Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

Parul Patel, Zhengyu Xue, Karen S King, Laura Parham, Susan Ford, Yu Lou, Kalpana K Bakshi, Kenneth Sutton, David Margolis, Arlene R Hughes, William R Spreen, Parul Patel, Zhengyu Xue, Karen S King, Laura Parham, Susan Ford, Yu Lou, Kalpana K Bakshi, Kenneth Sutton, David Margolis, Arlene R Hughes, William R Spreen

Abstract

Background: Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.

Objectives: To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).

Methods: Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809).

Results: Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%-50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%-24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10-5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT.

Conclusions: This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
Box and whiskers plot showing the effects of predicted UGT1A1 activity on (a) steady-state cabotegravir trough concentrations in pooled data from subjects receiving oral cabotegravir 30 mg/day; and (b) maximum on-treatment Tbili from subjects receiving oral cabotegravir 10, 30 or 60 mg/day in the LATTE study (NCT01641809). Boxes represent the range between the 25th and 75th percentiles, the horizontal lines within the boxes show medians and whiskers show the 5th and 95th percentiles. Panel (a) pale closed circles, UGT1A1*1 homozygotes; dark closed circles, UGT1A1*36 carriers; plus symbols, UGT1A1*6 carriers; asterisks, UGT1A1*37 carriers.
Figure 2.
Figure 2.
Mean (±95% CI) plasma cabotegravir concentrations by visit in the LATTE-2 study among subjects receiving parenteral cabotegravir LA plus rilpivirine LA maintenance (a) every 4 weeks (400 mg cabotegravir) or (b) every 8 weeks (600 mg cabotegravir) after suppressive treatment on daily oral cabotegravir and nucleoside analogues, according to normal, reduced or low predicted UGT1A1 activity. CAB, cabotegravir.
Figure 3.
Figure 3.
Trough cabotegravir concentrations for oral versus IM administration according to predicted UGT1A1 activity in subjects from LATTE-2 (NCT02120352) for (a) IM administration every 4 weeks and (b) IM administration every 8 weeks. L, low predicted UGT1A1 activity; N, normal predicted UGT1A1 activity; R, reduced predicted UGT1A1 activity. On Day 1, oral cabotegravir trough was assessed 20–28 h after the last oral cabotegravir 30 mg dose taken at home. Boxes represent the range between the 25th and 75th percentiles, the horizontal lines within the boxes show medians and whiskers show the 5th and 95th percentiles.

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Source: PubMed

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