Tinzaparin and other low-molecular-weight heparins: what is the evidence for differential dependence on renal clearance?

Kristian B Johansen, Torben Balchen, Kristian B Johansen, Torben Balchen

Abstract

Since low-molecular-weight heparins (LMWHs) are eliminated preferentially via the kidneys, the potential for accumulation of these agents (and an increased risk of bleeding) is of particular concern in populations with a high prevalence of renal impairment, such as the elderly and patients with cancer. The risk of clinically relevant accumulation of anticoagulant activity as a result of a reduction in renal elimination appears to differ between LMWHs. This review describes the elimination pathways for LMWHs and assesses whether the relative balance between renal and non-renal (cellular) clearance may provide a mechanistic explanation for the differences in accumulation that have been observed between LMWHs in patients with impaired renal function. Clearance studies in animals, cellular binding studies and clinical studies all indicate that the balance between renal and non-renal clearance is dependent on the molecular weight (MW): the higher the MW of the LMWH, the more the balance is shifted towards non-renal clearance. Animal studies have also provided insights into the balance between renal and non-renal clearance by examining the effect of selective blocking of one of the elimination pathways, and it is most likely that cellular clearance is increased to compensate for decreased renal function. Tinzaparin (6,500 Da) has the highest average MW of the marketed LMWHs, and there is both clinical and preclinical evidence for significant non-renal elimination of tinzaparin, making it less likely that tinzaparin accumulates in patients with renal impairment compared with LMWHs with a lower MW distribution. On the basis of our findings, LMWHs that are less dependent on renal clearance may be preferred in patient populations with a high prevalence of renal insufficiency.

Keywords: Clearance; Clinical; Elimination; Low-molecular-weight heparin (LMWH); Non-clinical; Pharmacodynamics; Pharmacokinetics; Renal insufficiency; Tinzaparin.

Figures

Figure 1
Figure 1
Effect of MW and dose on the balance between renal and non-renal elimination of UFH and LMWH: amount of 125I-UFH (circles) and 125I-nadroparin (squares) cleared from the blood according to the dose delivered. The solid lines show the total elimination. The curves have been decomposed by drawing a parallel to its linear part: the stippled lines (a) represent the non-saturable mechanism of disappearance and the dotted lines (b) represent the saturable mechanism of disappearance for the two test articles (nadroparin and UFH). Adapted and reprinted from Thrombosis Research, Vol 46, Boneu B et al, The disappearance of a low molecular weight heparin fraction (CY 216) differs from standard heparin in rabbits, pages 845–853, copyright 1987, with permission from Elsevier [20].

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