Bioavailability of etravirine 200mg administered as a single 200-mg tablet versus two 100-mg tablets in HIV-negative, healthy volunteers
Background: Etravirine has demonstrated activity in combination with other antiretrovirals in treatment-experienced, HIV-1-infected patients. The current formulation is a non-coated 100-mg tablet. To reduce pill burden, a 200-mg tablet was developed. Etravirine pharmacokinetics when administered as two 100-mg tablets or one 200-mg tablet, both film-coated and non-coated, were compared.
Methods: In a Phase I, open-label, randomised, 4-period crossover trial, healthy volunteers received single-dose etravirine 200mg with food in four sessions: 2x100-mg non-coated tablets (Treatment A), 2x100-mg film-coated tablets (Treatment B), 1x200-mg non-coated tablet (Treatment C), 1x200-mg film-coated tablet (Treatment D) with a washout period of ≥13 days between sessions. Pharmacokinetics of etravirine were determined over 96 hours. Safety and tolerability were also assessed.
Results: 24 volunteers (75% male, 92% White) participated. Etravirine pharmacokinetics were comparable irrespective of the formulation used.
| Pharmacokinetics of etravirine, mean (SD) | Treatment A (reference; n=24) | Treatment B (n=23) | Treatment C (n=23) | Treatment D (n=22) |
| Cmax, ng/mL | 392.2 (147.4) | 388.9 (194.1) | 425.0 (198.2) | 411.0 (175.2) |
| AUClast, ng.h/mL | 4,363 (1,983) | 4,399 (2,492) | 4,581 (2,424) | 4,589 (2,395) |
| AUC ∞ , ng.h/mL | 5,339 (3,055) | 5,248 (3,305) | 5,501 (3,384) | 5,520 (3,378) |
| LSM ratio (90% CI), % | Treatment B vs Treatment A | Treatment C vs Treatment A | Treatment D vs Treatment A | Treatment D vs Treatment C |
| Cmax | 92.11 (82.27-103.1) | 103.3 (94.42-113.0) | 99.35 (88.67-111.3) | 98.60 (88.84-109.4) |
| AUClast | 90.79 (79.62-103.5) | 97.99 (90.26-106.4) | 98.85 (89.42-109.3) | 103.8 (95.18-113.1) |
| SD = standard deviation; LSM = least square means; CI = confidence interval | ||||
All formulations were generally well tolerated. The incidence of adverse events (AEs) was similar between formulations (50-60% had at least 1 AE). All AEs occurring during the treatment period were grade 1 or 2 and resolved by the time of follow up. Headache was the most common AE, reported in 50% of subjects. No rash AEs were reported.
Conclusions: Etravirine 200-mg non-coated tablet displays comparable pharmacokinetics to two 100-mg non-coated tablets and is intended for commercialisation. Single-dose etravirine 200mg was generally safe and well tolerated, irrespective of formulation used.
T. Kakuda1, G. de Smedt2, R. Leemans3, M. Peeters2, V. Vyncke2, R. van Solingen-Ristea2, B. Woodfall2, R. Hoetelmans2
1Tibotec, Inc., Titusville, United States, 2Tibotec BVBA, Beerse, Belgium, 3Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium