Scientific backbone-paradigm shift from dose to exposure

E.P.S. Ng

Various combined hormonal contraceptive options have recently become available that offer different dosing regimens and alternative routes for the delivery of contraceptive hormones. NuvaRing®, the contraceptive vaginal ring, is one of these new options, and the only one that offers a once-a-month delivery system that is highly efficacious, easy to use, and delivers a low hormone dose.

Experts generally agree that women of all ages using hormonal contraceptives should use a low-dose formulation that provides the lowest possible hormone exposure. However, the dose of a given medication is not always proportional to the actual drug exposure within the body. Factors that may affect the actual systemic exposure include the dose, route of administration, and individual biologic variation. It is, therefore, systemic exposure that should be minimized, rather than the dose.

The route of administration has a significant impact on the level of hormone exposure of a given dose. This has been clearly illustrated by a pharmacokinetic comparison of the contraceptive transdermal patch, the contraceptive vaginal ring and a combined oral contraceptive (COC) in a study designed to compare overall systemic ethinylestradiol (EE) levels with the three methods. In the open-label, randomized, parallel group study, women used the vaginal ring (15 µg EE/day), the transdermal patch (20 µg EE/day), or the COC (30 µg EE/day) for 3 weeks (one cycle), after a synchronization period of 2-8 weeks. The results showed that, on average, the total monthly EE exposure with NuvaRing was 3.4 times lower compared with the transdermal patch and 2.1 times lower compared with the COC. The EE dose with NuvaRing was 50% lower than that of the COC, and correspondingly, EE exposure was half. However, while the EE dose of NuvaRing was 25% lower than the dose of the transdermal patch, it was 3.4 times lower in total monthly EE exposure. The study also showed that NuvaRing exhibited the lowest intra-patient variability and lowest daily hormonal fluctuations in serum EE levels. These results show that with NuvaRing, women will be exposed to a consistently low level of estrogen with the highest level of precision that is uniquely offered by the vaginal route of administration.

The results of the pharmacokinetic study suggest that we should change the ways in which we think about contraception. That route of administration is equally influential to dose in the determination of total hormonal exposure. And ultimately, that exposure to estrogen should be the lowest possible and not just the dose. Thus, the contraceptive vaginal ring may utilize a more optimal route of administration for hormonal contraception, one that enables low and consistent systemic exposure to EE. NuvaRing's distinctive pharmacokinetic profile is the key feature of its unique clinical profile.