Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study

التفاصيل البيبلوغرافية
العنوان: Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study
المؤلفون: John C. Panetta, Wayne L. Furman, Jessica Gartrell, Olivia Campagne, Clinton F. Stewart
المصدر: Clinical and Translational Science, Vol 14, Iss 6, Pp 2152-2160 (2021)
Clinical and Translational Science
بيانات النشر: Wiley, 2021.
سنة النشر: 2021
مصطلحات موضوعية: Male, Sorafenib, 030213 general clinical medicine, medicine.medical_specialty, Carcinoma, Hepatocellular, Adolescent, Dose, Urology, RM1-950, Models, Biological, 030226 pharmacology & pharmacy, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, medicine, Humans, Dosing, General Pharmacology, Toxicology and Pharmaceutics, Child, business.industry, Research, General Neuroscience, Liver Neoplasms, Infant, Articles, General Medicine, Clinical trial, Tolerability, Child, Preschool, Practice Guidelines as Topic, Toxicity, Female, Therapeutics. Pharmacology, Public aspects of medicine, RA1-1270, business, Pediatric Hepatocellular Carcinoma, medicine.drug
الوصف: Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady‐state exposures (area under the concentration curve from 0 to 12‐h [AUC0–>12 h]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m2/dose) or a pharmacokinetically guided dose targeting an AUC0–>12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in‐target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.
اللغة: English
تدمد: 1752-8054
1752-8062
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d74b242683dc0d3bfb494911bbea9a9Test
https://doaj.org/article/fa3bdba6f6544244bf67514913dc3bc8Test
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....2d74b242683dc0d3bfb494911bbea9a9
قاعدة البيانات: OpenAIRE