A Multi-Dose Pharmacokinetic Study of Dalteparin in Hemodialysis Patients

Abstract number: P1107

O'Shea^1,2,3* SI, Perry^1* SL, Byrne³ S, Szczech¹ L, Ortel^1,4 TL

^{1,2,3* 1* 1,4 11}Department of Medicine, Duke University Medical Center, Durham, NC, USA ³³School of Pharmacy, University College Cork, Ireland

Background:  Low molecular weight heparins (LMWHs) may be useful antithrombotic agents for patients with renal disease but limited data exists on the kinetics of LMWHs in hemodialysis (HD) patients. Since LMWHs are cleared by the kidney there is a risk of an accumulative anticoagulant effect in HD patients.

Methods:  We conducted a multi-dose pharmacokinetic (PK) study of dalteparin in 12 HD patients. Dalteparin 5000 IU was administered subcutaneously (SC) once daily for 4 days. Anti-factor Xa (anti-FXa) activity was determined at 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 hours after the 3^rd and 4^th doses. Data was analyzed using the WinNonlin® program, using a first-order input and elimination, one compartment model.

Results:  11 patients completed the study. There were no bleeding complications or HD problems. The mean (SD) PK parameters determined were: (1) time to peak antithrombotic effect 3.5 hours (±0.73): (2) peak anti-FXa activity 0.31 IU/mL (±0.18); (3) area under the curve (AUC) 3.24 IU/mL/hr (±1.93); and (4) elimination half-life 3.82 hours (±2.32). In 9 patients, the anti-FXa levels at 24 hrs on day 4 (mean 0.03 IU/mL) were statistically significantly increased compared with levels at 24 hours on day 3 (mean 0.02 IU/mL) (P= 0.007). Despite this low dose of dalteparin, 8 patients had a peak anti-factor FXa level (mean 0.40 IU/ml) close to the suggested range for treatment of thrombosis in patients without renal impairment. In patients without renal impairment the mean peak anti-FXa activity following a single sc dose of dalteparin 5000 IU is 0.41 ± 0.07 IU/mL.

Conclusions:  To our knowledge, this is the first multi-dose PK study of LMWH in HD patients. Our results suggest an accumulative anticoagulant effect of dalteparin in HD patients, which may be clinically significant. LMWHs may be safe, effective antithrombotic agents for HD patients but dose reduction and anti-FXa monitoring are necessary.