Tinzaparin Pharmacokinetics in Patients with Cancer: A Comparative Modeling Study

Abstract

Background

Cancer-associated thrombosis (CAT) is common and a leading cause of mortality in patients with cancer. In specific CAT scenarios, low-molecular-weight heparins (LMWHs), including tinzaparin, are preferred over direct oral anticoagulants. Despite the importance of understanding LMWH pharmacokinetics (PK) in cancer for optimizing CAT management, available data remain limited.

Objectives

To compare tinzaparin PK in cancer and non-cancer patients by developing a population PK model.

Methods

This prospective, multicenter, case–control trial enrolled patients receiving once-daily subcutaneous tinzaparin at a therapeutic dose of 175 IU·kg⁻¹, including matched cancer and non-cancer patients. Plasma anti-Xa activity was measured at multiple time points and analyzed using a non-linear mixed-effect modeling. A PK model was developed, and covariate effects were assessed for parameters of the model. The impact of cancer on tinzaparin PK was evaluated by incorporating cancer status as a categorical covariate.

Results

A total of 333 patients (including 46 matched cancer and non-cancer patients) were included in the analysis. A monocompartmental model with first-order absorption best described tinzaparin PK. The volume of distribution was associated with body weight, while clearance and anti-Xa activity were associated with creatinine clearance. No significant differences were observed between matched cancer and non-cancer patients in anti-Xa activity exposure at day 1 and steady state.

Conclusion

PK profiles were comparable between cancer and non-cancer patients. Additionally, further studies should clarify the role of renal function in guiding tinzaparin dosing.

Keywords

tinzaparin - cancer-associated thromboembolism - pharmacokinetics - modeling

Data Availability Statement

The data will be shared on reasonable request to the corresponding author.

^† Deceased.

