Jeanne Allard1, Mathilde Bonnet2, Lucie Laurent3, Mohamed Bouattour4, Marie-Pauline Gagaille2, Vincent Leclerc2. 1. Pharmacy Department, DMU PRISME, APHP, Beaujon Hospital, 92110, Clichy, France. jeanne.allard@aphp.fr. 2. Pharmacy Department, DMU PRISME, APHP, Beaujon Hospital, 92110, Clichy, France. 3. Department of Pancreatology, DMU DIGEST, APHP, Beaujon Hospital, 92110, Clichy, France. 4. Liver Cancer Unit, DMU DIGEST, APHP, Beaujon Hospital, 92110, Clichy, France.
Abstract
PURPOSE: Gemcitabine and nab-paclitaxel association can be used in first- or second-line treatment for metastatic pancreatic adenocarcinoma. Here, we report five cases of supposed gemcitabine-induced thrombotic microangiopathy (G-TMA), four of them with nab-paclitaxel. We assumed that nab-paclitaxel could be responsible for a potential drug interaction with gemcitabine, increasing the risk of thrombotic microangiopathy occurrence. METHODS: Clinicians reported cases of supposed G-TMA that were declared to the Pharmacovigilance center. We collected the patients' data (clinical and biological characteristics), calculated an incidence rate of G-TMA in our center, and a Naranjo score for each patient. We also reviewed literature on a potential drug interaction between nab-paclitaxel and gemcitabine. RESULTS: Four patients were treated with nab-paclitaxel/gemcitabine and one with gemcitabine alone. The time onset of supposed G-TMA was 2 to 11 months. Patients developed anemia, thrombocytopenia, and renal failure. The incidence rate of supposed G-TMA was 2.7% in our center compared to 0.31% (Meyler's Side Effect of Drugs) and 0.01% in the gemcitabine's summary of product characteristics. Literature review outlined an increase of gemcitabine's plasmatic concentrations induced by nab-paclitaxel (Drugs® website) and a potentiation of gemcitabine's effect by nab-paclitaxel in murine models. This study showed that nab-paclitaxel inhibits cytidine deaminase's activity (responsible for gemcitabine's metabolism) and increases gemcitabine's active metabolite concentrations (gemcitabine triphosphate) in tumor tissues. CONCLUSION: High incidence rate of G-TMA was observed in our cohort due to a potential drug interaction between nab-paclitaxel and gemcitabine with an increased risk of developing G-TMA. Additional pharmacological and pharmaco-epidemiological investigations are mandatory to explore this hypothesis.
PURPOSE: Gemcitabine and nab-paclitaxel association can be used in first- or second-line treatment for metastatic pancreatic adenocarcinoma. Here, we report five cases of supposed gemcitabine-induced thrombotic microangiopathy (G-TMA), four of them with nab-paclitaxel. We assumed that nab-paclitaxel could be responsible for a potential drug interaction with gemcitabine, increasing the risk of thrombotic microangiopathy occurrence. METHODS: Clinicians reported cases of supposed G-TMA that were declared to the Pharmacovigilance center. We collected the patients' data (clinical and biological characteristics), calculated an incidence rate of G-TMA in our center, and a Naranjo score for each patient. We also reviewed literature on a potential drug interaction between nab-paclitaxel and gemcitabine. RESULTS: Four patients were treated with nab-paclitaxel/gemcitabine and one with gemcitabine alone. The time onset of supposed G-TMA was 2 to 11 months. Patients developed anemia, thrombocytopenia, and renal failure. The incidence rate of supposed G-TMA was 2.7% in our center compared to 0.31% (Meyler's Side Effect of Drugs) and 0.01% in the gemcitabine's summary of product characteristics. Literature review outlined an increase of gemcitabine's plasmatic concentrations induced by nab-paclitaxel (Drugs® website) and a potentiation of gemcitabine's effect by nab-paclitaxel in murine models. This study showed that nab-paclitaxel inhibits cytidine deaminase's activity (responsible for gemcitabine's metabolism) and increases gemcitabine's active metabolite concentrations (gemcitabine triphosphate) in tumor tissues. CONCLUSION: High incidence rate of G-TMA was observed in our cohort due to a potential drug interaction between nab-paclitaxel and gemcitabine with an increased risk of developing G-TMA. Additional pharmacological and pharmaco-epidemiological investigations are mandatory to explore this hypothesis.
Authors: Thierry Conroy; Pascal Hammel; Mohamed Hebbar; Meher Ben Abdelghani; Alice C Wei; Jean-Luc Raoul; Laurence Choné; Eric Francois; Pascal Artru; James J Biagi; Thierry Lecomte; Eric Assenat; Roger Faroux; Marc Ychou; Julien Volet; Alain Sauvanet; Gilles Breysacher; Frédéric Di Fiore; Christine Cripps; Petr Kavan; Patrick Texereau; Karine Bouhier-Leporrier; Faiza Khemissa-Akouz; Jean-Louis Legoux; Béata Juzyna; Sophie Gourgou; Christopher J O'Callaghan; Claire Jouffroy-Zeller; Patrick Rat; David Malka; Florence Castan; Jean-Baptiste Bachet Journal: N Engl J Med Date: 2018-12-20 Impact factor: 91.245
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