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Clinical Pharmacokinetics

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09.03.2019 | Review Article

Revisiting the Pharmacology of Unfractionated Heparin

verfasst von: Abdallah Derbalah, Stephen Duffull, Fiona Newall, Katie Moynihan, Hesham Al-Sallami

Erschienen in: Clinical Pharmacokinetics | Ausgabe 8/2019

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Abstract

Unfractionated heparin (UFH) is a commonly used anticoagulant therapy for the acute treatment and prevention of thrombosis. Its short duration of action, reversibility of effect by protamine sulfate, and extensive clinical experience are some of the advantages that support its use. However, the choice of dose and dosing regimen of UFH remains challenging for several reasons. First, UFH has a narrow therapeutic window and wide variability in the dose–response relationship. Second, its pharmacodynamic (PD) properties are difficult to characterise owing to the complex multidimensional mechanisms of interaction with the haemostatic system. Third, the complex heterogeneous chemical composition of UFH precludes precise characterisation of its pharmacokinetic (PK) properties. This review provides a comprehensive mechanistic approach to the interaction of UFH with the haemostatic system. The effect of chemical structure on its PK and PD properties is quantitatively described, and a framework for characterisation of the dose–response relationship of UFH for the purpose of dose optimisation is proposed.

Jacqmin P, Snoeck E, van Schaick EA, Gieschke R, Pillai P, Steimer J-L, et al. Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn. 2007;34(1):57–85.CrossRefPubMed

Gabrielsson J, Jusko WJ, Alari L. Modeling of dose-response-time data: four examples of estimating the turnover parameters and generating kinetic functions from response profiles. Biopharm Drug Dispos. 2000;21(2):41–52.CrossRefPubMed

Duffull SB. Is the ideal anticoagulant a myth? Expert Rev Clin Pharmacol. 2012;5(3):231–6.CrossRefPubMed

Al-Sallami H, Newall F, Monagle P, Ignjatovic V, Cranswick N, Duffull S. Development of a population pharmacokinetic–pharmacodynamic model of a single bolus dose of unfractionated heparin in paediatric patients. Br J Clin Pharmacol. 2016;82(1):178–84.CrossRefPubMedPubMedCentral

Jia Z, Tian G, Ren Y, Sun Z, Lu W, Hou X. Pharmacokinetic model of unfractionated heparin during and after cardiopulmonary bypass in cardiac surgery. J Transl Med. 2015;13(1):45.CrossRefPubMedPubMedCentral

Delavenne X, Ollier E, Chollet S, Sandri F, Lanoiselée J, Hodin S, et al. Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass. Br J Anaesth. 2017;118(5):705–12.CrossRefPubMed

Brunet P, Simon N, Opris A, Faure V, Lorec-Penet AM, Portugal H, et al. Pharmacodynamics of unfractionated heparin during and after a hemodialysis session. Am J Kidney Dis. 2008;51(5):789–95.CrossRefPubMed

Bonate PL. The art of modeling. Pharmacokinetic–pharmacodynamic modeling and simulation. Boston: Springer US; 2011. p. 1–60.CrossRef

Wajima T, Isbister GK, Duffull SB. A comprehensive model for the humoral coagulation network in humans. Clin Pharmacol Ther. 2009;86(3):290–8.CrossRefPubMed

10.

Hoffman MM, Monroe DM. Rethinking the coagulation cascade. Curr Hematol Rep. 2005;4(5):391–6.PubMed

11.

Rosenberg RD. Role of heparin and heparinlike molecules in thrombosis and atherosclerosis. Fed Proc. 1985;44(2):404–9.PubMed

12.

Morawitz P. Die Chemie der Blutgerinnung. Ergebnisse der Physiologie. 1905;4(1):307–422.CrossRef

13.

Brinkhous KM, Smith HP, Warner ED, Seegers WH. The inhibition of blood clotting: an unidentified substance which acts in conjunction with heparin to prevent the conversion of prothrombin into thrombin. Am J Physiol Legacy Content. 1939;125(4):683–7.CrossRef

14.

Gerendas M. Inactivation of thrombin. Nature. 1946;157:837.CrossRefPubMed

15.

Gerendas M. Inactivation and stabilization of thrombin. Hung Acta Physiol. 1948;1(4–5):97–115.PubMed

16.

Owen WG. Evidence for the formation of an ester between thrombin and heparin cofactor. Biochim Biophys Acta (BBA) Protein Struct. 1975;405(2):380–7.CrossRef

17.

Carlson TH. Clearance of thrombin in vivo: significance of alternative pathways. Mol Cell Biochem. 1986;71(2):97–105.CrossRefPubMed

18.

