Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment
Autor: | Gerald J. Fetterly, Joel S. Owen, Julie A. Passarell, Kim Stuyckens, Juan Jose Perez-Ruixo, Arturo Soto-Matos, Peter Zannikos, Miguel Angel Izquierdo |
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Rok vydání: | 2007 |
Předmět: |
Adult
Male Cancer Research medicine.drug_class Finite Element Analysis Population Anti-Inflammatory Agents Antineoplastic Agents Dioxoles Pharmacology Toxicology Dexamethasone Clinical Trials Phase II as Topic Pharmacokinetics Tetrahydroisoquinolines Humans Medicine Computer Simulation Pharmacology (medical) education Transaminases Trabectedin Aged Aged 80 and over Analysis of Variance education.field_of_study Models Statistical Clinical Trials Phase I as Topic business.industry Alanine Transaminase Drug Tolerance Middle Aged Intercalating Agents NONMEM Oncology Data Interpretation Statistical Pharmacodynamics Transaminitis Corticosteroid Female Chemical and Drug Induced Liver Injury business Algorithms Software medicine.drug |
Zdroj: | Cancer Chemotherapy and Pharmacology. 62:135-147 |
ISSN: | 1432-0843 0344-5704 |
Popis: | Reversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients. Trabectedin was administered to 711 patients as monotherapy (dose range: 0.024–1.8 mg/m2) as 1-, 3-, or 24-h infusions every 21 days; 1- or 3-h infusions on days 1, 8, and 15 every 28 days; or 1-h infusions daily for five consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG performance status scores (89.7% pts ≤ 1), and body weight (36–122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected patient factors on the time course of ALT and the effectiveness of the dose reduction strategy. A precursor-dependent PKPD model described the temporal relationship between ALT elevation and trabectedin concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentrations. Overall, 66% of patients had transaminitis. Mean predicted (%SEM) baseline ALT (ALTo) and t 1/2 in plasma were 31.5 (5.1) IU/L and 1.5 days, respectively. The magnitude of the trabectedin stimulation of the ALT transfer rate from hepatocytes to plasma was 11.4% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of trabectedin-induced ALT release from hepatocyte by 63% (P |
Databáze: | OpenAIRE |
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