Scientific backbone-paradigm shift from dose to exposure

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


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.

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