title: Prolonged monitoring of ethinyl estradiol and levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives users.
abstract: BACKGROUND
  Pharmacokinetic (PK) parameters based on short sampling times (48 h or less) may contain inaccuracies due to their dependency on extrapolated values. This study was designed to measure PK parameters with greater accuracy in obese users of a low-dose oral contraceptive (OC) and to correlate drug levels with assessments of end-organ activity.
  
  
  METHODS
  Obese [body mass index (BMI) ≥30 kg/m2], ovulatory, otherwise healthy women (n=32) received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) for two cycles. EE and LNG PK parameters were characterized for 168 h at the end of Cycle 1. During cycle 2, biweekly outpatient visits were performed to assess cervical mucus, monitor ovarian activity with transvaginal ultrasound and obtain serum samples to measure EE, LNG, estradiol and progesterone levels. PK parameters were calculated and correlated with end-organ activity and compared against control samples obtained from normal and obese women sampled up to 48 h in a previous study. Standard determination of PK accuracy was performed, defined by the dependency on extrapolated values ('excess' area under the curve of 25% or less).
  
  
  RESULTS
  The mean BMI was 39.4 kg/m2 (SD 6.6) with a range of 30-64 kg/m2. Key LNG PK parameters were as follows: clearance, 0.52 L/h (SD 0.24); half-life, 65 h (SD 40); area under the curve (AUC), 232 h*ng/mL (SD 102); and time to reach steady state, 13.6 days (SD 8.4). The majority of subjects had increased ovarian activity with diameter of follicles ≥8 mm (n=25), but only seven women had follicles ≥10 mm plus cervical mucus scores ≥5. Evidence of poor end-organ suppression did not correlate with the severity of the alterations in PK. As compared to historical normal and obese controls (48-h PK sampling), clearance, half-life, AUC and time to reach steady state were found to be significantly different (p≤.05) in obese women undergoing a longer duration of PK sampling (168 h). Longer sampling also improved PK accuracy for obese women (excess AUC 20%) as compared to both normal and obese controls undergoing shorter sampling times (48 h) with excess AUCs of 25% and 50%, respectively.
  
  
  CONCLUSIONS
  Obesity results in significant alterations in OC steroid PK parameters, but the severity of these alterations did not correlate with end-organ suppression. A longer PK sampling interval (168 h vs. 48 h) improved the accuracy of PK testing.
authors.affiliation: Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR 97239, USA. edelmana@ohsu.edu
authors.forename: Alison B
authors.initials: AB
authors.lastname: Edelman
authors.forename: Ganesh
authors.initials: G
authors.lastname: Cherala
authors.forename: Myrna Y
authors.initials: MY
authors.lastname: Munar
authors.forename: Barent
authors.initials: B
authors.lastname: Dubois
authors.forename: Martha
authors.initials: M
authors.lastname: McInnis
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Jensen
mesh_terms: D000293:Adolescent; D000328:Adult; D015992:Body Mass Index; D015331:Cohort Studies; D003277:Contraceptives, Oral, Combined / Q000097:blood / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004958:Estradiol / Q000097:blood; D004997:Ethinyl Estradiol / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000097:blood / Q000493:pharmacokinetics*; D009765:Obesity / Q000378:metabolism*; D011374:Progesterone / Q000097:blood; D011446:Prospective Studies
chemical_list: D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; C072593:ethinyl estradiol, levonorgestrel drug combination; D004997:Ethinyl Estradiol; D011374:Progesterone; D004958:Estradiol; D016912:Levonorgestrel