This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Adamson, P. C. Articles by Poplack, D. G. Search for Related Content PubMed PubMed Citation Articles by Adamson, P. C. Articles by Poplack, D. G.

Pediatric Phase I Trial, Pharmacokinetic Study, and Limited Sampling Strategy for Piritrexim Administered on a Low-Dose, Intermittent Schedule

The Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892 [P. C. A., F. M. B., A. G., L. A., D. G. P.]; Mayo Clinic, Rochester, Minnesota 55902 [J. M., C. A.]; Children's Hospital Medical Center, Cincinnati, Ohio 45229 [R. J. W.]; and Burroughs Wellcome Co, Research Triangle Park, North Carolina 27709 [J. S. P., N. J. C.]

Piritrexim, an orally administered, lipid-soluble antifolate, was evaluated in a multi-institutional phase I trial in children. The starting dose was 10 mg/m²/dose administered every 8 h daily for 5 days for 3 consecutive weeks, with dose escalations in increments of 5 mg/m²/dose. Eighteen patients (16 with metastatic sarcoma, 1 with acute lymphoblastic leukemia, and 1 with a brainstem glioma), 3.5–20 years of age, with malignancy refractory to therapy, were entered into the study. The dose-limiting toxicities (DLTs), which were myelosuppression and mucositis, occurred in 4 of 4 patients treated at the 25-mg/m²/dose level but in none of the patients treated at the 15- and 20-mg/m²/dose levels. The recommended dose for phase II trials is 20 mg/m²/dose. Pharmacokinetic monitoring was performed in 15 of the 18 children. The area under the concentration-time curve (AUC) was linearly related to the dose administered. Piritrexim was rapidly absorbed, with the median time to peak level occurring 1.5 h after an oral dose. The terminal half-life of piritrexim ranged from 1.5 to 4.5 h. A limited sampling strategy developed earlier, capable of predicting the AUC based on the plasma concentrations at 3 and 6 h after an oral dose, was prospectively tested in this trial and proved to be highly predictive of the AUC (r = 0.98, P = 0.0001). Pharmacodynamic-pharmacokinetic correlations were obtained after combining data from this and the prior phase I pediatric trial. Trough plasma piritrexim concentration strongly correlated with DLT (P = 0.0016). A trough plasma piritrexim concentration >0.5 µM appeared to be predictive of toxicity. Eleven of 15 patients with trough concentrations exceeding this threshold experienced DLTs. Therapeutic drug monitoring may thus play an important role in adjusting the dose and schedule of piritrexim in future trials.

Received 9/ 6/91. Accepted 11/12/91.

This article has been cited by other articles:

				S. Malempati, H. S. Nicholson, J. M. Reid, S. M. Blaney, A. M. Ingle, M. Krailo, L. C. Stork, A. S. Melemed, R. McGovern, S. Safgren, et al. Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group J. Clin. Oncol., April 20, 2007; 25(12): 1505 - 1511. [Abstract] [Full Text] [PDF]

				D. P. Lee, J. M. Skolnik, and P. C. Adamson Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency J. Clin. Oncol., November 20, 2005; 23(33): 8431 - 8441. [Abstract] [Full Text] [PDF]

				J. C. Panetta, L. C. Iacono, P. C. Adamson, and C. F. Stewart The Importance of Pharmacokinetic Limited Sampling Models for Childhood Cancer Drug Development Clin. Cancer Res., November 1, 2003; 9(14): 5068 - 5077. [Abstract] [Full Text] [PDF]

				E. J. Estlin, S. Cotterill, C. B. Pratt, A. D. J. Pearson, and M. Bernstein Phase I Trials in Pediatric Oncology: Perceptions of Pediatricians From the United Kingdom Children's Cancer Study Group and the Pediatric Oncology Group J. Clin. Oncol., May 9, 2000; 18(9): 1900 - 1905. [Abstract] [Full Text] [PDF]

				C. H. Takimoto New Antifolates: Pharmacology and Clinical Applications Oncologist, February 1, 1996; 1(1): 68 - 81. [Abstract] [Full Text] [PDF]