Drug interaction profile of the HIV integrase inhibitor cabotegravir: assessment fromin vitrostudies and a clinical investigation with midazolam

Abstract

1. Cabotegravir (CAB; GSK1265744) is a potent HIV integrase inhibitor in clinical development as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection. 2. This work investigated if CAB was a substrate for efflux transporters, the potential for CAB to interact with drug-metabolizing enzymes and transporters to cause clinical drug interactions, and the effect of CAB on the pharmacokinetics of midazolam, a CYP3A4 probe substrate, in humans. 3. CAB is a substrate for Pgp and BCRP; however, its high intrinsic membrane permeability limits the impact of these transporters on its intestinal absorption. 4. At clinically relevant concentrations, CAB did not inhibit or induce any of the CYP or UGT enzymes evaluated in vitro and had no effect on the clinical pharmacokinetics of midazolam. 5. CAB is an inhibitor of OAT1 (IC50 0.81 µM) and OAT3 (IC50 0.41 µM) but did not or only weakly inhibited Pgp, BCRP, MRP2, MRP4, MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1, OCT2 or BSEP. 6. Based on regulatory guidelines and quantitative extrapolations, CAB has a low propensity to cause clinically significant drug interactions, except for coadministration with OAT1 or OAT3 substrates.

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol‐containing oral contraceptive in healthy adult women

“…The GLS mean ratios and 90% CIs for the differences in steady‐state AUC 0–τ , C max , and C τ between test (LNG/EO + CAB) and reference (LNG/EO alone) treatments were each within the limits of 0.80–1.25, confirming a lack of pharmacokinetically significant interaction between CAB and LNG or EO. These findings are consistent with in vitro and clinical drug interaction studies, which suggested that CAB has minimal interaction liability 7, 12, 13. In addition, steady‐state CAB plasma PK parameters observed in this study were comparable to historical values, suggesting that LNG/EO had no impact on CAB exposure, as expected 12, 13.…”

“…Cabotegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1 with a minor contribution by UGT 1A9 6. At clinically relevant concentrations, CAB does not inhibit or induce the major cytochrome P450 (CYP) or UGT enzymes in vitro and had no significant effect on the pharmacokinetics (PK) of midazolam, a sensitive CYP3A4 probe substrate 7.…”

Pharmacology of Antiretrovirals in the Female Genital Tract for HIV Prevention

“…With the exception of cabotegravir, these drugs appear to penetrate well to the female genital tract, although exposures are consistently lower than in colorectal tissue, consistent with higher P‐gp expression observed in vaginal tissue over colorectal tissue at mRNA level . In addition to P‐gp, cabotegravir has also been identified as a BCRP substrate; however, due to its high membrane permeability, the effect of transporters on cabotegravir transport may be clinically insignificant . Because target concentrations required for protection in the female genital tract have not been defined for the majority of these drugs, more research is needed to determine whether modulation of drug transporters could influence local tissue concentrations to a degree that plays a significant role in drug efficacy.…”

Effect of a High‐Fat Meal on the Pharmacokinetics of the HIV Integrase Inhibitor Cabotegravir

“…Cabotegravir is highly bound to serum albumin and has an in vitro protein‐adjusted 90% inhibitory concentration of 166 ng/mL . It is a class 2 compound (Biopharmaceutics Drug Disposition Classification System) exhibiting high passive permeability and low solubility . Cabotegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT)1A1 with a minor contribution by UGT1A9 to form glucuronic acid conjugates .…”

“…The primary metabolite, M1, and unchanged cabotegravir are both excreted in bile. Due high intrinsic membrane permeability, the impact of efflux transporters on intestinal absorption of cabotegravir is minimal …”