Effect of Ritonavir/Saquinavir on Stereoselective Pharmacokinetics of Methadone: Results of AIDS Clinical Trials Group (ACTG) 401

Abstract

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.

The Protease Inhibitor Lopinavir-Ritonavir May Produce Opiate Withdrawal in Methadone-Maintained Patients

“…One explanation for the difference in findings for this study and that by Clark et al [11] is that the mean trough methadone level (‫ע‬SD) after L/R administration for the participants in the current study who developed opiate-withdrawal symptoms was mg/L, well less than the minimum therapeutic 143.5 ‫ע‬ 16.7 trough methadone concentration of 200 mg/L. It has been suggested that the clinical consequences of the decrease in methadone levels seen in conjunction with protease inhibitor use may be mitigated by changes in protein binding and disparate effects on the 2 enantiomers of methadone [18]. However, in this instance, the significant increase in withdrawal symptoms was consistent with the observed reductions in the AUC and trough concentrations of methadone after L/R therapy.…”

“…Effective methadone maintenance treatment in persons with HIV disease requires that health care providers be aware of important drug interactions between antiretroviral medications and opioids. However, reports of reduced methadone exposure do not necessarily correlate with the need for increased doses of methadone [2,18,21]. The administration of antiretrovirals shown to induce methadone metabolism will require careful clinical assessment.…”

Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity

“…These recent investigations identified the prominent role of CYP2B6 in methadone metabolism in vitro , and the present observations may be consistent with a role for CYP2B6 in vivo . Recombinant CYP2B6 catalyzed methadone N-demethylation as effectively as CYP3A4, and moreover, unlike CYP3A4, metabolism by CYP2B6 was stereoselective (Gerber et al, 2004; Gerber et al, 2001; Kharasch et al, 2004a; Totah et al, 2007a; Totah et al, 2007b). In human liver microsomes, greater stereoselective metabolism (S>R) occurred in livers expressing high levels of CYP2B6 compared to CYP3A4, inhibition of CYPB6 caused the greatest reduction in methadone metabolism, and only CYP2B6 inhibition was stereoselective (Totah et al, 2007b).…”

Strategies to Improve Access to and Utilization of Health Care Services and Adherence to Antiretroviral Therapy Among HIV-Infected Drug Users

“…Second, drug treatment has been shown not only to reduce illicit drug use but also to improve health behaviors and HIV clinical outcomes (Palepu, Horton, Tibbetts, Meli, & Samet, 2004). Third, allowing a single medical provider to monitor both prescription and illicit drug use may reduce the occurrence of adverse drug–drug interactions, such as the known adverse effects of coadministration of methadone and many antiretroviral medications (Altice, Friedland, & Cooney, 1999; Bart et al, 2001; Beauverie, Taburet, Dessalles, Furlan, & Touzeau, 1998; Clarke, Mulcahy et al, 2002; Clarke et al, 2001a, 2001b; Gerber et al, 2001; McCance-Katz, Farber, Selwyn, & O’Connor, 2000; McCance-Katz, Rainey, Friedland, & Jatlow, 2003; Shelton et al, 2004; Stevens, Rapaport, Maroldo-Connelly, Patterson, & Bertz, 2003). Finally, integration of care is likely to decrease duplication of services and may therefore be more efficient and less costly.…”