Comparative modelling of foetal exposure to maternal long-acting injectable versus oral daily antipsychotics.

Abstract

This study employed physiologically based pharmacokinetic (PBPK) modelling to compare the extent of foetal 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 foetal exposure during pregnancy were predicted from concentration-time data at steady-state dosing for both oral and LAI formulations. Foetal C_max for aripiprazole was 59-78% higher with LAI than oral, and 68-181% higher with LAI olanzapine than the oral formulation. Predicted cord:maternal ratios (range) were 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 foetal exposure over 28 days from oral formulations were generally predicted to be lower compared with their therapeutic-equivalent LAI. As in utero foetal exposure to maternal drugs does not necessarily translate to risk, these data should be interpreted in a broader context that includes benefit-risk assessments.