Background:  TMC278 and efavirenz (EFV) share overlapping metabolic pathways, which could lead to drug-drug interactions when a switch from EFV to TMC278 is indicated. This phase I, open-label trial investigated the pharmacokinetics (PK), ex vivo antiviral activity (pharmacodynamics [PD]), safety, and tolerability of TMC278, following an EFV treatment (Tx) period, in healthy adult volunteers.

Methods: All subjects received a fixed sequence of treatments: Tx A, TMC278 25 mg once daily for 14 days, followed by a 14- to 21-day washout; Tx B, EFV 600 mg once daily for 14 days, immediately followed by Tx C, TMC278 25 mg once daily for 28 days. Twenty-four-hour PK profiles for TMC278 were determined on days 1 and 14 during Tx A and on days 1, 14, 21, and 28 during Tx C. EFV plasma concentrations were determined at regular time points during Tx B and C. Descriptive statistics are reported for the TMC278 PK parameters of all subjects receiving at least 1 dose of study drug and with available plasma concentration data. A linear mixed-effects model compared each time point in Tx C with the respective reference time point in Tx A. The total ex vivo antiviral activity in serum was measured in Tx A and C using an exploratory assay. Safety and tolerability were evaluated throughout the trial for the intent-to-treat population.

Results:  Twenty subjects (18 male) with a median (range) age of 26 (18 to 51) years received study drug; 17 subjects completed the study. At days 1, 14, and 21 of Tx C, TMC278 PK parameters were lower than in Tx A (Table). By day 28 of Tx C, TMC278 PK parameters were similar to Day 14 of Tx A, except for C_min. Plasma concentrations of EFV were <100 ng/mL (quantification limit) by 7 days after Tx B ended. In the PD analysis, at each time point in Tx C, the ex vivo antiviral activity showed no significant difference from reference (based on assay variability) in ≥80% of subjects (Table). No serious adverse events (AE) occurred; all AE were grade 1 or 2.

Conclusions:  Through 28 days post-EFV intake, TMC278 PK parameters in healthy volunteers were initially lower but then returned to levels comparable with those when TMC278 was administered without prior EFV treatment, except for C_min. Ex vivo antiviral activity in serum was ≥50% of the reference range in >80% of subjects, and TMC278 was generally safe and well-tolerated throughout the study. These data support the evaluation of a treatment switch from EFV to TMC278 in HIV⁺ subjects when clinically appropriate.