title: Top-down and bottom-up modeling in system pharmacology to understand clinical efficacy: An example with NRTIs of HIV-1.
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 (IC50values) of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, emtricitabine and tenofovir. In the 'top-down' approach, this requires to establish the dynamic link between the intracellularly active NRTI-triphosphates (which exert the effect) and plasma prodrug PK and to subsequently link this composite PK model to viral kinetics. The 'bottom-up' approach assesses inhibition of reverse transcriptase-mediated viral DNA polymerization by the intracellular, active NRTI-triphosphates, which has to be brought into the context of target cell infection. By using entirely disparate sets of data to derive and parameterize the respective models, our approach serves as a means to assess the clinical relevance of the 'bottom-up' approach. We obtain very good qualitative and quantitative agreement between 'top-down' vs. 'bottom-up' predicted IC50values, arguing for the validity of the 'bottom-up' approach. We noted, however, that the 'top-down' approach is strongly dependent on the sparse and noisy intracellular pharmacokinetic data. All in all, our work provides confidence that we can translate in vitro parameters into measures of clinical efficacy using the 'bottom-up' approach. This may allow to infer the potency of various NRTIs in inhibiting e.g. mutant viruses, to distinguish sources of interaction of NRTI combinations and to assess the efficacy of different NRTIs for repurposing, e.g. for pre-exposure prophylaxis.
authors.affiliation: Systems Pharmacology & Disease Control Group, Department of Mathematics and Computer Science, Freie Universität Berlin, Arnimallee 6, 14195 Berlin, Germany. Electronic address: sulav@zedat.fu-berlin.de.
authors.forename: Sulav
authors.initials: S
authors.lastname: Duwal
authors.affiliation: Systems Pharmacology & Disease Control Group, Department of Mathematics and Computer Science, Freie Universität Berlin, Arnimallee 6, 14195 Berlin, Germany. Electronic address: vkleist@zedat.fu-berlin.de.
authors.forename: Max
authors.initials: M
authors.lastname: von Kleist
mesh_terms: D019380:Anti-HIV Agents / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000068679:Emtricitabine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019259:Lamivudine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000494:pharmacology*; D000068698:Tenofovir / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine
keywords: Bottom-up; Intracellular pharmacokinetics; MMOA; Mechanistic; Pharmacodynamics; Top-down