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Rilpivirine Half-Life Lower in Real-World Cohort Than Phase 3 Trials
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17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
Population pharmacokinetic (PK) analysis of a 260-person group in France determined that rilpivirine half-life was substantially lower than reported in phase 3 trials of single-tablet rilpivirine/tenofovir/emtricitabine (19 versus 45 hours) [1]. Apparent oral clearance (CL/F) was significantly lower in people with body mass index (BMI) at or above 25 kg/m(2).
Coformulated rilpivirine, tenofovir, and emtricitabine (Complera) is licensed for once-daily dosing based on a rilpivirine terminal half-life (t1/2) of approximately 45 hours. French investigators conducted this study to determine rilpivirine population PKs in people taking Complera in practice. The researchers collected rilpivirine plasma concentrations from routine therapeutic drug monitoring, which French authorities recommend for rilpivirine. They developed and tested one- and two-compartment models incorporating age, gender, body mass index, and several other relevant variables. The French team used stepwise covariate model procedures to develop a covariate model and tested performance of the final model using standard goodness-of-fit plots.
The analysis involved 695 rilpivirine plasma concentrations from 260 people, 223 of whom (86%) took another regimen before Complera. Seventy people (27%) were women, median age stood at 46 years, median body mass index at 23.7 kg/m(2), and median viral load at 40 copies.
A two-compartment model best described rilpivirine PKs, with wide interindividual variability in PK parameters, particularly for V2/F and V3/F (apparent volume of the central compartment and the second compartment). Log linear regression determined a t1/2 of 18.7 hours. t1/2 for underweight/normal weight people was 19.9 hours. Apparent oral clearance (CL/F) proved significantly lower in overweight/obese people than in those with BMI below 25 kg/m(2) (8.1 versus 9.7 L/h (P < 0.01).
The researchers suggested the lower half-life in their study than in phase 3 trials (approximately 19 versus 45 hours) could reflect differences in the study populations, including differences in pathophysiology, comedications, or antiretroviral adherence. They plan to develop a pharmacokinetic/pharmacodynamic model "to establish concentrations-response relationships as a first basis for treatment optimization."
Reference
1. Neant N, Peytavin G, Gattacceca F, et al. Population pharmacokinetics of rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/ tenofovir/emtricitabine. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract P67.
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