P21 PBPK modeling in pregnancy: achievements, shortcomings and future perspectives. Issue 6 (17th May 2019)

• Record Type: Journal Article
• Authors: Dallmann, A; Mian, P; Annaert, P; Pfister, M; Allegaert, K; van den Anker, J
• Is Part Of: Archives of disease in childhood. Volume 104:Issue 6(2019)
• Page Start: e25
• Page End: e25
• Publication Date: 2019-05-17
• Subjects: Children -- Diseases -- Periodicals; Infants -- Diseases -- Periodicals; 618.920005
• DOI: 10.1136/archdischild-2019-esdppp.59
• Languages: English
• ISSNs: 0003-9888

Abstract

Abstract : Background: Physiologically-based pharmacokinetic (PBPK) models are considered a promising approach to better characterize and anticipate the effect of physiological changes on pharmacokinetics in pregnant women. Consequently, multiple pregnancy PBPK models have been developed and verified over the past years. Using acetaminophen (paracetamol) as example, PBPK modeling can provide specific insights into the expected pharmacokinetic changes throughout pregnancy. Methods: To obtain an overview of pregnancy PBPK models, the scientific literature was systematically screened for publications with a focus on pharmaceutical applications using relevant keywords. Additionally, a pregnancy PBPK model for acetaminophen was developed with the Open Systems Pharmacology software suite (www.open-systems-pharmacology.org) following an established workflow. After model verification around gestational week 30, the model was scaled to earlier stages of pregnancy and molar dose fractions converted to acetaminophen metabolites were estimated for each trimester. Results: Over the past years, more than 60 different pregnancy PBPK models for more than have 40 drugs been published. More than 70% of these models were developed for the third trimester, while few models have been applied to the first trimester. The developed PBPK model for acetaminophen indicated that the median dose fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI) was 11%, 9.0% and 8.2% in the first, second and third trimester, respectively, while for non-pregnant women a value of 7.7% was simulated. Conclusion: While the overall availability and quality of pregnancy PBPK models is varying considerably, the efforts to establish such models are promising in that they reflect an increased awareness of the necessity to better characterize pharmacokinetics during pregnancy. This is illustrated by the developed PBPK model for acetaminophen where information on NAPQI-formation in vivo is hitherto lacking. Although PBPK models are not a substitute for clinical trials, they constitute an important tool for clinicians in case of missing or incomplete information. Disclosure(s): Nothing to disclose