Interaction of Methadone with Didanosine and Stavudine

Abstract

For opiate-dependent injection drug users infected with HIV, methadone therapy may facilitate adherence to complex highly active antiretroviral therapy (HAART) regimens. Current HAART regimens include one or more nucleoside analogues. We investigated the effects of methadone on the pharmacokinetics of the tablet formulation of didanosine (ddI) and of stavudine (d4T) in 17 study subjects on stable methadone therapy and in 10 untreated controls. Methadone treatment reduced the measured areas under the time-concentration curve (AUC0-6) by 63% for ddI (p =.04) and by 25% for d4T (p =.005) and the extrapolated AUCs for the full dosing interval (AUC0-12) by 57% for ddI (p =.11) and by 23% for d4T (p =. 02). Peak drug concentrations (Cmax) were reduced by 66% (p =.007) and 44% (p =.001) for ddI and d4T, respectively. The effects on AUC and Cmax appeared to result primarily from decreases in bioavailability. Methadone also delayed drug absorption. Trough levels for methadone did not differ significantly from those in historical controls, suggesting that ddI and d4T did not substantially alter methadone disposition. The results suggest that larger doses of the tablet formulation or an alternate formulation may be needed when didanosine is given to study subjects treated with methadone.

Psychopharmacologic treatment of patients with HIV/AIDS

“…An in vitro study revealed that indinavir and saquinavir may inhibit methadone metabolism, although this same study showed ritonavir to be a much more potent inhibitor, which is contrary to the in vivo data mentioned previously [71]. Zidovudine, stavudine, and didanosine do not alter methadone levels; however, methadone may increase exposure to zidovudine (52% increase in area under the curve) [72] and may decrease exposure to didanosine (63% decrease in area under the curve) and stavudine (25% decrease in area under the curve) [73].…”

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

“…Several antiretroviral agents have been shown to have interactions of potential clinical significance with methadone [1][2][3][4][5], the opiate therapy most frequently used for the treatment of heroin addiction and currently the substance abuse pharmacotherapy of choice for opioid-addicted patients with HIV infection.…”

Drug interactions with antiretrovirals

“…These observations have been associated with an increased hematologic toxicity profile when they are combined. Methadone also decreases the AUC of didanosine (approximately 57%) and stavudine (approximately 23%) [27]. Several case reports have described methadone withdrawal during combined therapy with nevirapine or efavirenz [28].…”