Marie-Rose B S Crombag1,2, Aurelia H M de Vries Schultink3,4, Stijn L W Koolen5, Sophie Wijngaard5, Markus Joerger6, Jan H M Schellens4,7, Thomas P C Dorlo3,4, Nielka P van Erp8, Ron H J Mathijssen5, Jos H Beijnen3,4, Alwin D R Huitema3,4,9. 1. Department of Pharmacy &Pharmacology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, the Netherlands. m.crombag@nki.nl. 2. Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands. m.crombag@nki.nl. 3. Department of Pharmacy &Pharmacology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, the Netherlands. 4. Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands. 5. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 6. Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland. 7. Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands. 8. Department of Pharmacy and Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. 9. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Abstract
PURPOSE: Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel. METHODS: PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model. RESULTS: In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age. CONCLUSION: In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.
PURPOSE: Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel. METHODS: PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model. RESULTS: In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age. CONCLUSION: In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.
Entities:
Keywords:
age differences; older patients; paclitaxel; pharmacokinetics
Authors: Marie-Rose B S Crombag; Stijn L W Koolen; Sophie Wijngaard; Markus Joerger; Thomas P C Dorlo; Nielka P van Erp; Ron H J Mathijssen; Jos H Beijnen; Alwin D R Huitema Journal: Pharm Res Date: 2019-10-15 Impact factor: 4.200
Authors: Leni van Doorn; Marie-Rose B S Crombag; Hánah N Rier; Jeroen L A van Vugt; Charlotte van Kesteren; Sander Bins; Ron H J Mathijssen; Mark-David Levin; Stijn L W Koolen Journal: Pharmaceuticals (Basel) Date: 2021-01-09