Comparative modeling of fetal exposure to maternal long-acting injectable versus oral daily antipsychotics

Abstract

This study employed physiologically based pharmacokinetic (PBPK) modelling to compare the extent of fetal exposure between oral and long-acting injectable (LAI) aripiprazole and olanzapine. Adult and pregnancy PBPK models were developed and validated with relevant clinical data. Relevant indices of fetal exposure during pregnancy were predicted from concentration-time data at steady-state dosing for both oral and LAI formulations. Fetal Cmax for aripiprazole was 59-78% higher with LAI than oral, and 68-181% higher with LAI olanzapine than the oral formulation. Predicted C:M ratios (range) was 0.59-0.69 for oral aripiprazole and 0.61-0.66 for LAI aripiprazole, 0.34-0.64 for oral olanzapine and 0.89-0.96 for LAI olanzapine. Also, cumulative fetal exposure over 28 days from oral formulations were generally predicted to be lower compared with their therapeutic-equivalent LAI. As in utero fetal exposure to maternal drugs does not necessarily translate to risk, these data should be interpreted in a broader context that includes benefit-risk assessments.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

A. Olagunju reports research funding from the Wellcome Trust, including 227288/Z/23/Z (2024-2031).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

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