Leveraging Predictive Pharmacometrics-Based Algorithms to Enhance Perinatal Care-Application to Neonatal Jaundice

Gilbert Koch; Melanie Wilbaux; Severin Kasser; Kai Schumacher; Britta Steffens; Sven Wellmann; Marc Pfister

doi:10.3389/fphar.2022.842548

Leveraging Predictive Pharmacometrics-Based Algorithms to Enhance Perinatal Care-Application to Neonatal Jaundice

Front Pharmacol. 2022 Aug 11:13:842548. doi: 10.3389/fphar.2022.842548. eCollection 2022.

Authors

Gilbert Koch^{1

2}, Melanie Wilbaux¹, Severin Kasser³, Kai Schumacher⁴, Britta Steffens^{1

2}, Sven Wellmann^{2

3

4}, Marc Pfister^{1

2}

Affiliations

¹ Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.
² NeoPrediX AG, Basel, Switzerland.
³ Division of Neonatology, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.
⁴ Department of Neonatology, Hospital St. Hedwig of the Order of St. John of God, University Children's Hospital Regensburg (KUNO), University of Regensburg, Regensburg, Germany.

Abstract

The field of medicine is undergoing a fundamental change, transforming towards a modern data-driven patient-oriented approach. This paradigm shift also affects perinatal medicine as predictive algorithms and artificial intelligence are applied to enhance and individualize maternal, neonatal and perinatal care. Here, we introduce a pharmacometrics-based mathematical-statistical computer program (PMX-based algorithm) focusing on hyperbilirubinemia, a medical condition affecting half of all newborns. Independent datasets from two different centers consisting of total serum bilirubin measurements were utilized for model development (342 neonates, 1,478 bilirubin measurements) and validation (1,101 neonates, 3,081 bilirubin measurements), respectively. The mathematical-statistical structure of the PMX-based algorithm is a differential equation in the context of non-linear mixed effects modeling, together with Empirical Bayesian Estimation to predict bilirubin kinetics for a new patient. Several clinically relevant prediction scenarios were validated, i.e., prediction up to 24 h based on one bilirubin measurement, and prediction up to 48 h based on two bilirubin measurements. The PMX-based algorithm can be applied in two different clinical scenarios. First, bilirubin kinetics can be predicted up to 24 h based on one single bilirubin measurement with a median relative (absolute) prediction difference of 8.5% (median absolute prediction difference 17.4 μmol/l), and sensitivity and specificity of 95.7 and 96.3%, respectively. Second, bilirubin kinetics can be predicted up to 48 h based on two bilirubin measurements with a median relative (absolute) prediction difference of 9.2% (median absolute prediction difference 21.5 μmol/l), and sensitivity and specificity of 93.0 and 92.1%, respectively. In contrast to currently available nomogram-based static bilirubin stratification, the PMX-based algorithm presented here is a dynamic approach predicting individual bilirubin kinetics up to 48 h, an intelligent, predictive algorithm that can be incorporated in a clinical decision support tool. Such clinical decision support tools have the potential to benefit perinatal medicine facilitating personalized care of mothers and their born and unborn infants.

Keywords: algorithm; hyperbilirubinemia; jaundice; mechanism-based modeling; prediction.