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

Abstract 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 d...

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Autores principales:	John C. Panetta, Olivia Campagne, Jessica Gartrell, Wayne Furman, Clinton F. Stewart
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/fa3bdba6f6544244bf67514913dc3bc8
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spelling	oai:doaj.org-article:fa3bdba6f6544244bf67514913dc3bc82021-11-19T17:51:34ZPharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study1752-80621752-805410.1111/cts.13069https://doaj.org/article/fa3bdba6f6544244bf67514913dc3bc82021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13069https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract 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.John C. PanettaOlivia CampagneJessica GartrellWayne FurmanClinton F. StewartWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2152-2160 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 John C. Panetta Olivia Campagne Jessica Gartrell Wayne Furman Clinton F. Stewart Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study
description	Abstract 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.
format	article
author	John C. Panetta Olivia Campagne Jessica Gartrell Wayne Furman Clinton F. Stewart
author_facet	John C. Panetta Olivia Campagne Jessica Gartrell Wayne Furman Clinton F. Stewart
author_sort	John C. Panetta
title	Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study
title_short	Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study
title_full	Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study
title_fullStr	Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study
title_full_unstemmed	Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study
title_sort	pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: a simulation study
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/fa3bdba6f6544244bf67514913dc3bc8
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Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study

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