SummaryVenous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 ± 4 and 65 ± 3 yrs) and creati-nine clearance (114 ± 15 and 62 ± 6 ml · min –1). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 ± 11 yrs and creatinine clearance of 76 ± 8 ml · min –1. Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg–1 for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the begining and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.

What is already known about this subject • Creatinine clearance (CL) is used to assess glomerular filtration rate (GFR). However, it is known to slightly overestimate the true GFR, due to renal tubular secretion of creatinine. • During phase I‐III clinical trials, a 10–15% increase in serum creatinine has been observed both in healthy subjects and patients receiving the new antiarrhythmic agent dronedarone. What this study adds • Dronedarone affects the renal handling of creatinine and N‐methylnicotinamide, two cations, while leaving unchanged GFR, assessed through sinistrin CL, and renal plasma flow and anion secretion, assessed through para‐amino‐hippurate CL. • This suggests a specific action of dronedarone on renal organic cation transport explaining the limited, reversible effect of dronedarone on serum creatinine, which must not be interpreted as reflecting an impairment of renal function, but which may indicate an interaction potential with cationic drugs. Aims To assess the effects of dronedarone on renal function and tubular cation handling. Methods Twelve healthy males were enrolled in a randomized, cross‐over, placebo‐controlled, double‐blind study. They received 400 mg dronedarone or placebo twice daily for 7 days. Baseline and on‐treatment renal function tests were performed under strict standardization of intakes, by assessing creatinine, sinistrin, para‐amino‐hippurate (PAH) and N‐methylnicotinamide (NMN) CLs, and electrolyte excretion. Results Compared with placebo, dronedarone significantly decreased renal creatinine CL (mean 138–119 ml min−1 after dronedarone vs. 142–149 ml min−1 after placebo) and NMN CL (448–368 ml min−1vs. 435–430 ml min−1), but did not alter renal sinistrin CL, PAH CL and other renal parameters. Conclusions Dronedarone reduces renal creatinine and NMN clearance by about 18%, without evidence of an effect on GFR, renal plasma flow or electrolyte exchanges. This suggests a specific partial inhibition of tubular organic cation transporters (OCT). A limited increase in serum creatinine is therefore expected with dronedarone treatment, but does not mean there is a decline in renal function.

Background/Aims Creatinine clearance (CL) is used to assess glomerular filtration rate (GFR). During the clinical development of dronedarone, a new antiarrhythmic agent, a 10–15% increase in serum creatinine was noticed, as also shown recently for amiodarone. This study aimed to assess dronedarone effects on renal function and tubular cations handling. Methods 12 healthy males were enrolled in a randomised, cross‐over, placebo‐controlled, double‐blind study. They received 400mg dronedarone or placebo bid for 7 days. Baseline and on‐treatment renal function tests were performed under strict standardization of intakes, by assessing creatinine, sinistrin, para‐amino‐hippurate (PAH) and N‐methylnicotinamide (NMN) CLs, and electrolyte excretions. Results Dronedarone did not alter sinistrin CL compared to placebo, but decreased creatinine CL significantly (mean 138 to 119mL/min under dronedarone vs 142 to 149 under placebo; p=0.04) and NMN CL marginally (448 to 368 vs 435 to 431; p=0.06), while PAH CL and other renal parameters remained unaffected. Conclusion Dronedarone compared to placebo reduces renal creatinine and NMN CLs by about 17%, without evidence of a true effect on GFR, renal plasma flow or electrolyte exchanges. This suggests a specific inhibition of tubular organic cation transporters (OCT). A limited increase in serum creatinine is therefore expected under dronedarone treatment, but does not mean a decline in renal function. Clinical Pharmacology & Therapeutics (2005) 77, P10–P10; doi:

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