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Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule
P C Adamson1, F M Balis, J Miser
1Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
Insights
Piritrexim (a new antifolate) showed dose-limiting myelosuppression and mucositis in children. The maximum tolerated dose was 140 mg/m2/day, with pharmacokinetic monitoring aiding toxicity prediction.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Clinical Trials
Background:
- Piritrexim is a novel nonclassical antifolate agent.
- Antifolates are crucial in cancer chemotherapy.
- Evaluating new antifolates in pediatric populations is essential.
Purpose of the Study:
- To determine the safety and tolerability of piritrexim in children.
- To establish the maximum tolerated dose (MTD) of piritrexim.
- To characterize the pharmacokinetics of piritrexim in pediatric patients.
Main Methods:
- A multiinstitutional Phase I clinical trial was conducted in children.
- Piritrexim was administered orally every 12 hours for 5 consecutive days.
- Dose escalation with pharmacokinetic monitoring and toxicity assessment.
Main Results:
- Dose-limiting toxicities (myelosuppression, mucositis) occurred at higher doses (290 and 200 mg/m2/day).
- The maximum tolerated dose was determined to be 140 mg/m2/day.
- Pharmacokinetic analysis revealed a correlation between trough concentrations (>0.5 microM) and dose-limiting toxicities.
- A predictive pharmacokinetic sampling strategy was developed.
Conclusions:
- The recommended dose for Phase II trials is 140 mg/m2/day orally every 12 hours for 5 days.
- Pharmacokinetic monitoring can help predict piritrexim bioavailability and patient toxicity risk.
- Piritrexim demonstrates potential as a pediatric anticancer agent with careful dose management.
Abstract:
Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every 12 h for 5 consecutive days, with courses repeated every 21 days. Dose reduction, initially to 200 mg/m2/day and subsequently to 140 mg/m2/day, was required because dose limiting myelosuppression and mucositis were encountered at the 290- and 200-mg/m2/day dose levels. Non-dose limiting toxicities included transient elevations in liver function tests, mild nausea, and skin rashes. The maximum tolerated dose was 140 mg/m2/day for 5 days. Pharmacokinetic monitoring was performed at steady state during the first course. For the 140-, 200-, and 290-mg/m2/day dose groups, the mean +/- SE peak plasma concentrations were 5.3 +/- 0.84, 9.3 +/- 1.7, and 10.2 +/- 2.3 microM, respectively, and occurred at a median of 1.5 h following the p.o. dose. The mean area under the plasma concentration-time curves were 18.1 +/- 2.3, 45.4 +/- 8.9, and 56.9 +/- 16.3 microM.h, respectively. Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively. Dose limiting toxicities were observed in 9 of 10 patients with 12-h trough piritrexim concentrations greater than 0.5 microM, whereas only 2 of 7 patients with trough concentrations less than 0.5 microM experienced dose limiting toxicities. A limited pharmacokinetic sampling strategy that allowed the area under the plasma concentration-time curve to be accurately predicted from the 3- and 6-h plasma drug concentration was developed. The recommended dose for future phase II trials is 140 mg/m2/day administered p.o. every 12 h for 5 consecutive days. Pharmacokinetic monitoring at 3, 6, and 12 h postdose may be useful for estimating bioavailability and for predicting which patients are at greatest risk for developing toxicity.