Pharmacokinetic Evaluation of Blonanserin Transdermal Patch: Population Analysis and Simulation of Plasma Concentration and Dopamine D₂ Receptor Occupancy in Clinical Settings

Abstract

Blonanserin is an atypical antipsychotic drug with high affinity and selective antagonism for dopamine D2 and D3 and serotonin 5‐HT2A receptors. Blonanserin transdermal patch is the first transdermal formulation developed for the treatment of schizophrenia. The purpose of this population pharmacokinetic (PPK) analysis was to evaluate the characteristics of blonanserin pharmacokinetics after transdermal patch application, to estimate the daily fluctuation in blonanserin plasma concentration, and to evaluate the impact of patch application noncompliance to support usage in clinical settings. A total of 3747 plasma blonanserin concentrations from 9 clinical studies (93 healthy volunteers and 348 patients with schizophrenia) were used in the PPK analysis. The plasma concentration was predicted using the final PPK model, and dopamine D2 receptor occupancy was estimated on the basis of the results of a separately reported positron emission tomography study. A 2‐compartment, parallel zero‐order absorption with a lag time and first‐order elimination model was developed to describe the pharmacokinetics of blonanserin, including the change in absorption rate during patch application. The maximum/minimum ratio of plasma concentration was estimated as 1.10 at steady state, indicating minimal fluctuation. In the case of failure to remove the previous patch or a missing application, the increase or decrease in plasma concentration and dopamine D2 receptor occupancy was <20%. These results indicated that the plasma blonanserin concentration and dopamine D2 receptor occupancy were stable after blonanserin transdermal patch application, which may lead to improved tolerability during the treatment of patients with schizophrenia.

Prediction of Corresponding Dose of Transdermal Blonanserin to Oral Dose Based on Dopamine D2 Receptor Occupancy

“…2 D). 15 In the PET study, 11 peak D 2 occupancy during oral administrations was higher than at trough, with mean (minimum, maximum) difference of 13.5% (7.2%, 27.1%), while the difference during transdermal patch applications was small, 2.1% (−5.0%, 7.1%). Considering the fluctuation of occupancy with oral doses, the predicted occupancy was plotted against the time since the most recent dose and compared with the 90% intervals of the predicted occupancy for blonanserin transdermal patch (Fig.…”

“…The details of blood sampling and plasma concentration measurements using validated liquid chromatography–tandem mass spectrometry methods were reported previously. 15 …”

“…In addition, median and 90% prediction intervals of D 2 occupancy-time profiles were predicted based on those of plasma blonanserin concentration-time profiles in Japanese patients with schizophrenia, which were predicted using the previously reported population PK model, considering interindividual variability. 15 …”

“…(4) and (5) Plasma concentration data for occupancy prediction were selected. (6) and (7) Occupancy was predicted using concentration-occupancy model based on observed blonanserin concentrations or simulated concentration using population PK model 15 . (8) Distribution of predicted occupancy was compared between formulations and (9) predicted occupancy-time profiles were compared between formulations for evaluation of corresponding doses.…”

“…A population PK model of transdermal blonanserin patch reported by Kitamura et al 15 was used for PK simulations. The details of blood sampling and plasma concentration measurements using validated liquid chromatography–tandem mass spectrometry methods were reported previously 15 …”