title: Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting.
abstract: OBJECTIVE
  The human immundeficiency virus (HIV) protease inhibitor atazanavir is often used in once-daily observed therapy of methadone substituted former opiate drug users. We performed a matched-pairs analysis on 24 patients (12 men/women) taking atazanavir/ritonavir 300/100 mg daily plus reverse transcriptase inhibitors, with (n = 12) or without (n = 12) methadone co-administration.
  
  
  METHODS
  Twenty-four-hour pharmacokinetic profiles of atazanavir/ritonavir were assessed at steady-state and measured by liquid chromatography-tandem mass spectrometry. The geometric mean (GM, t test) minimum and maximum plasma drug concentrations (C(min), C(max)), area under the concentration-time curve (AUC), and total clearance (CL(total)) were compared between the groups of pairs, which were matched for age, sex, weight, and ethnicity.
  
  
  RESULTS
  The GM [90% confidence interval (CI)] of the atazanavir C(min), C(max), and AUC of patients taking the methadone oral solution at doses of 20-175 mg/day simultaneously with antiretroviral therapy were impaired compared to patients not taking methadone oral solution: C(min) = 315 (range 197-448) vs. 519 (279-793) ng/mL [GM ratio (GMR) = 0.61, p = 0.229]; C(max) = 1714 (1238-2262) vs. 3190 (2412-4076) ng/mL (GMR = 0.54, p = 0.018); AUC = 21,987 (15,870-29,327) vs. 35,572 (26,211-46,728) ng h/mL (GMR = 0.62, p = 0.074). Methadone dose, which is proportional to the amount of methadone oral solution (10 mg/mL), was significantly correlated to atazanavir C(max) (r (2) = 0.40, p = 0.001) and AUC (r (2) = 0.32, p = 0.006). Ritonavir pharmacokinetics was similar between the groups with C(min), C(max), and AUC GMR of 1.01, 0.80, and 0.96, respectively.
  
  
  CONCLUSIONS
  The partial decrease in atazanavir plasma concentrations in patients concomitantly taking racemic methadone oral solution in this daily observed therapy setting deserves further attention, and therapeutic drug monitoring should be considered.
authors.affiliation: HIVCENTER, Medical Clinics II, J.W.Goethe University Hospital, Frankfurt am Main, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Haberl
authors.forename: Manfred
authors.initials: M
authors.lastname: Moesch
authors.forename: Gabriele
authors.initials: G
authors.lastname: Nisius
authors.forename: Christoph
authors.initials: C
authors.lastname: Stephan
authors.forename: Markus
authors.initials: M
authors.lastname: Bickel
authors.forename: Pavel
authors.initials: P
authors.lastname: Khaykin
authors.forename: Michael
authors.initials: M
authors.lastname: Kurowski
authors.forename: Reinhard
authors.initials: R
authors.lastname: Brodt
authors.forename: Nils
authors.initials: N
authors.lastname: von Hentig
mesh_terms: D000328:Adult; D000069446:Atazanavir Sulfate; D002853:Chromatography, Liquid; D016903:Drug Monitoring; D005260:Female; D015497:HIV-1; D006801:Humans; D008297:Male; D008691:Methadone / Q000627:therapeutic use*; D009842:Oligopeptides / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019999:Pharmaceutical Solutions / Q000627:therapeutic use; D010949:Plasma / Q000821:virology; D011725:Pyridines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012996:Solutions / Q000627:therapeutic use; D014777:Virus Diseases / Q000188:drug therapy* / Q000821:virology
chemical_list: D009842:Oligopeptides; D019999:Pharmaceutical Solutions; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D012996:Solutions; D000069446:Atazanavir Sulfate; D019438:Ritonavir; D008691:Methadone