Bock SC. Antithrombin and the Serpin Family. In: Marder VJA, Bennett WC, Schulman JS, White S, Gilbert C, editors. Hemostasis and thrombosis: basic principles and clinical practice. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2013. p. 286–99.

19.

Jesty J. The kinetics of inhibition of thrombin by antithrombin in the presence of components of the hemostatic system. Blood. 1985;66(5):1189–95.PubMed

20.

Maaroufi RM, Jozefowicz M, Tapon-Bretaudière J, Fischer A-M. Mechanism of thrombin inhibition by antithrombin and heparin cofactor II in the presence of heparin. Biomaterials. 1997;18(3):203–11.CrossRefPubMed

21.

Downing MR, Bloom JW, Mann KG. Comparison of the inhibition of thrombin by three plasma protease inhibitors. Biochemistry. 1978;17(13):2649–53.CrossRefPubMed

22.

Olson ST, Bjork I, Sheffer R, Craig PA, Shore JD, Choay J. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. Resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem. 1992;267(18):12528–38.PubMed

23.

Jesty J. Measurement of the kinetics of inhibition of activated coagulation factor X in human plasma: The effect of plasma and inhibitor concentration. Anal Biochem. 1986;152(2):402–11.CrossRefPubMed

24.

Jordan RE, Oosta GM, Gardner WT, Rosenberg RD. The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J Biol Chem. 1980;255(21):10081–90.PubMed

25.

Scott CF, Schapira M, James HL, Cohen AB, Colman RW. Inactivation of factor XIa by plasma protease inhibitors: predominant role of alpha 1-protease inhibitor and protective effect of high molecular weight kininogen. J Clin Investig. 1982;69(4):844–52.CrossRefPubMed

26.

Pixley R, Schapira M, Colman R. Effect of heparin on the inactivation rate of human activated factor XII by antithrombin III. Blood. 1985;66(1):198–203.PubMed

27.

Conard J, Brosstad F, Lie Larsen M, Samama M, Abildgaard U. Molar antithrombin concentration in normal human plasma. Haemostasis. 1983;13(6):363–8.PubMed

28.

Collen D, Schetz J, de Cock F, Holmer E, Verstraete M. Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Investig. 1977;7(1):27–35.CrossRef

29.

Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al. Development of the human coagulation system in the full-term infant. Blood. 1987;70(1):165–72.PubMed

30.

Lu W, Mant T, Levy JH, Bailey JM. Pharmacokinetics of recombinant transgenic antithrombin in volunteers. Anesth Analg. 2000;90(3):531–4.CrossRefPubMed

31.

Moffett BS, Diaz R, Galati M, Mahoney D, Teruya J, Yee DL. Population pharmacokinetics of human antithrombin concentrate in paediatric patients. Br J Clin Pharmacol. 2017;83(11):2450–7.CrossRefPubMedPubMedCentral

32.

DeJongh J, Frieling J, Lowry S, Drenth H-J. Pharmacokinetics of recombinant human antithrombin in delivery and surgery patients with hereditary antithrombin deficiency. Clin Appl Thromb Hemost. 2013;20(4):355–64.CrossRefPubMed

33.

Lam LSL, Regoeczi E, Hatton MWC. In vivo behaviour of some antithrombin III–protease complexes. Br J Exp Pathol. 1979;60(2):151–60.PubMedPubMedCentral

34.

Esposito RA, Culliford AT, Colvin SB, Thomas SJ, Lackner H, Spencer FC. Heparin resistance during cardiopulmonary bypass. The role of heparin pretreatment. J Thorac Cardiovasc Surg. 1983;85(3):346–53.PubMed

35.

Porter P, Porter MC, Shanberge JN. Heparin cofactor and plasma antithrombin in relation to the mechanism of inactivation of thrombin by heparin. Clin Chim Acta. 1967;17(2):189–200.CrossRefPubMed

36.

Sie P, Dupouy D, Pichon J, Boneu B. Constitutional heparin co-factor II deficiency associated with recurrent thrombosis. Lancet. 1985;2(8452):414–6.CrossRefPubMed

37.

Tran TH, Duckert F. Heparin cofactor II determination–levels in normals and patients with hereditary antithrombin III deficiency and disseminated intravascular coagulation. Thromb Haemost. 1984;52(2):112–6.PubMed

38.

Baglin TP, Carrell RW, Church FC, Esmon CT, Huntington JA. Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism. Proc Natl Acad Sci. 2002;99(17):11079–84.CrossRefPubMed

39.

