Ddel-05. pharmacokinetic assessment of convection-enhanced delivery of small molecule drugs for h3 k27-altered diffuse midline glioma

Abstract H3 K27-altered diffuse midline gliomas (DMG) are uniformly lethal tumors for which no therapy has been found to be effective. The blood-brain barrier (BBB) restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) circumvents the BBB by directly infusing therapeutics into the tumor, facilitating homogenous distribution of drugs at high local concentrations with minimal systemic toxicity. However, most drugs given by CED are rapidly cleared from the brain, severely limiting its therapeutic potential. Here, we determine the impact of drug characteristics rather than mechanism of action on compatibility with CED. Various medicinal chemistry prediction models were interrogated to define drug categories predicated on inherent physicochemical properties of the drugs. A panel of FDA-approved drugs with biologically validated activity in DMG were selected for each group: panobinostat/ponatinib, everolimus/topotecan, tolnaftate/tretinoin, and carmofur/eltrombopag. In vivo pharmacokinetic studies of these drugs delivered by CED into the pons of tumor-naïve mice showed that drugs expected to be less likely to undergo active efflux persisted at the site of infusion over prolonged periods of time. Conversely, efflux transporter (ET) substrate drugs were quickly excreted from the brain and readily detectable in the plasma following CED. Based on the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were much higher for ET substrate drugs compared with ET non-substrates, resulting in a significant increase in the residence time (the time spent by drugs in the brain) in the absence of ET-mediated clearance. These properties were further validated in efficacy studies in DMG animal models. The proclivity of many drugs to be rapidly effluxed from the brain after CED generates a vulnerability that can be exploited for the development of novel therapeutic regimens, such as with pharmacokinetics-informed drug selection or concomitant dosing of ET-inhibiting drugs.