Top-down and bottom-up modeling in system pharmacology to understand clinical efficacy: An example with NRTIs of HIV-1

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Sulav Duwal, Max von Kleist

Abstract

A major aim of Systems Pharmacology is to understand clinically relevant mechanisms of action (MOA) of drugs and to use this knowledge in order to optimize therapy. To enable this mission it is necessary to obtain knowledge on how in vitro testable insights translate into clinical efficacy. Mathematical modeling and data integration are essential components to achieve this goal. Two modeling philosophies are prevalent, each of which in isolation is not sufficient to achieve the above described: In a 'top-down' approach, a minimal pharmacokinetic-pharmacodynamic (PK-PD) model is derived from- and fitted to available clinical data. This model may lack interpretability in terms of mechanisms and may only be predictive for scenarios already covered by the data used to derive it. A 'bottom-up' approach builds on mechanistic insights derived from in vitro/ex vivo experiments, which can be conducted under controlled conditions, but may not be fully representative for the in vivo/clinical situation. In this work, we employ both approaches side-by-side to predict the clinical potency (IC50 values) of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, emtricitabine and tenofovir. In the 'top-down' approach, this requires...Continue Reading

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Citations

Jul 22, 2016·CPT: Pharmacometrics & Systems Pharmacology·S DuwalM von Kleist
Jul 28, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Charlotte KloftChristoph A Ritter
Sep 11, 2018·Clinical Pharmacology and Therapeutics·Craig W Hendrix
Jan 31, 2019·PLoS Computational Biology·Sulav DuwalMax von Kleist
Oct 16, 2019·Annual Review of Medicine·Jared M BaetenSharon L Hillier
Aug 22, 2018·Immunological Reviews·Alison L HillRobert F Siliciano
Dec 27, 2019·Pediatric Blood & Cancer·Sebastiaan D T SassenRon A A Mathôt
May 29, 2018·Journal of Veterinary Pharmacology and Therapeutics·Marilyn N MartinezLudovic Pelligand

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