Tovar AMF, de Mattos DA, Stelling MP, Sarcinelli-Luz BSL, Nazareth RA, Mourão PAS. Dermatan sulfate is the predominant antithrombotic glycosaminoglycan in vessel walls: Implications for a possible physiological function of heparin cofactor II. Biochim Biophys Acta (BBA) Mol Basis Dis. 2005;1740(1):45–53.CrossRef

40.

Vinazzer H. Heparin cofactor II: structure, function, and clinical importance. In: Sas G, editor. The biology of antithrombins. Boca Raton: CRC Press; 1990. p. 141–55.

41.

O’Keeffe D, Olson ST, Gasiunas N, Gallagher J, Baglin TP, Huntington JA. The heparin binding properties of heparin cofactor II suggest an antithrombin-like activation mechanism. J Biol Chem. 2004;279(48):50267–73.CrossRefPubMed

42.

Sie P, Dupouy D, Pichon J, Boneu B. Turnover study of heparin cofactor II in healthy man. Thromb Haemost. 1985;54(3):635–8.CrossRefPubMed

43.

McLean J. The discovery of heparin. Circulation. 1959;19(1):75–8.CrossRefPubMed

44.

Oduah EI, Linhardt RJ, Sharfstein ST. Heparin: past, present, and future. Pharmaceuticals (Basel). 2016;9(3):38.CrossRef

45.

Nader HB, Chavante SF, dos-Santos EA, Oliveira TW, de-Paiva JF, Jeronimo SM, et al. Heparan sulfates and heparins: similar compounds performing the same functions in vertebrates and invertebrates? Braz J Med Biol Res. 1999;32(5):529–38.CrossRefPubMed

46.

Rodén L, Ananth S, Campbell P, Curenton T, Ekborg G, Manzella S, et al. Heparin—an introduction. In: Lane DA, Björk I, Lindahl U, editors. Heparin and related polysaccharides. Boston: Springer US; 1992. p. 1–20.

47.

Bianchini P, Liverani L, Mascellani G, Parma B. Heterogeneity of unfractionated heparins studied in connection with species, source, and production processes. Semin Thromb Hemost. 1997;23(1):3–10.CrossRefPubMed

48.

Mulloy B, Hogwood J, Gray E. Assays and reference materials for current and future applications of heparins. Biologicals. 2010;38(4):459–66.CrossRefPubMed

49.

Tovar AM, Santos GR, Capille NV, Piquet AA, Glauser BF, Pereira MS, et al. Structural and haemostatic features of pharmaceutical heparins from different animal sources: challenges to define thresholds separating distinct drugs. Sci Rep. 2016;6:35619.CrossRefPubMedPubMedCentral

50.

Rohatgi A. WebPlotDigitizer. 4.1 ed., Austin; 2018.

51.

Hogwood J, Mulloy B, Gray E. Precipitation and neutralization of heparin from different sources by protamine sulfate. Pharmaceuticals (Basel). 2017;10(3):E59.CrossRef

52.

Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forms of heparin. Biochem Biophys Res Commun. 1976;69(2):570–7.CrossRefPubMed

53.

Hook M, Bjork I, Hopwood J, Lindahl U. Anticoagulant activity of heparin: separation of high-activity and low-activity heparin species by affinity chromatography on immobilized antithrombin. FEBS Lett. 1976;66(1):90–3.CrossRefPubMed

54.

Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GE. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin iii and by gel filtration. Thromb Res. 1976;9(6):575–83.CrossRefPubMed

55.

Olson ST, Srinivasan KR, Bjork I, Shore JD. Binding of high affinity heparin to antithrombin III. Stopped flow kinetic studies of the binding interaction. J Biol Chem. 1981;256(21):11073–9.PubMed

56.

Rosenberg RD, Jordan RE, Favreau LV, Lam LH. Highly active heparin species with multiple binding sites for antithrombin. Biochem Biophys Res Commun. 1979;86(4):1319–24.CrossRefPubMed

57.

Olson ST, Shore JD. Demonstration of a two-step reaction mechanism for inhibition of alpha-thrombin by antithrombin III and identification of the step affected by heparin. J Biol Chem. 1982;257(24):14891–5.PubMed

58.

Craig PA, Olson ST, Shore JD. Transient kinetics of heparin-catalyzed protease inactivation by antithrombin III. Characterization of assembly, product formation, and heparin dissociation steps in the factor Xa reaction. J Biol Chem. 1989;264(10):5452–61.PubMed

59.

Scott C, Colman R. Factors influencing the acceleration of human factor XIa inactivation by antithrombin III. Blood. 1989;73(7):1873–9.PubMed

60.

Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW. The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci USA. 1997;94(26):14683–8.CrossRefPubMed

61.

Olson ST, Bjork I. Predominant contribution of surface approximation to the mechanism of heparin acceleration of the antithrombin–thrombin reaction. Elucidation from salt concentration effects. J Biol Chem. 1991;266(10):6353–64.PubMed

62.

Holmer E, Lindahl U, Bäckström G, Thunberg L, Sandberg H, Söderström G, et al. Anticoagulant activities and effects on platelets of a heparin fragment with high affinity for antithrombin. Thromb Res. 1980;18(6):861–9.CrossRefPubMed

63.

Holmer E, Kurachi K, Soderstrom G. The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin. Biochem J. 1981;193(2):395–400.CrossRefPubMedPubMedCentral

64.

Ellis V, Scully MF, Kakkar VV. The relative molecular mass dependence of the anti-factor Xa properties of heparin. Biochem J. 1986;238(2):329–33.CrossRefPubMedPubMedCentral

65.

Hoylaerts M, Owen WG, Collen D. Involvement of heparin chain length in the heparin-catalyzed inhibition of thrombin by antithrombin III. J Biol Chem. 1984;259(9):5670–7.PubMed

66.

Scully MF, Ellis V, Kakkar VV. Comparison of the molecular mass dependency of heparin stimulation of heparin cofactor II:thrombin interaction to antithrombin III:thrombin interaction. Thromb Res. 1987;46(3):491–502.CrossRefPubMed

67.

Griffith MJ. Kinetics of the heparin-enhanced antithrombin III/thrombin reaction. Evidence for a template model for the mechanism of action of heparin. J Biol Chem. 1982;257(13):7360–5.PubMed

68.

Machovich R. Mechanism of action of heparin through thrombin on blood coagulation. Biochim Biophys Acta. 1975;412(1):13–7.CrossRefPubMed

69.

Jordan RE, Oosta GM, Gardner WT, Rosenberg RD. The binding of low molecular weight heparin to hemostatic enzymes. J Biol Chem. 1980;255(21):10073–80.PubMed

70.

Jordan RE, Oosta GM, Gardner WT, Rosenberg RD. The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J Biol Chem. 1980;255(21):10081–90.PubMed

71.

Sie P, Petitou M, Lormeau JC, Dupouy D, Boneu B, Choay J. Studies on the structural requirements of heparin for the catalysis of thrombin inhibition by heparin cofactor II. Biochim Biophys Acta. 1988;966(2):188–95.CrossRefPubMed

72.

Petitou M, Lormeau JC, Perly B, Berthault P, Bossennec V, Sie P, et al. Is there a unique sequence in heparin for interaction with heparin cofactor II? Structural and biological studies of heparin-derived oligosaccharides. J Biol Chem. 1988;263(18):8685–90.PubMed

73.

Sheehan JP, Tollefsen DM, Sadler JE. Heparin cofactor II is regulated allosterically and not primarily by template effects. Studies with mutant thrombins and glycosaminoglycans. J Biol Chem. 1994;269(52):32747–51.PubMed

74.

75.

Tollefsen DM, Majerus DW, Blank MK. Heparin cofactor II. Purification and properties of a heparin-dependent inhibitor of thrombin in human plasma. J Biol Chem. 1982;257(5):2162–9.PubMed

76.

Monagle P, Berry L, O’Brodovich H, Andrew M, Chan A. Covalent heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate complexes. Characterization of novel anticoagulants. J Biol Chem. 1998;273(50):33566–71.CrossRefPubMed

77.

Abildgaard U, Lindahl AK, Sandset PM. Heparin requires both antithrombin and extrinsic pathway inhibitor for its anticoagulant effect in human blood. Haemostasis. 1991;21(4):254–7.PubMed

78.

Hansen JB, Sandset PM, Huseby KR, Huseby NE, Nordoy A. Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man. Thromb Haemost. 1996;76(5):703–9.CrossRefPubMed

79.

Broze GJ Jr, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP. The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood. 1988;71(2):335–43.PubMed

80.

Jesty J, Wun TC, Lorenz A. Kinetics of the inhibition of factor Xa and the tissue factor-factor VIIa complex by the tissue factor pathway inhibitor in the presence and absence of heparin. Biochemistry. 1994;33(42):12686–94.CrossRefPubMed

81.

Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):188S–203S.CrossRefPubMed

82.

Francis JL, Groce JB. Challenges in variation and responsiveness of unfractionated heparin. Pharmacotherapy. 2004;24(8P2):108S–19S.CrossRefPubMed

83.

Kuhle S, Eulmesekian P, Kavanagh B, Massicotte P, Vegh P, Lau A, et al. Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically ill children. Haematologica. 2007;92(4):554–7.CrossRefPubMed

84.

Moynihan K, Johnson K, Straney L, Stocker C, Anderson B, Venugopal P, et al. Coagulation monitoring correlation with heparin dose in pediatric extracorporeal life support. Perfusion. 2017;32(8):675–85.CrossRefPubMed

85.

Mann KG, Orfeo T, Butenas S, Undas A, Brummel-Ziedins K. Blood coagulation dynamics in haemostasis. Hamostaseologie. 2009;29(1):7–16.CrossRefPubMedPubMedCentral

86.

Newall F. Protamine titration. Methods Mol Biol. 2013;992:279–87.CrossRefPubMed

87.

Crowther MA, Berry LR, Monagle PT, Chan AK. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol. 2002;116(1):178–86.CrossRefPubMed

88.

Ramamurthy N, Baliga N, Wakefield TW, Andrews PC, Yang VC, Meyerhoff ME. Determination of low-molecular-weight heparins and their binding to protamine and a protamine analog using polyion-sensitive membrane electrodes. Anal Biochem. 1999;266(1):116–24.CrossRefPubMed

89.

Ignjatovic V, Summerhayes R, Gan A, Than J, Chan A, Cochrane A, et al. Monitoring unfractionated heparin (UFH) therapy: which anti factor Xa assay is appropriate? Thromb Res. 2007;120(3):347–51.CrossRefPubMed

90.

Bromfield SM, Barnard A, Posocco P, Fermeglia M, Pricl S, Smith DK. Mallard blue: a high-affinity selective heparin sensor that operates in highly competitive media. J Am Chem Soc. 2013;135(8):2911–4.CrossRefPubMed

91.

Warttinger U, Giese C, Harenberg J, Holmer E, Kramer R. A fluorescent probe assay (Heparin Red) for direct detection of heparins in human plasma. Anal Bioanal Chem. 2016;408(28):8241–51.CrossRefPubMed

92.

Li G, Yang B, Li L, Zhang F, Xue C, Linhardt RJ. Analysis of 3-O-sulfo group-containing heparin tetrasaccharides in heparin by liquid chromatography-mass spectrometry. Anal Biochem. 2014;455:3–9.CrossRefPubMedPubMedCentral

93.

Yoshimi Y, Yagisawa Y, Yamaguchi R, Seki M. Blood heparin sensor made from a paste electrode of graphite particles grafted with molecularly imprinted polymer. Sensors Actuators B Chem. 2018;259:455–62.CrossRef

94.

Barzu T, Molho P, Tobelem G, Petitou M, Caen J. Binding and endocytosis of heparin by human endothelial cells in culture. Biochim Biophys Acta. 1985;845(2):196–203.CrossRefPubMed

95.

Jaques L, Napke E, Levy S. The metachromatic activity of urine following the injection of heparin. Circ Res. 1953;1(4):321–30.CrossRefPubMed

96.

Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics determined by three assay methods. Clin Pharmacol Ther. 1982;31(1):104–13.CrossRefPubMed

97.

Bjornsson TD, Levy G. Pharmacokinetics of heparin. II. Studies of time dependence in rats. J Pharmacol Exp Ther. 1979;210(2):243–6.PubMed

98.

Boneu B, Caranobe C, Sie P. Pharmacokinetics of heparin and low molecular weight heparin. Baillieres Clin Haematol. 1990;3(3):531–44.CrossRefPubMed

99.

McAvoy TJ. Pharmacokinetic modeling of heparin and its clinical implications. J Pharmacokinet Biopharm. 1979;7(4):331–54.CrossRefPubMed

100.

Edward Conrad H. Heparin-binding proteins in hemostasis, Chapter 8. In: Edward Conrad H, editor. Heparin-binding proteins. San Diego: Academic Press; 1998. p. 239–300.CrossRef

101.

Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemost. 1992;67(6):639–43.CrossRefPubMed

102.

Lijnen HR, Hoylaerts M, Collen D. Heparin binding properties of human histidine-rich glycoprotein. Mechanism and role in the neutralization of heparin in plasma. J Biol Chem. 1983;258(6):3803–8.PubMed

Titel: Revisiting the Pharmacology of Unfractionated Heparin
verfasst von: Abdallah Derbalah
Stephen Duffull
Fiona Newall
Katie Moynihan
Hesham Al-Sallami
Publikationsdatum: 09.03.2019
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 8/2019
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-019-00751-7

Springer Medizin

Abstract

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