Luke Wittenburg

Vinblastine (VBL) is a vinca alkaloid‐class cytotoxic chemotherapeutic that causes microtubule disruption and is typically used to treat hematologic malignancies. VBL is characterized by a narrow therapeutic index, with key dose‐limiting toxicities being myelosuppression and neurotoxicity. Pharmacokinetics (PK) of VBL is primarily driven by ABCB1‐mediated efflux and CYP3A4 metabolism, creating potential for drug–drug interaction. To characterize sources of variability in VBL PK, we developed a physiologically based pharmacokinetic (PBPK) model in Mdr1a/b(−/−) knockout and wild‐type mice by incorporating key drivers of PK, including ABCB1 efflux, CYP3A4 metabolism, and tissue‐specific tubulin binding, and scaled this model to accurately simulate VBL PK in humans and pet dogs. To investigate the capability of the model to capture interindividual variability in clinical data, virtual populations of humans and pet dogs were generated through Monte Carlo simulation of physiologic and biochemical parameters and compared to the clinical PK data. This model provides a foundation for predictive modeling of VBL PK. The base PBPK model can be further improved with supplemental experimental data identifying drug–drug interactions, ABCB1 polymorphisms and expression, and other sources of physiologic or metabolic variability.

Cyclophosphamide (CP) is an alkylating agent commonly included in multi‐drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4‐hydroxycyclophosphamide (4‐OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto‐induction of metabolism in humans, with faster CP clearance and relatively increased 4‐OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200–250 mg/m 2 over 3 to 4 days in a prospectively identified population of cancer‐bearing dogs. Plasma concentrations of CP and 4‐OHCP were measured by ultra‐high performance liquid chromatography tandem‐mass spectrometry in eight dogs following the first and last doses to assess for auto‐induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 vs. 1.22 ± 0.5 h −1 ; p = .125). Additionally, no significant difference in dose‐normalized 4‐OHCP exposure was identified between first and last doses (5.9 ± 2.1 vs. 7.9 ± 6.4 h × ng/ml; p = .936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio‐activation of CP in dogs administered a dose of 200–250 mg/m 2 .