Abstract 7182: Blood brain barrier masks effects of dosing strategy
Authors: Stoddard Madison , Chen Andrew , Yuan Lin , Van Egeren Debra , Chakravarty Arijit 
Published: March 2024

Abstract
The penetration of the blood brain barrier (BBB) presents a significant challenge in the design of drugs targeting brain tumors. The BBB desynchronizes drug concentrations between the body and brain, complicating the relationships between drug dose, effective concentration, and toxicity. In this work, we sought to understand the nature of these relationships in the context of dose schedule, in order to suggest minimally toxic and maximally effective strategies. We developed a two-compartment pharmacokinetic model to simulate the exchange of a drug between the body and the brain. Drug exchange was based on passive diffusion through the barrier and active transport into the brain as described by Michaelis-Menten kinetics. In the model, tumor cells exhibit binary resistance to the drug under a logistic growth model. The drug reduces the growth rate of the sensitive population while the resistant population suffers a small growth penalty because of the mutation conferring resistance. Strategy effectiveness was quantified in terms of survival time, the time until 95% of carrying capacity was reached, and toxicity was evaluated as the peak moving average over 18 days. Although the BBB complicates prediction of drug action, it simplifies drug impact by masking schedule effects. Our work suggests that drug concentrations in the brain increase with initial treatment until equilibrium between active transport, diffusion, and drug metabolism is reached. Fluctuations in drug concentration resulting from breaks between bolus dosing are greatly reduced in the brain relative to the body, and high frequency (daily) dosing results in a nearly constant equilibrium drug concentration. The rate at which equilibrium is reached and the drug concentration in the brain are unaffected by dosing period, as long as the average dose per day is constant. Our model suggests that the impact of dosing cycle length on survival time is negligible. Neutropenia is minimized by schedules with dosing cycle lengths that factor evenly into the 18-day neutrophil recovery period. These schedules have consistent toxicity throughout. Strategies with two, three, six, nine, and eighteen day cycles induce neutropenia least. As fluctuations in drug concentration are small at the equilibrium steady-state, effects of scheduling on drug interactions are predicted to be minimal. As drug concentration in the brain at equilibrium and latency to equilibrium are independent of dosing period, these parameters must be modulated through changes in the amount of drug dosed. The use of a loading dose may compensate for latency. Although this analysis is based on hypothetical drugs, it provides practical insights that are applicable across a wide range of systemically dosed small-molecule therapeutics. Further, the modeling framework derived here can be readily extended to guide the design of dosing schedules for real-world therapeutic interventions.
Citation Format: Madison Stoddard, Andrew Chen, Lin Yuan, Debra Van Egeren, Arijit Chakravarty. Blood brain barrier masks effects of dosing strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7182.