Drug Interactions between capivasertib and tolterodine

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of tolterodine, which is primarily metabolized by this isoenzyme in most patients (referred to as "extensive metabolizers") to an active metabolite that is equipotent to tolterodine. A subset of the population (about 7%) is devoid of CYP450 2D6 (referred to as "poor metabolizers" or PMs) and uses CYP450 3A4 to metabolize tolterodine to an inactive metabolite instead. In a study to assess this interaction, fluoxetine (a potent CYP450 2D6 inhibitor) was administered concurrently with immediate release tolterodine. It was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine systemic exposure (AUC). There was a 52% decrease in the peak plasma concentration (Cmax) and a 20% decrease in the AUC of tolterodine's active metabolite. During this interaction the sums of unbound serum concentrations of tolterodine and its active metabolite are about 25% higher, meaning little alteration in the overall pharmacological activity of tolterodine is expected. However, increased plasma concentrations may increase the risk of adverse effects associated with tolterodine, including QT prolongation and anticholinergic effects.

MANAGEMENT: During concomitant therapy with drugs that inhibit CYP450 2D6 activity, the possibility of prolonged and/or increased pharmacologic effects of tolterodine should be considered. Increased monitoring may be particularly important when the CYP450 2D6 inhibitor has a similar adverse effect profile to that of tolterodine or when its inhibitory effects are long lasting (e.g., rolapitant can increase the plasma concentrations and risk of adverse effects of CYP450 2D6 substrates for at least 28 days). Patients should be counseled to report any increases in side effects or changes in condition.