A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients with Hematologic Malignancies.

Pralatrexate is a novel antifol designed to have high affinity for the reduced folate carrier, exhibiting improved internalization over other analogues. Phase 2 and subsequent Phase 1 studies revealed that patients with lymphoma exhibited a higher incidence of mucositis, compared to that reported in patients with solid tumors. The initial Phase 2 experiences employed dose escalation on an every other week schedule (135 to 240 mg/m² QOW) while the follow-on Phase 1 and 2 studies employed a weekly dosing schedule (30 to 45 mg/m² weekly for 6 of 7 weeks). The maximum tolerated dose (MTD) was 30 mg/m² weekly for 6 of 7 weeks in lymphoma patients. Preliminary population pharmacokinetic (PK) and adverse event (AE) evaluations suggested that pralatrexate exposure could be controlled with weight or body size based dosing, and that pretreatment with folic acid and vitamin B12 could abrogate the mucositis. PK and AE data from 47 patients were evaluated using NONMEM Version V level 1.1. Model building followed standard approaches. The best PK model was a three compartment linear model, fitted to the natural log-transformed concentration versus time data. Patient weight and methylmalonic acid (MMA) were found to be predictive of inter-patient PK variability, supporting weight or body surface area (BSA) based dosing. There are observations of an apparent association between MMA concentrations and PDX PK which need to be further explored. The PK model was evaluated using bootstrapping and a visual predictive check. An ordered categorical logistic regression was conducted to evaluate the relationship between pralatrexate exposure and grade of mucositis. In this evaluation, pralatrexate area under the curve (AUC) and MMA were found to be predictive of toxicity, where patients with higher MMA or AUC had a higher probability of mucositis. Individualized dosing combined with vitamin pretreatment significantly improved the toxicity profile, allowing for a shift in the dose-limiting toxicity (DLT) from mucositis to thrombocytopenia. Although the data from the present study were limited, the covariates identified in the population PK and adverse event evaluations were comparable with those identified for other anti-folate agents. MMA is a sensitive indicator of vitamin B12 deficiency and its impact on toxicity is commonly reported for this class of agents. The rationale behind the influence of MMA on clearance is less clear and may be correlated with other aspects of patient health. Pralatrexate has exhibited promising activity in patients with chemotherapy refractory peripheral T-cell lymphoma, leading now to an international multi-center Phase 2 study in peripheral T-cell lymphoma. The application of a population PK model based analysis was a critical component in the development of this agent. Model-based evaluations allowed the identification of the safest schedules and supported the need for vitamin supplementation for the safe administration.

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