Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2019 Apr;99(4):256-263.
doi: 10.1016/j.contraception.2018.12.009. Epub 2019 Jan 23.

Altered pharmacokinetics of combined oral contraceptives in obesity - multistudy assessment

Dandan Luo  1 , Carolyn L Westhoff  2 , Alison B Edelman  3 , Melissa Natavio  4 , Frank Z Stanczyk  4 , William J Jusko  5
Affiliations
Meta-Analysis

Altered pharmacokinetics of combined oral contraceptives in obesity - multistudy assessment

Dandan Luo et al. Contraception. 2019 Apr.

Abstract

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 Cmax (p<.0001) and AUCτ (p<.05) for both LNG and EE, but no correlation was found for Cmin (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 (Cmax and AUCτ); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives.

Keywords: Clearance; Combined oral contraceptives; Obesity; Pharmacokinetics; Volume of distribution.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

William J Jusko has been a recent consultant for Novartis, Boehringer Ingelheim, Reveragen, and Bayer Healthcare Products. A. Edelman: consultant for World Health Organization, Gynuity Health Projects, Genzyme, Agile Therapeutics, and HRAPharma. Nexplanon trainer for Merck and the recipient of a Merck-investigator initiated grant. Author for UptoDate (Royalties received). C Westhoff: consultant for Merck and Bayer, Agile Therapeutics. No conflicts of interest to disclose for the other authors.

Figures

Figure 1.
Figure 1.
General model fittings of serum levonorgestrel (LNG) and ethinyl estradiol (EE) concentrations versus time. (A) LNG 150 mcg [13, 16] or 100 mcg PK profiles[14, 15]; (B) EE 30 mcg [13, 16] or 20 mcg PK profiles [14, 15]. Population predicted (PRED) profiles are shown as black lines. Subjects with different extent of obesity are shown using different colors and shapes. Subjects with BMI 18.5–24.9 kg/m2 are considered normal, BMI 25.0–29.9 kg/m2 are overweight, BMI 30.0–39.9 kg/m2 are obese, and BMI greater than 40.0 kg/m2 are extremely obese.
Figure 2.
Figure 2.
LNG PK parameters in relation to body habitus metrics. (A) NCA parameters of individual subjects from 4 studies [–16] in relation to weight, BMI, or BSA. (B) Two-compartment model parameters of individual subjects from 4 studies [–16] in relation to weight, BMI, or BSA. Regression parameters and statistics are listed in Supplemental Table S-3. All linear regressions had slopes significantly different from 0 (p<0.05 or less), except for Cmin.
Figure 3.
Figure 3.
EE PK parameters in relation to body habitus metrics. (A) NCA parameters for individual subjects from 4 studies [–16] in relation to weight, BMI, or BSA. (B) Two-compartment model parameters for individual subjects from 4 studies [–16] in relation to weight, BMI, or BSA. Regression parameters and statistics are listed in Supplemental Table S-4. All linear regressions had slopes significantly different from 0 (p<0.05 or less), except for Ko and Cmin.
Figure 4.
Figure 4.
Correlation of LNG and EE PK parameters from 4 studies [–16]. Lines denote linear regressions with force to 0 intercepts. Regression parameters and statistics are listed in Supplemental Table S-5. All correlations are highly significant (p<0.05 or less).
Figure 5.
Figure 5.
Relationship between AUCT and Cmin values for LNG (left) and EE (right panel) from 4 studies [–16]. The lines depict regressions with a force through 0. Slopes and correlations are listed on the graphs.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Centers for Disease Control and Prevention. http://wwwcdcgov/nchs/hus/contents2013.
    1. Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States: 1982–2002. Adv Data. 2004:1–36. - PubMed
    1. Skouby SO. Contraceptive use and behavior in the 21st century: a comprehensive study across five European countries. Eur J Contracept Reprod Health Care. 2004;9:57–68. - PubMed
    1. Holt VL, Scholes D, Wicklund KG, Cushing-Haugen KL, Daling JR. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol. 2005;105:46–52. - PubMed
    1. Holt VL, Cushing-Haugen KL, Daling JR. Body weight and risk of oral contraceptive failure. Obstet Gynecol. 2002;99:820–7. - PubMed

Publication types

MeSH terms