Sorafenib Population Pharmacokinetics and Skin Toxicities in Children and Adolescents with Refractory/Relapsed Leukemia or Solid Tumor Malignancies
| Autor: | Lei Wang, Raul C. Ribeiro, Stanley Pounds, Sara M. Federico, Lie Li, John C. Panetta, Ching-Hon Pui, Jeffrey E. Rubnitz, Aksana Vasilyeva, Tanja A. Gruber, Sheila A. Shurtleff, Yong-Dong Wang, Sharyn D. Baker, Fariba Navid, Eric D. Eisenmann, Hiroto Inaba |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
0301 basic medicine Sorafenib Oncology Cancer Research medicine.medical_specialty Adolescent Bevacizumab Cyclophosphamide urologic and male genital diseases Skin Diseases Article Young Adult 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Neoplasms Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Clofarabine Tissue Distribution heterocyclic compounds Child neoplasms Leukemia business.industry Cytarabine medicine.disease female genital diseases and pregnancy complications digestive system diseases Regimen 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Neoplasm Recurrence Local business medicine.drug |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies. Patients and Methods: Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated. Results: In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; P < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (P = 7e−4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (P = 1e−4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (P < 0.003). In exposure–toxicity analysis, a shorter time to development of grade 2–3 hand–foot skin reaction (HFSR) was associated with concurrent (P = 0.0015) but not with sequential (P = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (P = 0.0004) and sorafenib N-oxide (P = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR. Conclusions: Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure–response relations for alternative dosing strategies to minimize skin toxicity. |
| Databáze: | OpenAIRE |
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