Short summary

This register-based study aims to investigate a potential drug-drug interaction between the chemotherapeutic agent paclitaxel and the thrombocyte inhibitor clopidogrel. The project examines whether simultaneous treatment of cancer patients with clopidogrel and paclitaxel increases the risk and severity of paclitaxel adverse events, necessitates premature termination of the treatment, or even impairs the overall survival. 

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Rationale

Paclitaxel is a chemotherapeutic drug used in the treatment of cancers, including ovarian, breast and lung cancer. Approximately 500, 4800 and 4500 new cases of each of these cancers were diagnosed in Denmark in year 2013. Paclitaxel is dosed individually according to body surface area. As for other chemotherapeutics, severe adverse events such as sensory neuropathy and neutropenia are frequent. Adverse events are classified in severity according to the Common Terminology Criteria of Adverse Events (CTCAE), and severe toxicity, grade III, typically necessitates hospital readmission. Grade III neuropathy and neutropenia occur in around 17% and 2% of the paclitaxel treated respectively, and variation in toxicity can be caused by e.g. genetics, comorbidity or perhaps by drug-drug interactions.

Clopidogrel is thrombocyte inhibitor used prophylactically to prevent the occurrence of atherosclerosis and ischemia. Many patients having received a stent in the coronary arteries are treated with clopidogrel in the following 12 months postoperatively. In a newly published study, it was found that a clopidogrel metabolite, clopidogrel acyl-Beta-D-glucuronide, inhibits the metabolism of the antidiabetic agent repaglinide through inhibition of the cytochrome P450 liver enzyme CYP2C8. As CYP2C8 is an important enzyme in the paclitaxel metabolism in the liver, it is reasonable to suggest that simultaneous paclitaxel and clopidogrel treatment will increase the risk and degree of paclitaxel toxicity. In a population of paclitaxel treated patients, between 2 and 7 % of these patients are estimated to receive clopidogrel at the same time, and hence are potentially at risk of developing serious adverse events.

From a previous study, we know of a single patient being treated simultaneously with both drugs. She developed serious toxicity that necessitated hospitalization and ultimately discontinuation due to adverse events. Furthermore, the case was backed up by an in vitro experiment that demonstrated a significant drug-drug interaction between paclitaxel and clopidogrel acyl-Beta-D-glucuronide. It is thus reasonable to investigate if there is a potentially clinically relevant drug-drug interaction between clopidogrel and paclitaxel.

This study aims to investigate a potential drug-drug interaction between the chemotherapeutic agent paclitaxel and the thrombocyte inhibitor clopidogrel. The project examines whether simultaneous treatment of cancer patients with clopidogrel and paclitaxel

1. increases the risk and severity of paclitaxel adverse events
2. necessitates premature termination of paclitaxel treatment
3. impairs the overall survival 

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Description of the cohort

Patients are included in the cohort from 7 different Departments of Oncology in Denmark. They are included if they have received at least one treatment of paclitaxel between 1/1-2004 and 31/7-2015. Paclitaxel is used in the treatment primarily of ovarian, breast and lung cancer, and we expect most patients to suffer from these diagnoses, and hence a large percentage to be women. The exposed population is simultaneously treated with clopidogrel and is expected to have a heart disease. To control for confounding by indication, the control population must therefore be in simultaneous treatment with a different thrombocyte inhibitor than clopidogrel. 

It is estimated that at least 4.000 patients have been treated with paclitaxel in the included hospital wards within the given time period. Of those, at least 2 % are expected to receive clopidogrel simultaneously, and thus the exposed population will roughly be 80 patients. Each exposed patient is matched to two controls, and thus expected number of participants is 240 patients.

Data and biological material

Each identified patient is screened in the Danish National Prescription Database for potential clopidogrel consumption using redemption of a clopidogrel prescription during the same period as the paclitaxel treatment as a proxy for clopidogrel consumption. Each exposed patient is matched according to age and sex to two unexposed control patients, from the identified paclitaxel treated cohort, with no redeemed clopidogrel prescription in the paclitaxel treatment period, but redemption of a prescription on acetylsalicylic acid. Thereby controls and cases have approximately equal degree of cardiovascular comorbidity.

Oncologists from each hospital review the medical charts of each identified patient in both the exposed and unexposed groups using a Case Report Form (CRF). Data will be collected on

• neuropathy (primary outcome)
• discontinuation of paclitaxel due to paclitaxel related toxicity
• reduction in dose of paclitaxel due to paclitaxel related toxicity
• leucocytes and neutrophils
• overall survival
• delay of next treatment due to paclitaxel related toxicity

Furthermore, data on dose regimen, type of cancer, cancer stage, performance status, co-medication, biochemical parameters, age, weight and sex of each patient is collected.

Collaborating researchers and departments

Clinical Pharmacology, University of Southern Denmark

• Principal Investigator and Stud.pharm Katrine Agergaard Sørensen
• Main Supervisor Troels K. Bergmann, MD, PhD
• Cand.pharm Tore Bjerregaard Stage, PhD
• Professor Jesper Hallas, MD
• Professor and Head of Research Unit Kim Brøsen, MD

Department of Oncology, Odense University Hospital

• Physician Trine Lembrecht Jørgensen

Department of Oncology, Vejle Hospital

• Senior physician and associate professor Karina Dahl Steffensen, MD, PhD

Department of Oncology, Aalborg University Hospital

• Physician Bente Lund
• Physician Marie Louise Milo

Department of Oncology, Aarhus University Hospital

• Specialist doctor Ranva Espergård Hessel

Department of Oncology, Herlev Hospital

• Physician Johannes Wirenfeldt Vad Pedersen, PhD

Department of Oncology, Copenhagen University Hospital, Rigshospitalet

• Senior Physician Paul Morten Mau-Sørensen, MD, PhD

Department of Oncology, Herning Region Hospital

• Senior Physician Nina Keldsen