A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma
| Autor: | Michael Saunders, K Sweeney, Paul A. Hamlin, Ellen Neylon, Steven M. Horwitz, Frank Sirotnak, Martin Fleisher, Owen A. O'Connor, Diane R. Mould, Stephen B. Duffull |
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| Rok vydání: | 2009 |
| Předmět: |
Oncology
Adult Male Mucositis medicine.medical_specialty Population Antineoplastic Agents Severity of Illness Index Drug Administration Schedule chemistry.chemical_compound Pharmacokinetics Predictive Value of Tests Recurrence Internal medicine medicine Body Size Humans Pharmacology (medical) Dosing education Aged Pharmacology education.field_of_study Models Statistical business.industry Incidence Lymphoma Non-Hodgkin Pralatrexate Middle Aged medicine.disease Hodgkin Disease NONMEM Aminopterin Vitamin B 12 chemistry Pharmacodynamics Area Under Curve Antifolate Immunology Folic Acid Antagonists Female business Biomarkers medicine.drug Methylmalonic Acid |
| Zdroj: | Clinical pharmacology and therapeutics. 86(2) |
| ISSN: | 1532-6535 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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