Integrating the gut microbiome into therapeutic drug monitoring and model-informed precision dosing: a clinical pharmacy perspective

Abstract

Interindividual variability in drug response remains a central obstacle to effective pharmacotherapy, and much of it persists after accounting for the pharmacogenomic factors that currently guide individualized treatment. Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have become a mature, covariate-driven discipline that tailors dose to renal function, body size, age, and genotype, yet one determinant of drug exposure is conspicuously absent from these frameworks: the gut microbiome. Although gut bacteria are now known to alter the pharmacokinetics of many drugs, microbial variation is not represented in dosing models and is instead absorbed into unexplained residual variability. This review reframes the gut microbiome as a measurable, dosing-relevant covariate rather than a mechanistic phenomenon. We organize the mechanisms by which gut bacteria shape drug pharmacokinetics into four classes (biotransformation, inactivation, bioaccumulation, and indirect modulation of host enzymes and enterohepatic recirculation) and summarize the landmark evidence that microbial variation produces measurable interindividual differences in exposure and response, graded explicitly by evidential tier so that causal and associative findings are not conflated. We then locate the microbiome blind spot within current TDM and MIPD, and propose an operational framework specifying what microbial features to measure, how they should be sampled and measured reproducibly, and how to integrate them into population-pharmacokinetic, Bayesian, machine-learning, and physiologically based dosing models, setting out for each route its data requirements, validation strategy, limitations, and current prototyping status, and illustrating the framework with three worked examples of differing evidential maturity. Finally, we translate the framework into strategies actionable by clinical pharmacists and delineate the biological, methodological, and translational obstacles ahead, including the workflow burden, cost, and biomarker-qualification requirements that adoption would entail. By treating the microbiome as a covariate, this perspective charts a route toward microbiome-informed precision dosing at the bedside.