Altered pharmacokinetics of combined oral contraceptives in obesity - multistudy assessment

The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women.

We pooled and reanalyzed data from 89 women with different body mass index (BMI) categories from four clinical studies. The LNG and ethinyl estradiol (EE) PKs were analyzed utilizing a zero-order absorption (K₀), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA).

Increasing of body habitus metrics is correlated with decreasing C_max (p<.0001) and AUC_τ (p<.05) for both LNG and EE, but no correlation was found for C_min (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V₁, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V₂, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V₁, CLd and V₂ also increased (p<.0001) in obese subjects. The half-life and steady-state volume were greater among obese women (p<.0001) for both LNG and EE. LNG and EE PK parameters correlated well (p≤.006 for all), indicating that individual subject physiology affected both drugs similarly.

The primary effects of obesity on LNG and EE were a modest increase in CL and a marked increase in distribution parameters. We observed no obesity-related differences in trough LNG and EE concentrations.

This population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (C_max and AUC_τ); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives.