Methadone is subject to hepatic metabolism. Previous data from in vitro experiments with human liver microsomes suggested that methadone is demethylated by the 3A4 isoform of the cytochrome P450 family (21
). These data suggest that the coadministration of drugs which inhibit 3A4 would lead to a rise in methadone exposure and to opiate intoxication. However, clinical trials which investigated the pharmacokinetics of methadone when it was coadministered with the CYP3A4 inhibitors indinavir, nelfinavir (NFV), and ritonavir (RTV) failed to confirm this assumption. Coadministration of indinavir did not lead to any change in methadone levels (8
). Coadministration of NFV led to a decrease in methadone concentrations (20
), and the AIDS Clinical Trials Group ACTG 401 trial found that there was a reduction in methadone levels when it was coadministered with saquinavir (SQV)-RTV (400/400 BID), the latter being a very strong inhibitor of CYP3A4 (17
). When given alone, RTV (100 mg BID) had no influence on methadone levels at all (25
). Inducers of CYP3A4 also failed to show the expected effects on methadone concentrations: in a study with patients receiving rifabutin, methadone levels remained unchanged (6
). These surprising results, together with recent in vitro data, suggest that the principal cytochrome of methadone metabolism may not be CYP3A4 but CYP2B6, followed by CYP2C19 (16
). In addition, in vitro and in vivo evidence suggests that methadone metabolism is stereoselective (13
). CYP2B6 has been shown to preferentially metabolize the inactive l
isomer, CYP2C19 has been shown to preferentially metabolize the active R
isomer, and CYP3A4 has been shown to preferentially metabolize both isomers (16
). Stereoselective metabolism may partly account for the fact that amprenavir reduces total methadone concentrations without provoking signs and symptoms of opioid withdrawal. A trial which investigated the effect of amprenavir on methadone levels in 16 healthy subjects showed that the AUC of the active isomer decreased by only 12%, whereas the AUC of the inactive (S
)-methadone was reduced by 40%. The opioid pharmacodynamic measures recorded in this trial were unchanged, and none of the participants complained of withdrawal symptoms (19
). Patients who took NFV or SQV-RTV with methadone also had greater decreases in the levels of the inactive isomer. Again, these patients did not experience opioid withdrawal (17
). However, SQV-RTV elevated the fraction of unbound methadone by displacing it from protein binding. This effect, which may also occur with NFV-methadone coadministration, could be an alternative explanation for the absence of withdrawal symptoms (17
). Two studies with patients taking methadone and lopinavir-RTV reported significant reductions in methadone AUCs (36% [10
] and 26% [25
]). Even though the data are conflicting, lopinavir-RTV administration does not seem to cause withdrawal symptoms in the majority of patients taking methadone. Neither study measured the levels of the methadone enantiomers.
NVP is metabolized by CYP3A4, CYP2B6, and CYP2C19 but has no inhibitory effect on any of these enzymes when it is present at therapeutic concentrations (34
). In vivo, NVP seems to induce the levels of expression of some of these cytochromes, but confirmatory data are scarce (23
; unpublished data from Boehringer Ingelheim).
The assay that we developed for this study was not stereoselective. However, 9 of our 20 patients were taking the methadone formulation, which contains only (R
)-methadone. Reductions in methadone AUCs were similar in both patients receiving racemic methadone and those receiving (R
)-methadone. Among the patients in both groups, all but three patients suffered from withdrawal symptoms. There was a slightly greater decrease in the AUC in the group of patients taking (R
)-methadone than in the group of patients taking racemic methadone, but this difference was not significant. Under the assumption that CYP3A4 may play a less important role in methadone metabolism, our results would indicate that CYP2B6 and possibly CYP2C19 are induced by NVP. This is consistent with the finding that the CYP2B6 inducer efavirenz also reduces methadone concentrations (12
The NVP trough levels measured in this study are similar to historical data (33
), which indicates that patients were adherent to their medication regimens and that the interaction was unidirectional.
It has previously been observed (11
) that patients need to increase their methadone doses during NVP therapy much less than would have been expected from pharmacological data. In our total study population, a theoretical median dose increase of 79% would have been required to compensate for the reduction in AUCs. This is in contrast to the median dose increase of 15%. Six subjects did not require any change in their methadone doses, despite significant reductions in methadone exposure. It has been suggested that a gradual detoxification from methadone occurs during NVP treatment (11
). Our data strengthen this hypothesis because, after having increased their methadone doses, almost all of the patients still had lower methadone AUCs without any withdrawal symptoms. Alternatively, some of the patients may have had methadone levels well above the threshold concentration at which point withdrawal symptoms occur. A reduction in the level of methadone exposure may have been tolerated by these individuals because the levels still remained above this threshold.
The policy concerning methadone dosing during this study permitted physicians to increase the dose according to the patients' needs. Therefore, it is likely that these data reflect the real need for additional methadone during NVP administration. However, no general recommendation can be given as to how much and when the dose of methadone should be increased. Therapeutic drug monitoring of methadone does not seem to be helpful because there is no clear correlation between the pharmacokinetics of methadone and its opioid effects. Decisions must be based on clinical grounds, and dose increases need to be individualized and should not be undertaken unless the patient complains about withdrawal symptoms, since severe intoxications leading to death have occurred during methadone treatment (7
). When symptoms occur, additional methadone should be allowed with increments in small steps of 5 or 10 mg.