Tissue transport affects how treatment scheduling increases the efficacy of chemotherapeutic drugs

Abstract

A method to predict the effect of tissue transport on the scheduling of chemotherapeutic treatment could increase efficacy. Many drugs with desirable pharmacokinetic properties fail in vivo due to poor transport through tissue. To predict the effect of treatment schedule on drug efficacy we developed an in silico method that integrates diffusion through tissue and cell binding into a pharmacokinetic model. The model was evaluated with an array of theoretical drugs that had different rates of diffusivity, binding, and clearance. The efficacy of each drug, quantified as the fraction of cells killed, was calculated for twenty dosage schedules. Simulations showed that efficacy strongly depended on tissue transport, with a range of 0.00 to 99.99%, despite each drug having equal plasma areas under the curve (AUC). For most drugs, schedules that increased exposure also increased efficacy. Drugs with fast clearance benefited the most from increasing the number of doses and this was most effective for those with intermediary binding. All drugs with slow diffusivity were ineffective. For a subset of drugs, increasing the number of doses decreased efficacy. This phenomenon was unexpected because, when considering uptake into tissue, sustained plasma levels from multiple doses are generally assumed to be more effective. This counterintuitive decrease in efficacy was caused by drug retention within tumor tissue. These results established a set of rules that suggests how transport parameters affect the efficacy of drugs at different schedules. The two most predominant rules are (1) multiple doses improve efficacy for drugs with fast clearance, fast diffusivity and low to intermediate cell binding; and (2) one dose is most effective for drugs with slow clearance, slow diffusivity or strong cell binding. Understanding the role of tissue transport when determining drug treatment schedules would improve the outcome of preclinical animal experiments and early clinical trials.