 |
|
|
| |
Pharmacokinetic interaction study between TMC278,an NNRTI, and the contraceptives norethindrone plus ethinylestradiol
|
| |
| |
Reported by Jules Levin
EACS Nov 13 2009 Cologne Germany
HM Crauwels,1 RPG van Heeswijk,1 L Cornelis,1 D McNeeley,2 A Buelens,1 A Clark,3 K Boven,2 RMW Hoetelmans1
1Tibotec BVBA, Mechelen, Belgium; 2Tibotec Inc., Yardley, PA, USA; 3Johnson & Johnson, High Wycombe, UK
ABSTRACT
Objectives
TMC278 (rilpivirine), a next-generation NNRTI, has demonstrated sustained efficacy at 25 mg qd through 96 weeks in antiretroviral (ARV)-naï ve HIV-infected patients (HIV9 2008). The current study evaluated the pharmacokinetic (PK) interaction between TMC278 and the contraceptives norethindrone plus ethinylestradiol.
Methods
This was an open-label trial in 18 HIV-negative female volunteers. Participants received norethindrone 1 mg and ethinylestradiol 35 µ g orally once-daily (fixed-dose combination Ovysmen® ) for three sequential 21-day cycles, with a 7-day pill-free period in between. In the third cycle, TMC278 25 mg orally qd was co-administered on the first 15 days. All treatments were taken following breakfast. At Day 15 of the second and third cycle, steady-state 24-hour PK profiles of norethindrone, ethinylestradiol and TMC278 were assessed, as applicable. Plasma samples were analysed using validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methods. PK parameters were calculated using non-compartmental analysis. The least square means (LSM) and associated 90% confidence interval (CI) of treatment ratios were calculated based on log-transformed PK parameters (minimum plasma concentration [Cmin], maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time of administration to 24 hours after dosing [AUC24h]). Serum levels of progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined on Days 1 and 14 of the second and third cycle.
Results
As shown in Table 1, norethindrone pharmacokinetics were unaffected by co-administration of TMC278. For ethinylestradiol, Cmin and AUC24h were unaffected, and Cmax increased by 17% in the presence of TMC278. The latter is not expected to result in a clinically relevant effect on the pharmacodynamics of ethinylestradiol. Steady-state PK parameters of TMC278 in the presence of norethindrone/ethinylestradiol were within the expected range. Co-administration of TMC278 25 mg qd and norethindrone/ethinylestradiol had no marked effect on FSH, LH and progesterone serum levels. Co-administration was generally safe and well tolerated. No grade 3 or 4 adverse events (AEs) and no serious AEs were reported. There were no discontinuations due to AEs.
Conclusions
TMC278 25 mg qd can be co-administered with norethindrone/ethinylestradiol-based contraceptives without dose modifications.
|
| |
|
|
|
|
|
