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Population pharmacokinetics-pharmacodynamics of sunitinib in pediatric patients with solid tumors. | LitMetric

Population pharmacokinetics-pharmacodynamics of sunitinib in pediatric patients with solid tumors.

Cancer Chemother Pharmacol

Pfizer Global Product Development, 10646 Science Center Drive, CB10, La Jolla, CA, 92121, USA.

Published: August 2020

AI Article Synopsis

  • The study investigated the safety profile of sunitinib, a cancer drug, in children with solid tumors, analyzing how drug exposure affects various safety endpoints.
  • It involved data from 59 children aged 2-21 and examined factors that could influence the drug's pharmacokinetics (PK) and pharmacodynamics (PD) using a nonlinear mixed-effects model.
  • The results showed that body surface area (BSA) significantly affected drug clearance and distribution, and higher sunitinib concentrations were linked to an increased likelihood of adverse effects, with no other demographic factors influencing this relationship.

Article Abstract

Purpose: The safety profile of sunitinib in children, including the impact of sunitinib exposure on safety endpoints, was assessed using population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models.

Methods: Data were from two clinical studies in 59 children with solid tumors (age range 2-21 years, 28 male/31 female, body weight range 16.2-100 kg, body surface are [BSA] range 0.7-2.1 m). Analysis of covariates that affected PK and PD parameters was conducted using a nonlinear mixed-effects model. Safety and tolerability endpoints were absolute neutrophil count, hepatic transaminases, diastolic blood pressure, hemoglobin, lymphocyte count, platelet count, white blood cell count, hand-foot syndrome, fatigue, nausea, intracranial hemorrhage, and vomiting.

Results: The models well described the time courses of concentrations of sunitinib and its primary active metabolite SU012662, as well as safety and tolerability endpoints. In PK models for sunitinib and SU012662, BSA was the only covariate that statistically significantly affected apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). Higher BSA was associated with greater CL/F and Vc/F. No statistically significant covariates were identified in the PK-PD models. For safety endpoints that had a sufficient number of adverse events, a higher probability of adverse events was associated with higher average plasma sunitinib concentrations.

Conclusion: In PK models, BSA was the only covariate that affected major PK parameters of sunitinib and SU012662. Based on analysis of safety and tolerability endpoints, the PK-PD relationships were mainly driven by sunitinib plasma exposures and were not affected by age, sex, respective baseline safety endpoint values, baseline Eastern Cooperative Oncology Group performance status, or body size.

Trial Registration: ClinicalTrials.gov: NCT00387920 (registered October 13, 2006), NCT01462695 (registered October 31, 2011).

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417410PMC
http://dx.doi.org/10.1007/s00280-020-04106-zDOI Listing

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