Drug interaction profile for GSK2248761, a next generation non‐nucleoside reverse transcriptase inhibitor

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In healthy subjects, GSK2248761 was shown to be safe and well tolerated with single doses up to 1200 mg once daily and with multiple doses up to 800 mg once daily for 7 days. Furthermore, a phase IIa monotherapy study demonstrated that GSK2248761 30 to 800 mg once daily for 7 days was well tolerated in HIV‐1–infected subjects and that doses ≥100 mg once daily were associated with antiviral activity (∼1.8 log10 copies ml−1). However, the potential for drug interactions with co‐administration of GSK2248761 and other antiretroviral medications or supportive medications is not known. WHAT THIS STUDY ADDS • These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated. In addition, these studies indicate that few dosage modifications would be necessary if GSK2248761 were to be administered with most antiretroviral therapies or supportive medications. AIM To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non‐nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV‐1 infection. METHODS A series of phase I drug interaction studies was conducted. RESULTS GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration–time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co‐administration of GSK2248761. Plasma raltegravir AUC(0,τ) and Cmax increased by 18% with no change in Cτ when raltegravir was co‐administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), Cmax and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and Cmax increased following co‐administration with GSK2248761, with the largest changes observed for simvastatin (3.7‐fold and 4.3‐fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co‐administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co‐administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25‐ to ≤2‐fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co‐administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug‐related AEs, and no treatment‐related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings. CONCLUSIONS These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.

Transgender women, hormonal therapy and HIV treatment: a comprehensive review of the literature and recommendations for best practices

“…These were reviewed for relevance, resulting in identification of 26 peer-reviewed articles, of which 8 were reviews [73,75–81]. Of the remaining 17 articles, one involved an ART agent no longer in use [82] and one was for an investigational drug [83]. The remaining 16 articles were used in this review [84–99].…”

Non‐nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability

“…GSK 2248761 is a weak CYP3A4 and CYP2D6 inhibitor [112]. In a clinical study designed to evaluate potential interactions of this drug with antiretroviral therapies or supportive therapies used in patients with HIV-1 infection, decreased plasma levels of lopinavir and increased plasma levels of simvastatin were observed when these drugs were administered with GSK 2248761 [113]. In February 2011, ViiV Healthcare announced that the FDA had placed a hold on its development, due to four reports of seizures as part of a clinical trial involving treatment-experienced patients, and it is unclear if or when development will continue [114].…”

Unexpected Finding of Delayed-Onset Seizures in HIV-Positive, Treatment-Experienced Subjects in the Phase Iib Evaluation of Fosdevirine (Gsk2248761)

“…The available data suggest that the development of seizures in treatment-experienced subjects with HIV receiving FDV in combination with DRV/r and RAL for ≥4 weeks was likely related to treatment with FDV. In a clinical drug interaction study, plasma FDV AUC 0-t , C max and C t increased 41%, 34% and 58%, respectively, and DRV/r exposures were unchanged when repeat doses of DRV/r 600 mg/100 mg twice daily were coadministered with FDV 100 mg once daily [3]. In addition, FDV levels were not appreciably higher in seizure subjects or the SONNET study compared with the SIGNET study.…”