Pharmacokinetics of three bioequivalent norethindrone/mestranol-50ug and three norethindrone/ethinyl estradiol-35ug oc formulations: Are “low-dose” pills really lower?

Abstract

We have examined the pharmacokinetic parameters derived from the analysis of plasma ethinyl estradiol (EE) and norethindrone levels after administration of a single dose of three bioequivalent norethindrone-lmg/mestranol (ME)-50ug formulations (Ortho-Novum R 1 50 , Norinyl R 1 50 and Norcept-M R 1 50 ) and three norethindrone-lmg/ethinyl estradiol-35ug formulations (Ortho-Novum 1 35 R, Norinyl R 1 35 , Norcept-E R 1 35 ) in a randomized crossover design involving 24 women for the 35ug and 27 women for the 50ug agents. Differences between the AUC-EE of pairs from the same manufacturer (1 + 35 and 1 + 50) were not significantly different, indicating that 50ug of mestranol was equivalent to 35ug ethinyl estradiol with respect to this pharmacokinetic parameter. The C max values were also similar. Inter-individual coefficients of variation (C.V.) for the AUC-EE were 47% and 57% for the 1 + 35 and 1 + 50 agents, respectively. Intra-individual C.V.s were 41% and 42%, respectively. For norethindrone, the AUC was larger with the 1 + 50 formulations than with the 1 + 35 group (87.9 vs. 72.8 pg hr/ml). Additionally, the C max values were larger for the 1 50 group (17.7 vs. 14.0). Since the amount of norethindrone in the two dosage groups was the same, this difference in the pharmacokinetics between the 35ug EE and the 50ug ME formulations remains unexplained. The inter-individual C.V. averaged 56% for both dosage groups. The intra-individual C.V.s were 17% and 46% for the 1 + 35 and 1 + 50 groups, respectively. The large variation in blood levels of ethinyl estradiol and norethindrone between and within individuals may overshadow clinical differences attributable to differences in dosage.