Altered pharmacokinetics of combined oral contraceptives in obesity — multistudy assessment

Dandan Luo, Carolyn L. Westhoff, Alison Edelman, Melissa Natavio, Frank Z. Stanczyk, William J. Jusko

Research output: Contribution to journalArticle

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 (K 0 ), 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 (V 1 , p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V 2 , p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V 1 , CLd and V 2 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.

Original languageEnglish (US)
JournalContraception
DOIs
StatePublished - Jan 1 2019

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Contraceptives, Oral, Combined
Pharmacokinetics
Obesity
Levonorgestrel
Body Mass Index
Body Surface Area
Contraceptive Agents
Weights and Measures
Area Under Curve
Ethinyl Estradiol
Oral Contraceptives
levonorgestrel drug combination ethinyl estradiol
Half-Life

Keywords

  • Clearance
  • Combined oral contraceptives
  • Obesity
  • Pharmacokinetics
  • Volume of distribution

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Altered pharmacokinetics of combined oral contraceptives in obesity — multistudy assessment. / Luo, Dandan; Westhoff, Carolyn L.; Edelman, Alison; Natavio, Melissa; Stanczyk, Frank Z.; Jusko, William J.

In: Contraception, 01.01.2019.

Research output: Contribution to journalArticle

Luo, Dandan ; Westhoff, Carolyn L. ; Edelman, Alison ; Natavio, Melissa ; Stanczyk, Frank Z. ; Jusko, William J. / Altered pharmacokinetics of combined oral contraceptives in obesity — multistudy assessment. In: Contraception. 2019.
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AU - Stanczyk, Frank Z.

AU - Jusko, William J.

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AB - 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 (K 0 ), 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 (V 1 , p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V 2 , p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V 1 , CLd and V 2 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.

KW - Clearance

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KW - Pharmacokinetics

KW - Volume of distribution

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