PURPOSE: Marked interindividual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage individualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization. PATIENTS AND METHODS: Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi (99mTc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood sampling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment. RESULTS: There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P < .01) and hepatic (99m)Tc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P < .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02). CONCLUSION: Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.
PURPOSE: Marked interindividual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage individualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization. PATIENTS AND METHODS: Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi (99mTc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood sampling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment. RESULTS: There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P < .01) and hepatic (99m)Tc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P < .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02). CONCLUSION: Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.
Authors: Kathleen M Giacomini; Shiew-Mei Huang; Donald J Tweedie; Leslie Z Benet; Kim L R Brouwer; Xiaoyan Chu; Amber Dahlin; Raymond Evers; Volker Fischer; Kathleen M Hillgren; Keith A Hoffmaster; Toshihisa Ishikawa; Dietrich Keppler; Richard B Kim; Caroline A Lee; Mikko Niemi; Joseph W Polli; Yuichi Sugiyama; Peter W Swaan; Joseph A Ware; Stephen H Wright; Sook Wah Yee; Maciej J Zamek-Gliszczynski; Lei Zhang Journal: Nat Rev Drug Discov Date: 2010-03 Impact factor: 84.694
Authors: Michael Michael; Winston Liauw; Sue-Anne McLachlan; Emma Link; Annetta Matera; Michael Thompson; Michael Jefford; Rod J Hicks; Carleen Cullinane; Athena Hatzimihalis; Ian G Campbell; Simone Rowley; Phillip J Beale; Christos S Karapetis; Timothy Price; Mathew E Burge Journal: Cancer Chemother Pharmacol Date: 2021-03-23 Impact factor: 3.333
Authors: Jacqueline S L Kloth; Heinz-Josef Klümpen; Huixin Yu; Karel Eechoute; Caroline F Samer; Boen L R Kam; Alwin D R Huitema; Youssef Daali; Aeilko H Zwinderman; Bavanthi Balakrishnar; Roelof J Bennink; Mark Wong; Jan H M Schellens; Ron H J Mathijssen; Howard Gurney Journal: Clin Pharmacokinet Date: 2014-03 Impact factor: 6.447
Authors: Ariel R Topletz; Jennifer B Dennison; Robert J Barbuch; Chad E Hadden; Stephen D Hall; Jamie L Renbarger Journal: Drug Metab Dispos Date: 2013-06-18 Impact factor: 3.922