title: Correcting oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial.
abstract: OBJECTIVE
  To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use.
  
  
  METHODS
  Obese [body mass index (BMI)≥30 kg/m(2)], ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to the following: continuous cycling (CC, a dose neutral arm using the same OC with no hormone-free interval) or increased dose (ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically). During Cycles 2, 3 and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞) and time to steady state as well as pharmacodynamics. These key PK parameters were calculated and compared within groups between baseline and treatment cycles.
  
  
  RESULTS
  A total of 31 women enrolled and completed the study (CC group, n=16; ID group, n=15). Demographics were similar between groups [mean BMI: CC, 38 kg/m(2) (S.D. 5.1); ID, 41 kg/m(2) (S.D. 7.6)]. At baseline, the key LNG PK parameters were no different between groups; average time to reach steady state was 12 days in both groups; Cmax were CC: 3.82±1.28 ng/mL and ID: 3.13±0.87 ng/mL; and AUC0-∞ were CC: 267±115 h ng/mL and ID: 199±75 h ng/mL. Following randomization, the CC group maintained steady-state serum levels whereas the ID group had a significantly higher Cmax (p<.001) but again required 12 days to achieve steady state. However, AUC was not significantly different between CC (412±255 h ng/mL) and ID (283±130 h ng/mL). Forty-five percent (14/31) of the study population had evidence of an active follicle-like structure prior to randomization and afterwards this decreased to 9% (3/31).
  
  
  CONCLUSIONS
  Both increasing the OC dose and continuous dosing appear to counteract the impact of obesity on key OC PK parameters.
  
  
  CONCLUSIONS
  Obesity adversely affects the pharmacokinetics of very low dose OC pills. Although the impact of these changes on OC efficacy is still under debate, PK parameters can be normalized in obese users by continuous dosing or increasing to a low-dose pill.
authors: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: edelmana@ohsu.edu.
authors: Alison B
authors: AB
authors: Edelman
authors: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97239, USA; Oregon State University and Oregon Health & Science University College of Pharmacy, Portland, OR 97239, USA.
authors: Ganesh
authors: G
authors: Cherala
authors: Oregon State University and Oregon Health & Science University College of Pharmacy, Portland, OR 97239, USA.
authors: Myrna Y
authors: MY
authors: Munar
authors: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Martha
authors: M
authors: McInnis
authors: Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Frank Z
authors: FZ
authors: Stanczyk
authors: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Jeffrey T
authors: JT
authors: Jensen
mesh_terms: D000328:Adult; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009765:Obesity / Q000097:blood*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D003277:Contraceptives, Oral, Combined; D004997:Ethinyl Estradiol; D016912:Levonorgestrel
keywords: BMI; Continuous dosing; Drug levels; Hormonal contraception