title: Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy.
abstract: OBJECTIVE
  Pharmacokinetics of norethindrone in combination oral contraceptive regimen are well described among HIV+ women treated with ritonavir-boosted protease inhibitor therapies; however, such characterization is lacking in women using progestin-only contraception. Our objective is to characterize pharmacokinetics of norethindrone in HIV+ women using ritonavir-boosted atazanavir treatment during progestin-only contraceptive regimens.
  
  
  METHODS
  An open-label, prospective, nonrandomized trial to characterize the pharmacokinetics of norethindrone in HIV+ women receiving ritonavir-boosted atazanavir (n=10; treatment group) and other antiretroviral therapy known to not alter norethindrone levels (n=17; control group) was conducted. Following informed consent, women were instructed to take a single daily fixed oral dose of 0.35 mg norethindrone and 300 mg/100 mg atazanavir/ritonavir for 22 days. On day 22, serial blood samples were collected by venous catheter at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h. Whole blood was processed to collect serum and stored at -20°C until later analysis using radioimmunoassay. Pharmacokinetic parameters were estimated using noncompartmental method.
  
  
  RESULTS
  In the treatment group, compared to the control group, an increase in area under the curve₀₋₂₄ (16.69 h*ng/mL vs. 25.20 h*ng/mL; p<.05) and maximum serum concentration (2.09 ng/mL vs. 3.19 ng/mL; p<.05), decrease (25%-40%) in apparent volume of distribution and apparent clearance, and unaltered half-life were observed.
  
  
  CONCLUSIONS
  Our findings suggest that progestin-only contraceptives, unlike combination oral contraceptives, benefit from drug-drug interaction and achieve higher levels of exposure. Further studies are needed to establish whether pharmacokinetic interaction leads to favorable clinical outcomes.
  
  
  CONCLUSIONS
  Norethindrone-based progestin-only contraceptives, unlike combination oral contraceptives, exhibit greater drug exposure when co-administered with ritonavir-boosted atazanavir regimen and thus may not warrant a category 3 designation by the World Health Organization. Prospective studies are needed to confirm whether pharmacokinetic interaction results in favorable clinical outcomes.
authors.affiliation: Oregon State University & Oregon Health Science University College of Pharmacy, Portland, OR, USA.
authors.forename: Barent N
authors.initials: BN
authors.lastname: DuBois
authors.affiliation: Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Atrio
authors.affiliation: Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.affiliation: Oregon State University & Oregon Health Science University College of Pharmacy, Portland, OR, USA; Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, USA. Electronic address: cheralag@ohsu.edu.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Cherala
mesh_terms: D000293:Adolescent; D000328:Adult; D000069446:Atazanavir Sulfate; D003280:Contraceptives, Oral, Synthetic / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006679:HIV Seropositivity / Q000097:blood / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D009640:Norethindrone / Q000097:blood / Q000493:pharmacokinetics*; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use*; D011372:Progestins / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011863:Radioimmunoassay; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D003280:Contraceptives, Oral, Synthetic; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011372:Progestins; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir; D009640:Norethindrone
keywords: Norethindrone; Pharmacokinetics; Progestin-only contraception; Ritonavir