Abstracts

To investigate the effects of Microgynon 30[reg]("COC"; 30 mcg ethinylestradiol+150 mcg levonorgestrel) upon the pharmacokinetics (PK) and tolerability of lamotrigine and of any effect of lamotrigine upon the PK of the COC. Sixteen healthy young female subjects completed this open-label study. Day 1 was defined as the first day of the COC after enrollment into the study. Subjects took the COC once daily for 21 days, followed by a 7 day pill-free period. A PK profile of the COC components was performed on Day 21. After a 7 day pill-free interval, subjects restarted the COC on Day 29 and commenced titration of lamotrigine up to 300 mg/day. On Day 105 of the study, when subjects had received lamotrigine 300 mg for 35 days and were on Day 21 of the COC cycle, PK profiling for the COC components and lamotrigine was performed. Subjects discontinued the COC on Day 105, but continued with 300 mg lamotrigine for a further 3 weeks. On Day 126, PK profiling for lamotrigine was performed. A 25% change in the PK of lamotrigine and a 30% change in the PK of the COC components were determined a [italic]priori[/italic] as being clinically meaningful effects. Predose PK samples were also collected during the first week after discontinuation of the COC. Additional blood samples were taken on Days 20-22 and Days 104-106 for determination of progesterone concentrations. (a) the COC had a clinically relevant effect on the pharmacokinetics of lamotrigine (on average, AUC(0-24) decreased 52% and Cmax decreased by 39% in the presence of the COC); (b) lamotrigine had no effect on the pharmacokinetics of the ethinylestradiol component of the COC; (c) lamotrigine had a modest effect on the PK of the levonorgestrel component of the COC (on average, AUC(0-24) decreased 19% and Cmax decreased by 12% in the presence of lamotrigine) which is unlikely to be of clinical relevance; and (d) Relative to the COC co-administration period, predose serum lamotrigine concentrations were, on average, 27%, 63% and 116% higher on the 3rd, 5th and 7th days, respectively, of the first week after COC withdrawal. A lack of change in progesterone levels between Days 20-22 and Days 104-106 is supportive of maintenance of the COC pill efficacy during co-administration with lamotrigine. In general, lamotrigine was well-tolerated at doses of up to 300 mg in healthy young females when co-administered with the COC. Systemic lamtorigine exposures in the presence of the COC pill were found, on average, to be approximately 50% of exposures in the absence of the COC pill. This interaction may result in a change in the efficacy of lamotrigine, particularly in women on a stable lamotrigine dose who start the COC. In contrast, lamotrigine appears to have no clinically relevant effect on the PK of the COC pill components.