Therapeutic Drug Monitoring and Model-Informed Precision Dosing of Oral TKIs and PARP Inhibitors: A Practical Framework for Clinical Implementation.

Abstract

Oral tyrosine kinase inhibitors and poly (adenosine diphosphate-ribose) polymerase inhibitors are widely used across solid tumors and hematologic malignancies and are typically administered at fixed doses. However, substantial interindividual pharmacokinetic variability results in heterogeneous systemic exposure, potentially leading to underexposure with reduced antitumor efficacy or overexposure with preventable toxicity. Therapeutic drug monitoring and model-informed precision dosing have emerged as complementary strategies to individualize dosing and optimize the exposure-response balance in routine oncology practice. This narrative problem-oriented review evaluates the clinical applicability of therapeutic drug monitoring and model-informed precision dosing for selected oral targeted agents, including epidermal growth factor receptor, anaplastic lymphoma kinase, BCR-ABL, vascular endothelial growth factor receptor, mitogen-activated protein kinase kinase, and multi-kinase inhibitors, as well as poly(adenosine diphosphate-ribose) polymerase inhibitors. For each agent, we assessed the presence of clinically meaningful exposure-response or exposure-toxicity relationships, the availability of validated assays, and the existence of actionable concentration thresholds. We also integrated an updated therapeutic drug monitoring usefulness score to contextualize the strength of recommendation. High-level evidence, including prospective interventional studies, supports exposure-guided dosing for imatinib and sunitinib, demonstrating improved molecular or clinical outcomes when predefined trough concentration targets are achieved. For alectinib, cabozantinib, trametinib, and lenvatinib, consistent exposure-response or exposure-toxicity relationships and pragmatic concentration thresholds support selective implementation, although randomized validation remains limited. For agents such as osimertinib, brigatinib, olaparib, and niraparib, monitoring appears most clinically relevant in toxicity-driven scenarios rather than for efficacy optimization. In contrast, lorlatinib currently lacks a clearly defined therapeutic window, limiting routine applicability. Across drugs, steady-state trough concentration remains the default sampling strategy. Clinical scenarios warranting measurement include early or unexpected disease progression, recurrent or severe adverse events, suspected drug-drug interactions, altered absorption, organ dysfunction, or concerns regarding adherence. Model-informed precision dosing extends conventional monitoring by integrating patient-specific covariates with pharmacokinetic models to simulate individualized dosing regimens. In conclusion, therapeutic drug monitoring and model-informed precision dosing are ready for selective clinical adoption in a subset of oral targeted therapies. Future prospective trials integrating pharmacometric tools with patient-centered outcomes are required to refine exposure targets and expand evidence-based implementation.