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

Abstract

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 C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) 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.

Trial registration: ClinicalTrials.gov NCT00920088 NCT01101893 NCT01138072 NCT01195974.

Figure 1

Mean plasma concentration vs. time on day 7 for atazanavir (ATV) 100 mg, ATV 100 mg + ritonavir (RTV) 100 mg, ATV 100 mg + GSK2248761 100 mg and ATV 100 mg + GSK2248761 800 mg. ATV (); ATV + RTV (100 mg) (); ATV + GSK2248761 (100 mg) (); ATV + GSK2248761 (800 mg) ()

Figure 2

Mean plasma concentration vs. time on day 14 for (A) tenofovir disoproxil fumarate (TDF) and (B) emtricitabine (FTC) each alone and with GSK2248761. (A) TDF (); TDF + GSK2248761 (). (B) FTC (); FTC + GSK2248761 ()

Figure 3

Mean plasma concentration vs. time for (A) GSK2248761 200 mg once daily alone and with raltegravir (RAL) 400 mg twice daily and (B) raltegravir 400 mg twice daily alone and with GSK2248761 200 mg once daily. (A) GSK2248761 (); GSK2248761 + RAL (). (B) RAL (); GSK2248761 + RAL ()

Figure 4

Mean plasma concentration vs. time for (A) simvastatin and simvastatin acid, (B) atorvastatin and ortho-hydroxy atorvastatin (inset of first 12 h post dose) and (C) rosuvastatin each alone and with GSK2248761. (A) Simvastatin (); Simvastatin + GSK2248761 (). (B) Atorvastatin (); Atorvastatin + GSK2248761 (). (C) Rosuvastatin (); Rosuvastatin + GSK2248761 ()