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Etravirine Lowers Levels of S/GSK Integrase Inhibitor, But PIs Counter Effect
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11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Etravirine, the newest nonnucleoside, significantly lowered concentrations of the investigational integrase inhibitor S/GSK1349572 in healthy adults [1]. But ritonavir-boosted lopinavir or darunavir attenuated that effect.
GlaxoSmithKline (GSK) and Shionogi investigators concluded that "S/GSK1349572 may be co-administered with etravirine without a dosage adjustment if lopinavir/ritonavir or darunavir/ritonavir is concurrently administered."
Viral loads fell 2.5 log in a 10-day trial of S/GSK1349572 monotherapy at a dose of 50 mg once daily in integrase-inhibitor-naive people [2]. S/GSK1349572 relies primarily on the UGT1A1 enzyme for metabolism, though CYP3A4 offers a secondary metabolism pathway. S/GSK1349572 has no significant effects on tenofovir or midazolam, a drug used as a probe in studies of CYP3A4 inhibition. The experimental integrase inhibitor, now in phase 2 trials, has to be taken 2 hours before or 6 hours after antacids. Tenofovir, unboosted atazanavir, and boosted atazanavir, lopinavir, and darunavir have no significant interaction with S/GSK1349572.
Shionogi and ViiV Healthcare mounted two open-label trials in healthy volunteers, the first involving 16 healthy adults who took 50 mg of S/GSK1349572 once daily for 5 days, then added 200 mg of etravirine every 12 hours with food for 14 days. No one dropped out because of side effects, and there were no clinically significant changes in lab values, vital signs, or ECGs. Headache was the most frequent problem judged to be drug related, affecting 4 people.
Researchers collected samples for plasma level measurements on the last day of each dosing period and collected additional samples for trough measures on days 8, 11, 13, and 14 of the combined-drug period. Adding etravirine lowered S/GSK1349572 area under the curve (AUC) 70%, maximum concentration (Cmax) 52%, and trough concentration 88%. The geometric least squares mean ratios (and 90% confidence intervals [CIs]) for S/GSK1349572 plus etravirine versus S/GSK1349572 alone were:
· AUC: 0.294 (90% CI 0.257 to 0.337)
· Cmax: 0.484 (90% CI 0.433 to 0.542)
· Trough: 0.121 (90% CI 0.093 to 0.157)
The second study involved 18 healthy adults who began with 50 mg of S/GSK1349572 once daily for 5 days then added either etravirine plus lopinavir/ritonavir (200/400/100 mg every 12 hours) or etravirine plus darunavir/ritonavir (200/600/100 mg every 12 hours) for 14 days. Researchers collected samples for plasma level measurements on the same days as in the first trial. Again, no one dropped out of the study because of side effects. Two people reported constipation, and 2 had headaches.
Etravirine plus lopinavir/ritonavir had no effect on S/GSK1349572 steady-state AUC, Cmax, or trough. Etravirine plus darunavir/ritonavir "modestly decreased" S/GSK1349572 AUC by 25%, Cmax by 12%, and trough by 37%. The investigators figured that the effect of etravirine plus darunavir/ritonavir on S/GSK1349572 is not clinically relevant.
The Shionogi/ViiV Healthcare team proposed that etravirine lowers exposure to S/GSK1349572 by inducing UGT1A1. The resulting shift to CYP3A4-mediated metabolism leads to lower levels of the integrase inhibitor. But adding a boosted protease inhibitor minimizes use of the CYP3A4 pathway. They concluded that S/GSK1349572 cannot be taken with etravirine unless a person is also taking lopinavir/ritonavir or darunavir/ritonavir (or perhaps another strong CYP3A4 inhibitor, though the investigators did not suggest that).
References
1. Song I, Min S, Borland J, et al. The effect of etravirine alone and with boosted protease inhibitors on the pharmacokinetics of the integrase inhibitor, S/GSK1349572. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 26.
2. Lalezari J, Sloan L, Dejesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB105.
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