Abstract | PURPOSE: To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies. PATIENTS AND METHODS: 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.
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Authors | Hiroto Inaba, John C Panetta, Stanley B Pounds, Lei Wang, Lie Li, Fariba Navid, Sara M Federico, Eric D Eisenmann, Aksana Vasilyeva, Yong-Dong Wang, Sheila Shurtleff, Ching-Hon Pui, Tanja A Gruber, Raul C Ribeiro, Jeffrey E Rubnitz, Sharyn D Baker |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 25
Issue 24
Pg. 7320-7330
(12 15 2019)
ISSN: 1557-3265 [Electronic] United States |
PMID | 31455680
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | ©2019 American Association for Cancer Research. |
Chemical References |
- Cytarabine
- Bevacizumab
- Clofarabine
- Cyclophosphamide
- Sorafenib
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Topics |
- Adolescent
- Adult
- Antineoplastic Combined Chemotherapy Protocols
(adverse effects, pharmacokinetics)
- Bevacizumab
(administration & dosage)
- Child
- Clofarabine
(administration & dosage)
- Cyclophosphamide
(administration & dosage)
- Cytarabine
(administration & dosage)
- Drug Resistance, Neoplasm
(drug effects)
- Humans
- Leukemia
(drug therapy, pathology)
- Neoplasm Recurrence, Local
(drug therapy, pathology)
- Neoplasms
(drug therapy, pathology)
- Skin Diseases
(chemically induced, pathology)
- Sorafenib
(administration & dosage)
- Tissue Distribution
- Young Adult
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