Pharmacokinetics of methadone in human-immunodeficiency-virus-infected patients receiving nevirapine once daily

Abstract

The effect of nevirapine once-daily dosing on the pharmacokinetics of methadone and its main metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, was evaluated in ten HIV positive patients on stable methadone therapy. Nevirapine 200 mg once daily was administered orally from day 1 to day 14. On day 15, nevirapine dose was increased to 400 mg once daily for the following 7 days of study and thereafter. On days 0, 8, and 22, concentration-time profiles of methadone and its metabolite were collected after methadone intake. Noncompartmental pharmacokinetic analysis was performed. Pharmacokinetic parameters obtained on days 8 and 22 were compared with those obtained before nevirapine administration. After starting nevirapine treatment, nine out of ten patients experienced symptoms of abstinence syndrome, and methadone dose had to be increased by 20% on average during the course of the study. After 7 days with nevirapine 200 mg, methadone area under the plasma concentration time curve (AUC) and maximum concentration (C(max)) values were reduced by 63.3% and 55.2%, respectively. Switching to high dose nevirapine (400 mg once daily) did not result in a greater decrease in the methadone AUC and C(max) compared with 200 mg nevirapine. None of the noncompartmental pharmacokinetic parameters of methadone metabolite evidenced statistically significant differences across the three study periods. The decrease in methadone AUC and C(max) administrated once daily was similar to that seen in other studies with nevirapine administrated twice daily, suggesting that the degree of induction of methadone metabolism by nevirapine is similar for both dosing regimens.