Microangiopathy associated with gemcitabine: a drug interaction with nab-paclitaxel? A case series and literature review

• Published in: European journal of clinical pharmacology 2022-07, Vol.78 (7), p.1087-1093
• Main Authors: Allard, Jeanne, Bonnet, Mathilde, Laurent, Lucie, Bouattour, Mohamed, Gagaille, Marie-Pauline, Leclerc, Vincent
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Adenocarcinoma - secondary; Albumins; Animal models; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cytidine deaminase; Deoxycytidine - analogs & derivatives; Drug interaction; Drug Interactions; Epidemiology; Gemcitabine; Humans; Literature reviews; Metastases; Mice; Paclitaxel; Paclitaxel - adverse effects; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Patients; Pharmacodynamics; Pharmacology/Toxicology; Pharmacovigilance; Renal failure; Thrombocytopenia; Thrombotic Microangiopathies - chemically induced; Thrombotic Microangiopathies - drug therapy; Thrombotic microangiopathy; Tumors
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-022-03324-z

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.