Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Abstract

Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval ( No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.

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

“…However, another study reported lower ETR concentrations than those reported here (12). Etravirine is metabolized by CYP2C9 and CYP2C19, each of which has been shown to be inhibited by S/GSK1265744 to a small extent in vitro.…”

“…However, a case series of four patients reporting virologic failure while receiving ETR and RAL showed significant decreases in trough concentrations of RAL (13). It is unclear if these case reports represented induction of UGT1A1, poor absorption, or the well-described large magnitude of intersubject PK variability with RAL (12)(13)(14)(15). This study demonstrated that coadministration of S/GSK1265744 and ETR had no effect on the PK of S/GSK1265744.…”

“…As DTG is metabolized via UDP-glucuronyltransferase 1A1 (UGT1A1; major metabolic pathway) and CYP3A4 (minor metabolic pathway), ETR induction of UGT1A1 has been suggested to be partially responsible for the reduction in DTG exposure (11). Raltegravir also is metabolized via UGT1A1, but coadministration of ETR and RAL in healthy subjects reduced the AUC from 0 to 12 h (AUC 0 -12 ) by 10% (geometric mean ratio, 0.90; 90% CI, 0.68 to 1.18) (12). Although the wide variation in the CIs suggests significant interindividual variability, this decrease was considered not to be clinically significant (12).…”

“…Raltegravir also is metabolized via UGT1A1, but coadministration of ETR and RAL in healthy subjects reduced the AUC from 0 to 12 h (AUC 0 -12 ) by 10% (geometric mean ratio, 0.90; 90% CI, 0.68 to 1.18) (12). Although the wide variation in the CIs suggests significant interindividual variability, this decrease was considered not to be clinically significant (12). However, a case series of four patients reporting virologic failure while receiving ETR and RAL showed significant decreases in trough concentrations of RAL (13).…”

Canadian Consensus Guidelines for the Optimal Use of Etravirine in the Treatment of HIV‐Infected Adults

“…No dose adjustment of either etravirine or raltegravir is required when coadministered, based on pharmacokinetic data (75). Favourable clinical results are available for a single patient using a regimen that includes both etravirine and raltegravir in combination with other agents (76).…”