Publication History

Received: 11 July 2025

Accepted after revision: 05 November 2025

Article published online:
25 November 2025

• References

• 1 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122 (10) 1712-1723
• 2 Boire A, Burke K, Cox TR. et al. Why do patients with cancer die?. Nat Rev Cancer 2024; 24 (08) 578-589
• 3 Elshoury A, Schaefer JK, Lim MY, Skalla DP, Streiff MB. Update on guidelines for the prevention of cancer-associated thrombosis. J Natl Compr Canc Netw 2022;20(13)
• 4 Frere C, Wahl C, Rueda-Camino JA. et al. A review of latest clinical practice guidelines for the management of cancer-associated thrombosis. Best Pract Res Clin Haematol 2022; 35 (01) 101348
• 5 Frere C, Farge D, Schrag D, Prata PH, Connors JM. Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials. J Hematol Oncol 2022; 15 (01) 69
• 6 Laporte S, Benhamou Y, Bertoletti L. et al; INNOVTE CAT Working Group. Management of cancer-associated thromboembolism in vulnerable population. Arch Cardiovasc Dis 2024; 117 (01) 45-59
• 7 Mahé I, Mayeur D, Couturaud F. et al; INNOVTE CAT Working Group. Anticoagulant treatment of cancer-associated thromboembolism. Arch Cardiovasc Dis 2024; 117 (01) 29-44
• 8 Merli GJ, Groce JB. Pharmacological and clinical differences between low-molecular-weight heparins: implications for prescribing practice and therapeutic interchange. P&T 2010; 35 (02) 95-105
• 9 Amerali M, Politou M. Tinzaparin—a review of its molecular profile, pharmacology, special properties, and clinical uses. Eur J Clin Pharmacol 2022; 78 (10) 1555-1565
• 10 Nutescu A, Spyropoulos AC. Differences among various low-molecular-weight heparins in patients with severe renal insufficiency: an analysis of recent clinical trials. Blood 2008; 112 (11) 4047
• 11 Vathiotis IA, Syrigos NK, Dimakakos EP. Tinzaparin safety in patients with cancer and renal impairment: a systematic review. Clin Appl Thromb Hemost 2021; 27: 1076029620979592
• 12 Rosner MH, Jhaveri KD, McMahon BA, Perazella MA. Onconephrology: the intersections between the kidney and cancer. CA Cancer J Clin 2021; 71 (01) 47-77
• 13 Laporte S, Bertoletti L, Romera A, Mismetti P, Pérez de Llano LA, Meyer G. Long-term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: a meta-analysis of 5 randomized trials in non-cancer and cancer patients. Thromb Res 2012; 130 (06) 853-858
• 14 Bertoletti L, Madridano O, Jiménez D. et al. Cancer-associated thrombosis: trends in clinical features, treatment, and outcomes from 2001 to 2020. JACC Cardiooncol 2023; 5 (06) 758-772
• 15 Chee CE, Ashrani AA, Marks RS. et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood 2014; 123 (25) 3972-3978
• 16 Schmaier AA, Ambesh P, Campia U. Venous thromboembolism and cancer. Curr Cardiol Rep 2018; 20 (10) 89
• 17 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
• 18 Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e24S-e43S
• 19 Atiq F, van den Bemt PM, Leebeek FW, van Gelder T, Versmissen J. A systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency. Eur J Clin Pharmacol 2015; 71 (08) 921-929
• 20 Vermeiren P, Vandevelde A, Devreese K. Stability of anti-factor Xa activity after sample storage. In: XXXVth International Symposium on Technical Innovations in Laboratory Hematology, Abstracts. 2022
• 21 Kuhn E, Lavielle M. Maximum likelihood estimation in nonlinear mixed effects models. Comput Stat Data Anal 2005; 49 (04) 1020-1038
• 22 Samson A, Lavielle M, Mentré F. Extension of the SAEM algorithm to left-censored data in nonlinear mixed-effects model: application to HIV dynamics model. Comput Stat Data Anal 2006; 51 (03) 1562-1574
• 23 Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008; 48: 303-332
• 24 Holford NHG, Anderson BJ. Allometric size: the scientific theory and extension to normal fat mass. Eur J Pharm Sci 2017; 109S: S59-S64
• 25 Hanks F, Philips B, Barton G, Hakes L, McKenzie C. How critical illness impacts drug pharmacokinetics and pharmacodynamics. Pharm J 2022; 308: 1-22
• 26 Siguret V, Pautas E, Février M. et al. Elderly patients treated with tinzaparin (Innohep) administered once daily (175 anti-Xa IU/kg): anti-Xa and anti-IIa activities over 10 days. Thromb Haemost 2000; 84 (05) 800-804
• 27 Yeung J, Dix CHK, Ritchie AG, Kow M, Chen VMY. Tinzaparin for venous thromboembolism in patients with renal impairment: a single-centre, prospective pilot study. Intern Med J 2023; 53 (01) 68-73
• 28 Pautas E, Gouin I, Bellot O, Andreux JP, Siguret V. Safety profile of tinzaparin administered once daily at a standard curative dose in two hundred very elderly patients. Drug Saf 2002; 25 (10) 725-733
• 29 Siguret V, Gouin-Thibault I, Pautas E, Leizorovicz A. No accumulation of the peak anti-factor Xa activity of tinzaparin in elderly patients with moderate-to-severe renal impairment: the IRIS substudy. J Thromb Haemost 2011; 9 (10) 1966-1972
• 30 Lim W, Crowther M, Wang L. et al. Serial trough anti-Xa levels to assess low molecular weight heparin accumulation in patients with chronic kidney disease: analysis of CrCl <30 ml/min from the Trivet study. Blood 2016; 128 (22) 90
• 31 Food and Drug Administration. Innohep® (tinzaparin sodium injection) [online]. Accessed March 30, 2025 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020484s011lbl.pdf
• 32 Fossler MJ, Barrett JS, Hainer JW. et al. Pharmacodynamics of intravenous and subcutaneous tinzaparin and heparin in healthy volunteers. Am J Health Syst Pharm 2001; 58 (17) 1614-1621
• 33 Barrett JS, Gibiansky E, Hull RD. et al. Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis. Int J Clin Pharmacol Ther 2001; 39 (10) 431-446
• 34 Gouin-Thibault I, Mansour A, Caribotti C. et al. Tinzaparin, an alternative to subcutaneous unfractionated heparin, in patients with severe and end-stage renal impairment: a retrospective observational single-center study. J Thromb Haemost 2024; 22 (10) 2864-2872
• 35 Rostin M, Montastruc JL, Houin G, D'Azemar P, Bayrou B, Boneu B. Pharmacodynamics of CY 216 in healthy volunteers: inter-individual variations. Fundam Clin Pharmacol 1990; 4 (01) 17-23
• 36 Carreño FO, Gerhart JG, Helfer VE. et al; Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee. Characterizing enoxaparin's population pharmacokinetics to guide dose individualization in the pediatric population. Clin Pharmacokinet 2024; 63 (07) 999-1014
• 37 Sytema JG, Loef BG, Loovers HM, Boer M, Touw DJ, van Hulst M. The right time to measure anti-Xa activity in critical illness: pharmacokinetics of therapeutic dose nadroparin. Res Pract Thromb Haemost 2023; 7 (04) 100185
• 38 Yáñez JA, Remsberg CM, Sayre CL, Forrest ML, Davies NM. Flip-flop pharmacokinetics—delivering a reversal of disposition: challenges and opportunities during drug development. Ther Deliv 2011; 2 (05) 643-672
• 39 Bounameaux H, de Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost 2004; 2 (04) 551-554