Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401.
The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infected, methadone-using study subjects.


METHODS
A 24-hour methadone pharmacokinetic study was performed before antiretroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R- and S-methadone, but only the R-isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored.


RESULTS
Ritonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC0-24hr and 32% decrease in R-methadone area under the curve (AUC)0-24hr, and both changes were statistically significant (p =.001 for both). When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R-methadone free AUC0-24hr decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p =.129 and p =.0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required.


CONCLUSIONS
Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S-methadone. However, approximately 37% of the decrease in the total R-methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV-infected people taking methadone without routine dose adjustments.
Gerber
J G
JG
University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262, USA. John.Gerber@UCHSC.edu
Rosenkranz
S
S
Segal
Y
Y
Aberg
J
J
D'Amico
R
R
Mildvan
D
D
Gulick
R
R
Hughes
V
V
Flexner
C
C
Aweeka
F
F
Hsu
A
A
Gal
J
J
D000328:Adult; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008297:Male; D008691:Methadone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D009294:Narcotics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage* / Q000097:blood; D019258:Saquinavir / Q000008:administration & dosage* / Q000097:blood; D013237:Stereoisomerism; D015819:Substance Abuse, Intravenous / Q000150:complications / Q000534:rehabilitation
D017320:HIV Protease Inhibitors; D009294:Narcotics; D019258:Saquinavir; D019438:Ritonavir; D008691:Methadone