A Population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-hodgkin's or hodgkin's lymphoma Journal Article
| Authors: | Mould, D. R.; Sweeney, K.; Duffull, S. B.; Neylon, E.; Hamlin, P.; Horwitz, S.; Sirotnak, F.; Fleisher, M.; Saunders, M. E.; O'Connor, O. A. |
| Article Title: | A Population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-hodgkin's or hodgkin's lymphoma |
| Abstract: | In a pralatrexate phase I study, patients displayed a high incidence of mucositis of grades 3 and 4. Preliminary evaluations of the pharmacokinetics of the drug and its association with mucositis suggested that pralatrexate exposure (area under the concentration-time curve (AUC)) could be controlled with body size (e.g., weight or body surface area)-based dosing and that pretreatment with folic acid and vitamin B 12 might diminish the incidence and severity of mucositis. The study was amended, with revised dosing and vitamin B 12 administration. Data from 47 patients were evaluated using NONMEM. Weight and methylmalonic acid (MMA) level were predictive of pharmacokinetic (PK) variability. AUC and MMA level were positively correlated with the risk of developing mucositis. A lower AUC schedule with vitamin B 12 pretreatment may control mucositis without compromising efficacy. The covariates identified in this study are comparable with other antifolate analogs. The application of modeling was a critical step in the development of pralatrexate, yielding important suggestions for dose, scheduling, and pretreatment modifications. |
| Keywords: | adult; cancer chemotherapy; clinical article; aged; middle aged; clinical trial; drug tolerability; neutropenia; area under the curve; diarrhea; drug dose reduction; drug efficacy; antineoplastic agents; biological markers; multiple cycle treatment; phase 2 clinical trial; mucosa inflammation; nausea; thrombocytopenia; vomiting; drug administration schedule; incidence; recurrence; prediction; risk factor; hodgkin disease; drug dose escalation; febrile neutropenia; nonhodgkin lymphoma; severity of illness index; lymphoma, non-hodgkin; models, statistical; clinical evaluation; predictive value of tests; vitamin supplementation; cancer relapse; body size; area under curve; folic acid; drug blood level; phase 1 clinical trial; folic acid antagonists; mucositis; pralatrexate; aminopterin; repeated drug dose; cyanocobalamin; methylmalonic acid; refractory period; vitamin b 12 |
| Journal Title: | Clinical Pharmacology & Therapeutics |
| Volume: | 86 |
| Issue: | 2 |
| ISSN: | 0009-9236 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2009-08-01 |
| Start Page: | 190 |
| End Page: | 196 |
| Language: | English |
| DOI: | 10.1038/clpt.2009.80 |
| PUBMED: | 19474785 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 30 November 2010" - "CODEN: CLPTA" - "Source: Scopus" |
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