Dose-finding therapeutic window

Mianserin is a chiral tetracyclic antidepressant for which the S enantiomer is the eutomer. The influence of carbamazepine, an enzyme inducer of CYP3A4, on mianserin enantiomer concentrations was examined in 12 inpatients treated for depression [141]. The patients received at least 7 days of therapy with mianserin (60 mg per day) prior to study. In the control situation (before carbamazepine), the S R ratios of 12h postdose mianserin plasma concentrations were approximately twofold. At that point, the patients were coadministered carbamazepine 400mg/day for 4 weeks along with their daily dose of mianserin. By week 4 of carbamazepine treatment, concentrations of the S and R enantiomers had declined by 49% and 38%, respectively. This corresponded with 2.0- and 1.6-fold increases, respectively, in the S- and R- desmethylmianserin mianserin ratios. The findings confirmed the involvement of CYP3A4 in the metabolism of mianserin enantiomers to desmethylmianserine. Because of the possibility of a therapeutic window for S-mianserin, it was suggested that the dose of mianserin would need to be increased by a factor of two in the presence of carbamazepine [141]. 

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