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Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors.

ABSTRACT: Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the safety, efficacy, and pharmacokinetics of intravenous topotecan given in combination with erlotinib.Patients received 150 mg of oral erlotinib daily and a 30 min intravenous infusion of topotecan on days 1-5 of a 21-day cycle. Dosage escalation of topotecan occurred with a starting dosage of 0.75 mg/m(2). The pharmacokinetics of topotecan was evaluated on day 1 of cycle 1 without erlotinib and on day 1 of cycle 2 or 3 with erlotinib.Twenty-nine patients were enrolled. The maximum tolerated dosage was determined to be 1.0 mg/m(2). Dose-limiting toxicities included neutropenia and thrombocytopenia. The average duration of treatment was 97 days. Two partial responses were observed. Topotecan clearance and exposure were similar with and without erlotinib.The combination of topotecan and erlotinib is tolerable at clinically effective doses. Erlotinib does not affect the disposition of topotecan to a clinically significant extent.

SUBMITTER: Stewart CF

PROVIDER: S-EPMC3965853 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other

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Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors.

Stewart Clinton F CF Tagen Michael M Schwartzberg Lee S LS Blakely L Johnetta LJ Tauer Kurt W KW Smiley Linda M LM

Cancer chemotherapy and pharmacology 20140122 3

<h4>Purpose</h4>Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the safety, efficacy, and pharmacokinetics of intravenous topotecan given in combination with erlotinib.<h4>Methods</h4>Patients received 150 mg of oral erlotinib daily and a ...[more]

PMID: 24448640

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Project description:Contezolid is a novel oxazolidinone antibiotic with a promising safety profile. Oral contezolid and its intravenous (IV) prodrug contezolid acefosamil (CZA) are in development for treatment of diabetic foot and acute bacterial skin and skin structure infections (ABSSSI). The prodrug CZA is converted to active contezolid via intermediate MRX-1352. This study aimed to provide the pharmacokinetic rationale for safe, effective, and flexible dosage regimens with initial IV CZA followed by oral contezolid. We simultaneously modeled plasma concentrations from 110 healthy volunteers and 74 phase 2 patients with ABSSSI via population pharmacokinetics (using the importance sampling estimation algorithm), and optimized dosage regimens by Monte Carlo simulations. This included data on MRX-1352, contezolid, and its metabolite MRX-1320 from 66 healthy volunteers receiving intravenous CZA (150-2400 mg) for up to 28 days, and 74 patients receiving oral contezolid [800 mg every 12 h (q12h)] for 10 days. The apparent total clearance for 800 mg oral contezolid with food was 16.0 L/h (23.4% coefficient of variation) in healthy volunteers and 17.7 L/h (53.8%) in patients. CZA was rapidly converted to MRX-1352, which subsequently transformed to contezolid. The proposed dosage regimen used an IV CZA 2000 mg loading dose with 1000 mg IV CZA q12h as maintenance dose(s), followed by 800 mg oral contezolid q12h (with food). During each 24-h period, Monte Carlo simulations predicted this regimen to achieve consistent areas under the curve of 91.9 mg·h/L (range: 76.3-106 mg·h/L) under all scenarios. Thus, this regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.IMPORTANCEThis study provides the population pharmacokinetic rationale for the dosage regimen of the intravenous (IV) prodrug contezolid acefosamil (CZA) followed by oral contezolid. We developed the first integrated population model for the pharmacokinetics of the MRX-1352 intermediate prodrug, active contezolid, and its main metabolite MRX-1320 based on data from three clinical studies in healthy volunteers and phase 2 patients. The proposed regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.

Dataset Information

Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors.

Publications

Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors.

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