title: Effect of protease inhibitors on steady-state pharmacokinetics of oral norethindrone contraception in HIV-infected women.
abstract: OBJECTIVE
  Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV-infected women.
  
  
  METHODS
  We conducted an open-label, prospective, nonrandomized trial to characterize the steady-state pharmacokinetics of serum NET in HIV-infected women receiving PI compared with a control group of HIV-infected women receiving other noninteracting drugs. After 21 days of 0.35 mg of NET ingestion once daily, serial serum samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours. The area under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal approximation.
  
  
  RESULTS
  Thirty-five women were enrolled, 2 withdrew. Sixteen women in the PI group and 17 controls completed the study. NET half-life and maximum concentration were not significantly different between the 2 groups. Minimum concentration of NET was significantly higher in the PI group (P = 0.01). The ratio of the geometric mean NET area under the curve in the PI group compared with controls was 1.5 (90% confidence interval: 1.21 to 1.86). NET serum concentrations were significantly higher in HIV-infected women taking a PI compared with controls (P = 0.004).
  
  
  CONCLUSIONS
  Coadministration of PI inhibits NET metabolism as shown by higher serum NET area under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This study supports the increased utilization of progestin-only pills in HIV-infected women receiving certain PI regimens.
authors.affiliation: *Department of Obstetrics and Gynecology; and †Laboratory of Applied Pharmacokinetics, Keck School of Medicine, University of Southern California, Los Angeles, CA; ‡Department of Pharmacy Practice, College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, OR; and §Maternal Child and Adolescent Center for Infectious Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Atrio
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.forename: Michael
authors.initials: M
authors.lastname: Neely
authors.forename: Ganesh
authors.initials: G
authors.lastname: Cherala
authors.forename: Andrea
authors.initials: A
authors.lastname: Kovacs
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mishell
mesh_terms: D000328:Adult; D003280:Contraceptives, Oral, Synthetic / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009640:Norethindrone / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D003280:Contraceptives, Oral, Synthetic; D017320:HIV Protease Inhibitors; D009640:Norethindrone
references.citation: MMWR Morb Mortal Wkly Rep. 2012 Jun 22;61(24):449-52
references.pmid: 22717514
references.citation: Contraception. 2009 Nov;80(5):412-6
references.pmid: 19835713
references.citation: Am J Obstet Gynecol. 1993 May;168(5):1400-6
references.pmid: 8498419
references.citation: Pharmacogenet Genomics. 2005 Jan;15(1):1-5
references.pmid: 15864119
references.citation: J Reprod Fertil. 1967 Apr;13(2):199-203
references.pmid: 4164525
references.citation: Curr Drug Metab. 2009 Sep;10(7):730-53
references.pmid: 19702527
references.citation: Contraception. 1990 Jul;42(1):67-96
references.pmid: 2143719
references.citation: Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007541
references.pmid: 20091638
references.citation: Br Med J. 1969 Jun 21;2(5659):730-4
references.pmid: 4182352
references.citation: Contraception. 1978 Dec;18(6):615-33
references.pmid: 750188
references.citation: Expert Opin Drug Metab Toxicol. 2013 May;9(5):559-72
references.pmid: 23425052
references.citation: J Steroid Biochem Mol Biol. 2008 May;110(1-2):56-66
references.pmid: 18356043
references.citation: Contraception. 2010 Jul;82(1):113-8
references.pmid: 20682149
references.citation: Clin Endocrinol (Oxf). 1979 Jan;10(1):29-38
references.pmid: 436304
references.citation: Ther Drug Monit. 2012 Aug;34(4):467-76
references.pmid: 22722776
references.citation: MMWR Recomm Rep. 2010 Jun 18;59(RR-4):1-86
references.pmid: 20559203
references.citation: Br Med J. 1968 May 4;2(5600):266-9
references.pmid: 4171574
references.citation: Am J Obstet Gynecol. 1971 Feb 15;109(4):531-5
references.pmid: 5100077
references.citation: Clin Pharmacokinet. 2000 Jan;38(1):41-57
references.pmid: 10668858
references.citation: Br Med J. 1967 Jun 17;2(5554):730-2
references.pmid: 4164963