Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting.
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.
Haberl
Annette
A
HIVCENTER, Medical Clinics II, J.W.Goethe University Hospital, Frankfurt am Main, Germany.
Moesch
Manfred
M
Nisius
Gabriele
G
Stephan
Christoph
C
Bickel
Markus
M
Khaykin
Pavel
P
Kurowski
Michael
M
Brodt
Reinhard
R
von Hentig
Nils
N
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
D009842:Oligopeptides; D019999:Pharmaceutical Solutions; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D012996:Solutions; D000069446:Atazanavir Sulfate; D019438:Ritonavir; D008691:Methadone