N de Rouw1, S Croes2, R Posthuma3, D E Agterhuis3, J J A O Schoenmaekers3, H J Derijks4, D M Burger5, A M Dingemans3, R Ter Heine5. 1. Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, the Netherlands; ZANOB Hospital Pharmacy, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands. Electronic address: Nikki.derouw@radboudumc.nl. 2. Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, Maastricht, the Netherlands; CAPHRI-Care and Primary Health Research Institute, Maastricht University Medical Center, Maastricht, the Netherlands. 3. Department of Pulmonology, GROW, Maastricht University Medical Center, Maastricht, the Netherlands. 4. Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, the Netherlands; ZANOB Hospital Pharmacy, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands. 5. Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, the Netherlands.
Abstract
OBJECTIVES: Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment. METHODS: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg·h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated. RESULTS: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg·h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed. CONCLUSION: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.
OBJECTIVES:Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment. METHODS: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg·h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated. RESULTS: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg·h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed. CONCLUSION: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.
Authors: Nikki de Rouw; Berber Piet; Hieronymus J Derijks; Michel M van den Heuvel; Rob Ter Heine Journal: Drug Saf Date: 2021-11-06 Impact factor: 5.606
Authors: Nikki de Rouw; Sabine Visser; Stijn L W Koolen; Joachim G J V Aerts; Michel M van den Heuvel; Hieronymus J Derijks; David M Burger; Rob Ter Heine Journal: Cancer Chemother Pharmacol Date: 2019-12-18 Impact factor: 3.333