Effect of intrinsic and extrinsic factors on the pharmacokinetics of TMC278 in antiretroviral-naïve, HIV-1-infected patients in ECHO and THRIVE

The current analysis examined the pharmacokinetics of the next-generation investigational NNRTI, TMC278, in the pooled double-blind Phase III trials ECHO (NCT00540449) and THRIVE (NCT00543725) in ARV-naïve, HIV-1-infected adults [1] and explored the influence of intrinsic and extrinsic factors on the pharmacokinetic parameters.

A total of 1368 patients (24% female) were randomised (1:1) to either TMC278 25 mg q.d. or EFV 600 mg q.d., in combination with TDF/FTC (ECHO) or a choice of either TDF/FTC or AZT/3TC or ABC/3TC (THRIVE). The pharmacokinetics of TMC278 were best described by a two-compartment disposition model in which absorption was characterised by a lag time followed by a sequential zero- and first-order process. Individual values for TMC278 trough plasma concentrations (C_trough) and area under the plasma concentration-time profile over the dosing interval (AUC_24h) were estimated from sparse pharmacokinetic sampling in 679 patients in the TMC278 treatment group (8 samples/48 weeks/patient) using the population pharmacokinetic model. In addition, the potential relationship between selected covariates and the TMC278 apparent oral clearance was evaluated.

There were no differences in the pharmacokinetics of TMC278 between the two trials. The mean (SD) TMC278 C_trough and AUC_24h for the pooled trials were 80.0 (36.5) ng/mL and 2397 (1032) ng*h/mL, respectively. The apparent oral clearance of TMC278 was estimated to be 11.8 L/h (inter-individual variability 39%) and the apparent volume of the central compartment was estimated to be 152 L (inter-individual variability 117%). The exposure to TMC278 was not influenced by N(t)RTI background medication, age, bodyweight, BMI, estimated glomerular filtration rate and hepatitis B and/or C co-infection status. Gender and race had a statistically significant effect on the TMC278 apparent oral clearance, resulting in a slightly lower apparent oral clearance (and thus higher AUC_24h) in females (13.6% lower clearance), and in Asian patients (17.2% lower clearance). These small effects had little impact on the overall inter-individual variability in apparent oral clearance and are considered not to be of clinical relevance.

A population pharmacokinetic model was developed, describing the pharmacokinetics of TMC278 in ARV-naïve, HIV-1-infected adults receiving TMC278 25 mg q.d. No covariates with a clinically relevant effect on exposure to TMC278 were identified.