Effects of Etravirine on the Pharmacokinetics of the Integrase Inhibitor S/GSK1265744

Abstract

HIV integrase inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and crossresistance have been observed. The nonnucleoside reverse transcriptase inhibitor etravirine (ETR) may be used in combination with integrase inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational integrase inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.T he emergence of the HIV integrase inhibitor (INI) class has expanded treatment and regimen sequencing options for patients with HIV. Although these agents have demonstrated excellent potency with favorable safety profiles, treatment-emergent resistance has been observed in patients failing regimens containing the INI raltegravir (RAL) (1, 2). Furthermore, cross-resistance between RAL and the investigational agent elvitegravir has also been reported (3). Therefore, there is a need for newer INIs with higher genetic barriers to resistance and a lower risk of crossresistance. S/GSK1265744 is an INI selected for clinical development as a long-acting parenteral based on (i) a potential for a higher genetic barrier to resistance demonstrated through in vitro testing and (ii) a pharmacokinetic (PK) profile allowing low-dose, oral, once-daily dosing or parenteral once-monthly dosing (or longer) without the need for coadministration with a cytochrome P4503A (CYP3A) isozyme inhibitor such as ritonavir (4-6).Etravirine (ETR) is a nonnucleoside reverse transcriptase inhibitor and an inducer of CYP3A enzymes (7) which may be involved in the clearance of some INIs. Since ETR has the potential to reduce concentrations of INIs, an assessment of the potential drug interaction between S/GSK1265744 and ETR was warranted. As ETR is predominantly metabolized by CYP enzymes and as S/GSK...

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.…”

“…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.…”

Formulation and pharmacology of long-acting cabotegravir

“…A clinical drug-interaction study with repeat doses of etravirine was conducted to assess the impact of CYP450 induction on cabotegravir disposition [21]. CYP-mediated metabolism of cabotegravir is expected to be minimal, as evidenced by the lack of effect on cabotegravir pharmacokinetic parameters when co-administered with repeat doses of etravirine, a known CYP3A inducer in 12 healthy volunteers.…”

Lack of Pharmacokinetic Interaction between Rilpivirine and Integrase Inhibitors Dolutegravir and GSK1265744

“…Preliminary findings suggest that GSK1265744 is primarily metabolized via UGT, with low potential for drug interactions as a perpetrator or victim. Coadministration with etravirine (a CYP3A inducer and an inhibitor of CYP2C9, CYP2C19, and Pgp) did not affect the concentrations of GSK1265744 in plasma (7).…”