Obesity and efficacy of combined OCs

Obese women who use combined oral contraceptives (COCs) are at no greater risk of unintended pregnancy than women with a normal body mass index (BMI) who take the drugs, according to results of research that evaluated pharmacokinetics (PK) of levonorgestrel-containing COCs.

The study in the journal Contraception concluded that the primary effects of obesity on levonorgestrel (LNG) and ethinyl (EE) were a modest increase in oral clearance (metabolism) of the two drugs, but an appreciably greater distribution into their larger tissue mass.

However, there were no obesity-related differences in 24-hour trough LNG and EE concentrations.

Obesity increased clearance of LNG alone, likely due to lower sex hormone binding globulin (SHBG) concentrations and binding.

“The clearance of LNG and EE in combined oral contraceptives is complicated because EE induces SHBG production, which in turn decreases the clearance of LNG,” said study coordinator William Jusko, PhD, a distinguished professor of pharmaceutical sciences at the University at Buffalo, State University of New York (SUNY), who has had a long-time interest in PK of contraceptive products, as well as effects of obesity on PK of various drugs.

Dr. Jusko noticed that previously published studies of EE and LG had relatively small numbers of subjects. “I approached authors of several of these studies to see if they would share their data for a meta-analysis,” he said.

For the meta-analysis, data from 89 women with different BMI categories from four clinical studies were pooled and reanalyzed.

“Several published studies about the efficacy of oral contraceptives, particularly ‘Plan B’ LNG, are conflicting as to whether the drug is less effective in obese women,”Dr. Jusko told Contemporary OB/GYN. 

The current study examined whether there were differences in exposures of oral doses of EE and LNG in relation to body size.

“The exposures (peak and time-course of drug concentrations) were lower in the obese women, but not sufficient to offer concern about increased risk of pregnancy during use of typical and proper dosing regimens,” Dr. Jusko said. 

Due to the fact that EE and LNG have appreciable solubility in lipids (fat), increased distribution into the larger tissue mass was to be expected. “However, the metabolism of drugs in obesity can change in unpredictable ways, thus requiring definitive studies such as this one,” Dr. Jusko said.

A major strength of the analysis is that all LNG and EE assays of all included studies were performed at the same laboratory, using long-established and validated radioimmunoassay.

The PK (exposures) of drugs is an important determinant of their clinical efficacy, according to Dr. Jusko, and this study offers clarification on the phenomenon. “Still, other physiological and hormonal disturbances occur in obesity, which need further study,” he said. 

Although standard doses of the combined (EE/LNG) oral contraceptives should continue to be used in women of various body weights, “our findings may not apply to emergency contraception (Plan B) or products administered in different ways (intrauterine, patches),” Dr. Jusko said.

The study findings are also limited to COC contraceptives containing LNG and EE – not to any other combinations, progestins, or the etonogestrol implant. “Because there are interactions between LNG and EE, our findings are not relevant to EE combined with other progestins,” Dr. Jusko said.

Disclosures:

Dr. Jusko reports no relevant financial disclosures.