Impact of concomitant acetylcholinesterase inhibitor use on the pharmacokinetic profile of pimavanserin in patients with dementia‐related psychosis: Modeling data from the phase 3 HARMONY study

Abstract

AbstractBackgroundPimavanserin is a selective serotonin modulator with inverse agonist/antagonist activity at the 5HT2A receptor, and to a lesser extent at the 5HT2C receptor. Pimavanserin efficacy and safety were evaluated in patients with dementia‐related psychosis (DRP) in the phase 3 HARMONY study. Many patients with DRP receive acetylcholinesterase inhibitors (AChEIs) to treat their dementia. This analysis evaluated the pharmacokinetic (PK) profile of pimavanserin in patients receiving concomitant AChEIs using data from HARMONY.MethodsHARMONY was a randomized discontinuation study in patients with DRP. Patients received open‐label pimavanserin, 34 mg daily with flexible dosing (20 mg) based on tolerability, for 12 weeks, and those with sustained response were randomized into the 26‐week double‐blind period where they continued their pimavanserin or switched to placebo. PK samples were collected at baseline and weeks 12, 13, 22, and 38 (or end of treatment). Individual Bayesian estimates of pimavanserin apparent clearance (CL/F) and apparent volume of distribution (V/F) were obtained using a previously developed population PK model for patients with/without concomitant AChEIs. Steady‐state area under the plasma concentration‐time curve (AUC) and maximum drug concentration (Cmax) were computed for pimavanserin doses normalized to 34 mg daily.Results158/337 (46.9%) patients in HARMONY had concomitant AChEI use (donepezil, galantamine, rivastigmine). In patients with/without AChEI use, CL/F and V/F showed no apparent differences between groups. Covariate testing found no statistically significant effect (α = 0.05) of AChEI use on CL/F or V/F. Minimal differences in predicted steady‐state pimavanserin exposures were observed between patients with concomitant AChEI use and those without (Table 1); median Cmax was 8.4% higher (with AChEI: 57.9 ng/mL; without AChEI: 53.4 ng/mL) and median AUC was 9.2% higher (with AChEI: 1328.9 ng × h/mL; without AChEI: 1216.5 ng × h/mL).ConclusionsConcomitant AChEIs had no significant effect on the PK parameters of pimavanserin. Differences in exposure measures (Cmax and AUC) between groups were negligible (<10%). These results suggest that concomitant AChEI use does not have a clinically relevant impact on the PK profile of pimavanserin.