis. Crit Care. 2012;16(2):211.
    1. Song IH, Borland J, Savina PM, et al. Pharmacokinetics of single‐dose dolutegravir in HIV‐seronegative subjects with moderate hepatic impairment compared to healthy matched controls. Clin Pharmacol Drug Develop. 2013;2(4):342–348.
    1. Castellino S, Moss L, Wagner D, et al. Metabolism, excretion, and mass balance of the HIV‐1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother. 2013;57(8):3536–3546.
    1. Johns BA, Kawasuji T, Weatherhead JG, et al. Carbamoyl pyridone HIV‐1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J Med Chem. 2013;56(14):5901–5916.

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