Thierry Gustot1,2,3,4,5, Rob Ter Heine6, Elisa Brauns1, Frédéric Cotton7, Frédérique Jacobs8, Roger J Brüggemann6,9. 1. Department of Gastroenterology and Hepato-Pancreatology, CUB Erasme, Brussels, Belgium. 2. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium. 3. Inserm Unité 1149, Centre de Recherche sur l'inflammation (CRI), Paris, France. 4. UMR S_1149, Université Paris Diderot, Paris, France. 5. The EASL-CLIF Consortium, European Foundation-CLIF, Barcelona, Spain. 6. Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands. 7. Clinical Chemistry Department, LHUB-ULB, Brussels, Belgium. 8. Department of Infectious Diseases, CUB Erasme, Brussels, Belgium. 9. Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.
Abstract
Background: Controversies remain over caspofungin dosage adjustments in cirrhosis, particularly Child-Pugh (CP) B or C. The product information for of caspofungin recommends a maintenance dose reduction from 50 to 35 mg for patients with CP-B cirrhosis. Objectives: To quantify the impact of cirrhosis and the severity of hepatic impairment on the pharmacokinetics (PK) of caspofungin. Patients and methods: We performed PK studies of a single 70 mg dose of caspofungin in patients with decompensated CP-B (n = 10) or CP-C (n = 10) cirrhosis and of multiple doses in 21 non-cirrhotic ICU patients with hypoalbuminaemia. A Monte Carlo simulation was performed to investigate the impact of a maintenance dose reduction from 50 to 35 mg on the steady-state area under the 24 h concentration-time curve. Results: We observed a marginal reduction of caspofungin clearance in a PK study in patients with decompensated CP-B or CP-C cirrhosis. Dose reduction to 35 mg in cirrhotic patients resulted in lower drug exposure than with the approved dose in non-cirrhotic patients. Conclusions: In contrast to the product information, we recommend giving the full dose of caspofungin regardless of the presence and severity of cirrhosis to avoid a subtherapeutic exposure.
Background: Controversies remain over caspofungin dosage adjustments in cirrhosis, particularly Child-Pugh (CP) B or C. The product information for of caspofungin recommends a maintenance dose reduction from 50 to 35 mg for patients with CP-B cirrhosis. Objectives: To quantify the impact of cirrhosis and the severity of hepatic impairment on the pharmacokinetics (PK) of caspofungin. Patients and methods: We performed PK studies of a single 70 mg dose of caspofungin in patients with decompensated CP-B (n = 10) or CP-C (n = 10) cirrhosis and of multiple doses in 21 non-cirrhotic ICU patients with hypoalbuminaemia. A Monte Carlo simulation was performed to investigate the impact of a maintenance dose reduction from 50 to 35 mg on the steady-state area under the 24 h concentration-time curve. Results: We observed a marginal reduction of caspofungin clearance in a PK study in patients with decompensated CP-B or CP-C cirrhosis. Dose reduction to 35 mg in cirrhotic patients resulted in lower drug exposure than with the approved dose in non-cirrhotic patients. Conclusions: In contrast to the product information, we recommend giving the full dose of caspofungin regardless of the presence and severity of cirrhosis to avoid a subtherapeutic exposure.
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