Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction.
BACKGROUND
Effective antiretroviral treatment of opiate-addicted drug users with HIV infection often requires concomitant substance abuse treatment, commonly with methadone. Pharmacological interactions between antiretroviral drugs and methadone may result in opiate withdrawal or increased side effects.


OBJECTIVE
To determine if atazanavir, a once-daily protease inhibitor and moderate inhibitor of P450 CYP3A4, exhibited pharmacokinetic interactions with (R)-methadone.


METHODS
Methadone pharmacokinetic parameters were measured in 16 patients on chronic methadone therapy prior to and after 14 days of daily administration of atazanavir. Steady-state pharmacokinetic values for total, (R)- (active) and (S)- (inactive) isomers of methadone were derived from plasma concentrations versus time data. Symptoms of opiate withdrawal and excess were monitored.


RESULTS
For the active isomer (R)-methadone, the ratio of geometric means for coadministration with atazanavir relative to methadone alone were 1.03 [90% confidence interval (CI), 0.95-1.10] for the area under the concentration-time curve (AUC), 0.91 (90% CI, 0.84-1.00) for plasma maximal concentration and 1.11 (90% CI, 1.02-1.20) for plasma trough concentration. Confidence intervals for all three were within the no-effect or bioequivalence range of 0.80-1.25 for (R)-methadone. Inactive (S)-methadone was modestly reduced during atazanavir coadministration. Clinically relevant symptoms of opiate withdrawal or excess were not detected. Exposures to atazanavir were within range of previously reported values.


CONCLUSIONS
No clinically relevant pharmacokinetic interactions were found between atazanavir and methadone. Dosage adjustment need not be recommended for either methadone or atazanavir when co-administered to patients treated for opiate abuse and HIV disease.
Friedland
Gerald
G
AIDS Program, Yale School of Medicine, New Haven, Connecticut 06510, USA. Gerald.Friedland@yale.edu
Andrews
Laurie
L
Schreibman
Tanya
T
Agarwala
Sangeeta
S
Daley
Leith
L
Child
Michael
M
Shi
Julia
J
Wang
Yonghua
Y
O'Mara
Edward
E
D000328:Adult; D000069446:Atazanavir Sulfate; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008691:Methadone / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D009293:Opioid-Related Disorders / Q000097:blood* / Q000150:complications / Q000534:rehabilitation; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D008691:Methadone