No clinically relevant interactions between TMC278 and oral contraceptives (norethindrone plus ethinylestradiol)
Polly Clayden, HIV i-Base
An open label trial conducted by Crauwels and colleagues evaluated the pharmacokinetic (PK) interaction between TMC278 and norethindrone plus ethinylestradiol.
In this analysis, 18 HIV-negative volunteers received 1mg norethindrone plus ethinylestradiol 35ug (combined oral contraceptive pill, Ovysmen) once a day for three sequential 21-day cycles spaced with with 7-day intervals. TMC278 was co-administered for the first 15 days of the third cycle at a once daily dose of 25 mg. TMC278 and Ovysmen were taken within 10 minutes after breakfast.
At day 15 of the second and third cycles 24 PK profiles of norethindrone, ethinylestradiol and TMC278 were obtained. Plasma samples were analysed using validated LC-MS/MS methods, with a lower limit of quantification of 1.0 ng/mL for TMC278, 50.0 pg/mL for norethindrone and 2.0 pg/mL for ethinylestradiol. Serum levels of progesterone luteinising hormone (LH) and follicle-stimulating hormone (FSH) were determined on days 1 and 14 of the second and third cycles.
PK parameters were calculated using non-compartmental analysis. Statistical analysis compared the test treatment, Ovysmen+TMC278 to the reference, Ovysmen alone.
The women in the study were a median age of 26 years, weight 69.5kg and BMI 24.6. The majority (67%) were white.
The investigators reported no effect on norethindrone PK when co-administered with TMC278. With ethinylestriol, neither the Cmin, nor the AUC24h were affected and Cmax increased by 17% in the presence of TMC278. This increase is not expected to have a clinically relevant effect. See Table 1 for results of PK parameter ratios for norethindrone and ethinylestriol in the presence of TMC278.
Table 1: PK parameter ratios for norethindrone and ethinylestriol in the presence of TMC278
|Parameter||n/n||Norethindrone (90% CI)||Ethinylestradiol (90%
|AUC24h pg.h/mL||14/15||0.89 (0.84-0.94)||1.14 (1.10-1.19)|
|Cmax pg.h/m||15/17||0.94 (0.83-1.06)||1.17 (1.06-1.30)|
|Cmin pg.h/mL||15/17||0.99 (0.90-1.08)||1.09
Steady state PK parameters of TMC278 25mg/QD in the presence of noretindrone and ethinylestriol were comparable to values observed in previous trials of TMC278 alone. TMC278 25mg/QD had no clinically relevant effect on FSH, LH or progesterone serum levels in the presence of noretindrone and ethinylestriol.
The investigators concluded that the contraceptive efficacy of 1mg norethindrone plus ethinylestradiol 35ug is expected to be maintained in the presence of TMC278 25mg/qd without dose modifications.
Ref: Crauwels et al. Pharmacokinetic interaction study between TMC278 an NNRTI, and the contraceptives northindrone plus ethinylesradiol. Abstract PE4.3/3