Altered pharmacokinetics of combined oral contraceptives in obesity - multistudy assessment

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

Study design: 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).

Results: 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.

Conclusions: 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.

Implications: 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.