Prediction methods of drug-drug interactions of non-oral CYP3A4 substrates based on clinical interaction data after oral administrations – Validation with midazolam, alfentanil, and verapamil after intravenous administration and prediction for blonanserin transdermal patch

Tomita, Yoshifumi; Yahata, Masahiro; Hashimoto, Michie; Nishimuta, Haruka; Kawaguchi, Haruko; Matsushita, Hajime; Kitamura, Akihiro; Nishibe, Hironori; Natsui, Kiyoshi; Watanabe, Takao

doi:10.1016/j.dmpk.2020.03.006

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…As blonanserin is predominantly metabolized by CYP3A during first pass after oral administrations, transdermal route is effective to avoid first-pass metabolism and related drug-drug interactions. 25 The plasma concentration ratio of the active metabolite M-1/blonanserin was 0.8 during oral administrations 26 and 0.04 during transdermal applications. 27 The in vitro Ki of M-1 for dopamine D 2 receptor is 1.38, approximately 10 times less inhibitory potential than of blonanserin 5 and free fraction of M-1 from plasma protein binding is 0.007, about twice that of blonanserin.…”

Section: Discussionmentioning

confidence: 93%

“…Pharmacokinetic property of blonanserin transdermal patch can add an explanation to such discrepancy. As blonanserin is predominantly metabolized by CYP3A during first pass after oral administrations, transdermal route is effective to avoid first-pass metabolism and related drug-drug interactions 25 . The plasma concentration ratio of the active metabolite M-1/blonanserin was 0.8 during oral administrations 26 and 0.04 during transdermal applications 27 .…”

Section: Discussionmentioning

confidence: 99%

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

Tomita

Takagaki

Kitamura

et al. 2022

J Clin Psychopharmacol

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Background/Purpose Blonanserin is an atypical antipsychotic, a potent selective antagonist of dopamine D 2 receptor (D 2 ), prescribed as oral formulations in patients with schizophrenia. Blonanserin transdermal patch was developed to provide a new treatment option, but the corresponding dose to oral blonanserin was not clear. The aims of this study were to clarify the pharmacokinetic (PK)-pharmacodynamic characteristics of blonanserin after transdermal patch application and to evaluate the corresponding dose to oral formulation based on striatal D 2 occupancy. Methods The relationship between D 2 occupancy and plasma blonanserin concentration was analyzed using an E max model based on data from positron emission tomography study with oral and transdermal blonanserin. D 2 occupancy was simulated using E max models based on the observed plasma concentrations and the simulated plasma concentrations obtained from population PK model. Results Plasma blonanserin concentration levels after repeated patch applications were nearly stable throughout the day and no effect of sex, advanced age, or application site was detected. The concentration at half maximal D 2 occupancy during transdermal patch applications, 0.857 ng/mL, was higher than that after oral doses, 0.112 ng/mL, suggesting metabolite contribution after oral doses. The median predicted D 2 occupancy during blonanserin patch applications at doses of 40 and 80 mg/d was 48.7% and 62.5%, respectively, and the distribution of D 2 occupancy at these doses could cover most of that at oral doses of 8 to 24 mg/d. Conclusions Predicted D 2 occupancy suggested that a 40- to 80-mg/d blonanserin transdermal patch dose corresponds to an 8- to 24-mg/d oral dose for the treatment of schizophrenia.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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

Tomita

Takagaki

Kitamura

et al. 2022

J Clin Psychopharmacol

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“…Daily fluctuations in plasma concentration and striatum dopamine D 2 receptor occupancy are expected to be minimal at steady state. The transdermal formulation could circumvent the first‐pass effect through the intestine and liver and minimize drug‐drug interactions across cytochrome P450 (CYP) 3A, 6 which is the main enzyme involved in blonanserin metabolism 7 . The transdermal route of administration may be associated with better adherence, which is a major consideration in the treatment of schizophrenia 8…”

mentioning

confidence: 99%

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

Kitamura

Takagaki

Nemoto

et al. 2021

The Journal of Clinical Pharma

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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.

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Population pharmacokinetics of blonanserin in Japanese adolescent and adult patients with schizophrenia

Nemoto,

Takagaki,

Kitamura

et al. 2024

Drug Metabolism and Pharmacokinetics

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Prediction methods of drug-drug interactions of non-oral CYP3A4 substrates based on clinical interaction data after oral administrations – Validation with midazolam, alfentanil, and verapamil after intravenous administration and prediction for blonanserin transdermal patch

Cited by 7 publications

References 21 publications

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

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

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

Population pharmacokinetics of blonanserin in Japanese adolescent and adult patients with schizophrenia

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Prediction methods of drug-drug interactions of non-oral CYP3A4 substrates based on clinical interaction data after oral administrations – Validation with midazolam, alfentanil, and verapamil after intravenous administration and prediction for blonanserin transdermal patch

Cited by 7 publications

References 21 publications

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

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

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

Population pharmacokinetics of blonanserin in Japanese adolescent and adult patients with schizophrenia

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