UCSF

Models are frequently and ubiquitously used in all pharmacokinetic investigations. The familiar inductive equation-based pharmacokinetic models formulate hypotheses about data; they alone cannot provide mechanistic insights. We need models that have extant, working mechanisms that generate emergent properties analogous to how phenomena emerge during wet-laboratory experiments.

In this dissertation, I report a new class of synthetic, agent-based, discrete events models and simulations, with the objective to provide mechanistic insights. Validated, biomimetic software components are plugged together to form in silico analogues of the referent experimental systems. Each synthetic analogue is a mechanistic hypothesis: execution produces an observable phenomenon.

The recirculating in silico livers (RISLs) are in silico analogues of isolated perfused rat livers during an experiment in which digoxin is administered, alone or in combination with either an uptake or efflux inhibitor. A RISL that comprised four time-variant mechanisms and new enzyme and transporter components achieved the most stringent similarity measure: simulated digoxin and metabolite perfusate levels were experimentally indistinguishable from the referent data. The mechanisms simulated unanticipated loss of hepatic viability during the original experiments: erosion of hepatic accessibility and of enzyme and transporter activities.

In silico experimental Caco-2 (cell monolayer) cultures (ISECC) are analogues of the confluent, asymmetric cell monolayer used in vectorial transport studies. To seek an explanation for the observed paradoxical saquinavir transport data, I followed an iterative refinement protocol that enabled discovery of plausible, new mechanistic details. The ISECC surviving the most stringent similarity challenge produced transport data statistically indistinguishable from referent observations. It required heterogeneous intracellular spaces; a biased distribution of metabolizing enzymes; and restrictions on intracellular drug movement.

Experimenting on synthetic analogues, such as RISLs and ISECCs, provides a formerly unavailable means of discovering and testing new mechanistic hypotheses. It is a powerful expansion of the scientific method: an independent, scientific means to challenge, explore, and improve any inductive mechanism. Validated, biomimetic analogues are concrete instances of hypothetical yet plausible mechanisms, and would replace vague, unverified concepts. The collection of mechanisms, rules, assemblies, and interactions of components can be subjected to testing and falsification, and in the absence of other competing theories, stands as the current best mechanistic hypothesis for the phenomena.