Dataset Information

Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors.

ABSTRACT: PURPOSE:Erlotinib (Tarceva®), a potent small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been evaluated to treat infants and children with primary brain tumors. The pharmacokinetics of erlotinib and its primary metabolite OSI-420 were characterized and exposure-safety associations were investigated. METHODS:This analysis involved patients enrolled in two clinical studies and receiving oral erlotinib once daily as part of treatment. Single-dose and steady-state erlotinib and OSI-420 plasma concentrations were assayed using HPLC-MS/MS methods. Population pharmacokinetic modeling and univariate covariate analysis evaluating demographic, clinical and selected CYP3A5, CYP3A4, ABCB1, and ABCG2 genotypes were performed. Associations between erlotinib and OSI-420 pharmacokinetics, and with toxicities (diarrhea and skin rash) occurring post-dose were explored. RESULTS:Data from 47 patients (0.7-19 years old) were collected and best fitted by one-compartment linear models. Erlotinib and OSI-420 apparent clearances (CL/F and CLm/Fm) were higher in patients?

SUBMITTER: Reddick SJ

PROVIDER: S-EPMC6773504 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors.

Reddick Samuel J SJ Campagne Olivia O Huang Jie J Onar-Thomas Arzu A Broniscer Alberto A Gajjar Amar A Stewart Clinton F CF

Cancer chemotherapy and pharmacology 20190807 4

<h4>Purpose</h4>Erlotinib (Tarceva<sup>®</sup>), a potent small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been evaluated to treat infants and children with primary brain tumors. The pharmacokinetics of erlotinib and its primary metabolite OSI-420 were characterized and exposure-safety associations were investigated.<h4>Methods</h4>This analysis involved patients enrolled in two clinical studies and receiving oral erlotinib once daily as part of treatment. Si ...[more]

PMID: 31392390

Similar Datasets

Project description:Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors.A 3?+?3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1. The primary objectives of the study were to assess safety and tolerability, identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose, and identify the recommended phase II dose (RP2D). Evaluation of a dose-expansion cohort at the RP2D was performed.Fifty-seven patients were treated in the study. All patients experienced at least one adverse event (AE). Grade ?3 AEs, serious AEs, and deaths were reported in 38 (66.7%), 19 (33.3%), and 4 (7.0%) patients, respectively. DLTs occurred in nine patients across eight cohorts and the RP2D was determined to be 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib. Two patients (3.5%) experienced partial response and 19 (33.3%) had stable disease.Combining pictilisib with erlotinib in patients with advanced solid tumors is feasible; however, antitumor activity is limited. Additional studies may identify patients likely to benefit from combined inhibition of EGFR and PI3K pathways.Combining drugs targeting different signaling pathways in cancer growth and survival could overcome drug resistance and improve antitumor activity. In this first-in-human study for the combination, addition of the PI3K inhibitor pictilisib to the EGFR tyrosine kinase inhibitor erlotinib resulted in toxicity that led to dose and schedule modifications to identify a tolerable recommended phase II dose of 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib daily. The limited antitumor activity observed, however, suggests that additional studies are needed to identify patients most likely to benefit from combined EGFR and PI3K inhibition.

Dataset Information

Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors.

Publications

Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets