nach oben

Clinical Pharmacokinetics

Erschienen in:

01.11.2008 | Original Research Article

Physiology-Based Simulations of a Pathological Condition

Prediction of Pharmacokinetics in Patients with Liver Cirrhosis

verfasst von: Dr Andrea N. Edginton, Stefan Willmann

Erschienen in: Clinical Pharmacokinetics | Ausgabe 11/2008

Einloggen, um Zugang zu erhalten

Abstract

Background: Liver cirrhosis is a progressive disease characterized by loss of functional hepatocytes with concomitant connective tissue and nodule formation in the liver. The morphological and physiological changes associated with the disease substantially affect drug pharmacokinetics. Whole-body physiologically based pharmacokinetic (WB-PBPK) modelling is a predictive technique that quantitatively relates the pharmacokinetic parameters of a drug to such (patho-)physiological conditions.

Objective: To extend an existing WB-PBPK model, based on the physiological changes associated with liver cirrhosis, which allows for prediction of drug pharmacokinetics in patients with liver cirrhosis.

Methods: The literature was searched for quantitative measures of the physiological changes associated with the presence of Child-Pugh class A through C liver cirrhosis. The parameters that were included were the organ blood flows, cardiac index, plasma binding protein concentrations, haematocrit, functional liver volume, hepatic enzymatic activity and glomerular filtration rate. Predictions of pharmacokinetic profiles and parameters were compared with literature data for the model compounds alfentanil, lidocaine (lignocaine), theophylline and levetiracetam.

Results: The predicted versus observed plasma concentration-time profiles for alfentanil and lidocaine were similar, such that the pharmacokinetic changes associated with Child-Pugh class A, B and C liver cirrhosis were adequately described. The theophylline elimination half-life was greatly increased in Child-Pugh class B and C patients compared with controls, as predicted by the model. Levetiracetam urinary excretion was consistently reduced with disease progression and very closely resembled observed values.

Conclusion: Consideration of the physiological differences between healthy individuals and patients with liver cirrhosis was important for the simulation of drug pharmacokinetics in this compromised group. The WB-PBPK model was altered to incorporate these physiological differences with the result of adequate simulation of drug pharmacokinetics. The information provided in this study will allow other researchers to further validate this liver cirrhosis model within a WB-PBPK model.

Bosch J, Garcia-Pagan JC. Complications of cirrhosis: I. Portal hypertension. J Hepatol 2000; 32 (1 Suppl.): 141–56PubMedCrossRef

Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371(9615): 838–51PubMedCrossRef

Dincer D, Besisk F, Demirkol O, et al. Relationships between hemodynamic alterations and Child-Pugh score in patients with cirrhosis. Hepatogastroenterology 2005; 52(65): 1521–5PubMed

Andersen ME. Toxicokinetic modeling and its applications in chemical risk assessment. Toxicol Lett 2003; 138(1-2): 9–27PubMedCrossRef

Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet 2006; 45(10): 1013–34PubMedCrossRef

Bjorkman S, Wada DR, Berling BM, et al. Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model. J Pharm Sci 2001; 90(9): 1226–41PubMedCrossRef

Lupfert C, Reichel A. Development and application of physiologically based pharmacokinetic-modeling tools to support drug discovery. Chem Biodivers 2005; 2(11): 1462–86PubMedCrossRef

Willmann S, Schmitt W, Keldenich J, et al. A physiological model for the estimation of the fraction dose absorbed in humans. J Med Chem 2004; 47(15): 4022–31PubMedCrossRef

International Commission on Radiological Protection (ICRP). Basic anatomical and physiological data for use in radiological protection: reference values. ICRP publication no. 89. Amsterdam: Elsevier Science, 2002

10.

Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol 2005; 59(6): 691–704PubMedCrossRef

11.

Annet L, Materne R, Danse E, et al. Hepatic flow parameters measured with MR imaging and Doppler US: correlations with degree of cirrhosis and portal hypertension. Radiology 2003; 229(2): 409–14PubMedCrossRef

12.

Yamamoto M, Iwasa M, Matsumura K, et al. Improvement of regional cerebral blood flow after oral intake of branched-chain amino acids in patients with cirrhosis. World J Gastroenterol 2005; 11(43): 6792–9PubMed

13.

Chawla Y, Santa N, Dhiman RK, et al. Portal hemodynamics by duplex Doppler sonography in different grades of cirrhosis. Dig Dis Sci 1998; 43(2): 354–7PubMedCrossRef

14.

Froomes PR, Morgan DJ, Smallwood RA, et al. Comparative effects of oxygen supplementation on theophylline and acetaminophen clearance in human cirrhosis. Gastroenterology 1999; 116(4): 915–20PubMedCrossRef

15.

Woitas RP, Stoffel-Wagner B, Flommersfeld S, et al. Correlation of serum concentrations of cystatin C and creatinine to inulin clearance in liver cirrhosis. Clin Chem 2000; 46(5): 712–5PubMed

16.

Barry M, Keeling PW, Weir D, et al. Severity of cirrhosis and the relationship of alpha 1-acid glycoprotein concentration to plasma protein binding of lidocaine. Clin Pharmacol Ther 1990; 47(3): 366–70PubMedCrossRef

17.

Wong F, Girgrah N, Graba J, et al. The cardiac response to exercise in cirrhosis. Gut 2001; 49(2): 268–75PubMedCrossRef

18.

Sansoe G, Ferrari A, Castellana CN, et al. Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis. Clin Sci (Lond) 2002; 102(1): 91–8CrossRef

19.

Proulx NL, Akbari A, Garg AX, et al. Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis. Nephrol Dial Transplant 2005; 20(8): 1617–22PubMedCrossRef

20.

Willmann S, Lippert J, Schmitt W. From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools. Expert Opin Drug Meta Toxicol 2005; 1(1): 159–68CrossRef

21.

Virgolini I, Muller C, Angelberger P, et al. Functional liver imaging with 99Tcm-galactosyl-neoglycoalbumin (NGA) in alcoholic liver cirrhosis and liver fibrosis. Nucl Med Commun 1991; 12(6): 507–17PubMedCrossRef

22.

George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 1995; 21(1): 120–8PubMed

23.

Hardman JG, Limbird LE, Gilman A. Goodman and Gilman’s: the pharmacological basis of therapeutics. 10th ed. New York: McGraw Hill, 2001

24.

Brockmöller J, Thomsen T, Wittstock M, et al. Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests. Clin Pharmacol Ther 2005; 77(6): 529–41PubMedCrossRef

25.

Coupez R, Nicolas JM, Browne TR. Levetiracetam, a new antiepileptic agent: lack of in vitro and in vivo pharmacokinetic interaction with valproic acid. Epilepsia 2003; 44(2): 171–8PubMedCrossRef

26.

Willmann S, Lippert J, Sevestre M, et al. PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. Biosilico 2003; 1(4): 121–4CrossRef

27.

Willmann S, Hohn K, Edginton A, et al. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn 2007; 34(3): 401–31PubMedCrossRef

28.

US National Center for Health Statistics. Third National Health and Nutrition Examination Survey (NHANES III). Hyattsville (MD): National Center for Health Statistics Hyattsville, 1997 [online]. Available from URL: http://www.cdc.gov/nchs/datawh/nchsdefs/bmi.htm [Accessed 2008 Aug 19]

29.

Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharma 1981; 9(4): 503–12

30.

Roure P, Jean N, Leclerc AC, et al. Pharmacokinetics of alfentanil in children undergoing surgery. Br J Anaesth 1987; 59(11): 1437–40PubMedCrossRef

31.

Macfie AG, Magides AD, Reilly CS. Disposition of alfentanil in burns patients. Br J Anaesth 1992; 69(5): 447–50PubMedCrossRef

32.

Chauvin M, Bonnet F, Montembault C, et al. The influence of hepatic plasma flow on alfentanil plasma concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction coefficient. Anesth Analg 1986; 65(10): 999–1003PubMedCrossRef

33.

Kharasch ED, Russell M, Mautz D, et al. The role of cytochrome P450 3A4 in alfentanil clearance: implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology 1997; 87(1): 36–50PubMedCrossRef

34.

Mazoit JX, Dalens BJ. Pharmacokinetics of local anaesthetics in infants and children. Clin Pharmacokinet 2004; 43(1): 17–32PubMedCrossRef

35.

Bailey DN, Briggs JR. The binding of selected therapeutic drugs to human serum [alpha]-1 acid glycoprotein and to human serum albumin in vitro. Ther Drug Monit 2004; 26(1): 40–3PubMedCrossRef

36.

Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32(3): 210–58PubMedCrossRef

37.

Mihaly GW, Moore G, Thomas J, et al. The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. Eur J Clin Pharmacol 1978; 13(2): 143–52PubMedCrossRef

38.

Orlando R, Piccoli P, De Martin S, et al. Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. Clin Pharmacol Ther 2004; 75(1): 80–8PubMedCrossRef

39.

Valko K, Nunhuck S, Bevan C, et al. Fast gradient HPLC method to determine compounds binding to human serum albumin: relationships with octanol/water and immobilized artificial membrane lipophilicity. J Pharm Sci 2003; 92(11): 2236–48PubMedCrossRef

40.

Dorne JL, Walton K, Renwick AG. Uncertainty factors for chemical risk assessment: human variability in the pharmacokinetics of CYP1A2 probe substrates. Food Chem Toxicol 2001; 39(7): 681–96PubMedCrossRef

41.

DrugBank. Levetiracetam [online]. Available from URL: http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD01068.txt [Accessed 2007 Dec 1]

42.

Nicolas JM, Collart P, Gerin B, et al. In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab Dispos 1999; 27(2): 250–4PubMed

43.

Ferrier C, Marty J, Bouffard Y, et al. Alfentanil pharmacokinetics in patients with cirrhosis. Anesthesiology 1985; 62(4): 480–4PubMedCrossRef

44.

Kim WR, Poterucha JJ, Wiesner RH, et al. The relative role of the Child-Pugh classification and the Mayo natural history model in the assessment of survival in patients with primary sclerosing cholangitis. Hepatology 1999; 29(6): 1643–8PubMedCrossRef

45.

Orlando R, Piccoli P, De MS, et al. Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function. Br J Clin Pharmacol 2003; 55(1): 86–93PubMedCrossRef

46.

Shi BM, Wang XY, Mu QL, et al. Value of portal hemodynamics and hypersplenism in cirrhosis staging. World J Gastroenterol 2005; 11(5): 708–11PubMed

47.

Denys A, Menu Y. Portal and splanchnic blood flow measurements in vivo: US Doppler or MR angiography? J Hepatol 1997; 26(2): 437–8PubMedCrossRef

48.

Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol 1985; 249 (5 Pt 1): G549–56PubMed

49.

Braillon A, Cales P, Valla D, et al. Influence of the degree of liver failure on systemic and splanchnic haemodynamics and on response to propranolol in patients with cirrhosis. Gut 1986; 27(10): 1204–9PubMedCrossRef

50.

Carrella M, Hunter JO, Fazio S, et al. Capillary blood flow to the skin of forearm in cirrhosis. Angiology 1992; 43(12): 969–74PubMedCrossRef

Titel: Physiology-Based Simulations of a Pathological Condition
Prediction of Pharmacokinetics in Patients with Liver Cirrhosis
verfasst von: Dr Andrea N. Edginton
Stefan Willmann
Publikationsdatum: 01.11.2008
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 11/2008
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200847110-00005

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 11/2008

Pharmacokinetics of Subcutaneous Recombinant Methionyl Human Leptin Administration in Healthy Subjects in the Fed and Fasting States

Clinical Pharmacokinetic and Pharmacodynamic Profile of Etoricoxib

Regulatory Aspects of Pharmacokinetic Profiling in Special Populations

Pharmacokinetic/Pharmacodynamic Modelling of Venlafaxine

Blood and Plasma Pharmacokinetics of Ciclosporin in Diabetic Kidney Transplant Recipients