The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease

Clinical Pharmacokinetics

Volumn 50, Issue 1, 2011, Pages 1-24

  Sherwin, Catherine M T ^a   Fukuda, Tsuyoshi ^a,b   Brunner, Hermine I ^a,b   Goebel, Jens ^a,b   Vinks, Alexander A ^a,b  

^a CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

^b UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

Author keywords

Autoimmune disorders; Drug monitoring; Enterohepatic circulation; Immunosuppressants, pharmacokinetics; Metabolism; Mycophenolate mofetil, pharmacokinetics; Mycophenolate sodium, pharmacokinetics; Mycophenolic acid, pharmacokinetics; Organ transplant; Pharmacokinetic modelling; Population pharmacokinetics; Renal transplant; Stem cell transplant; Systemic lupus erythematosus

Indexed keywords

ALUMINUM MAGNESIUM HYDROXIDE; CYCLOSPORIN; DRUG METABOLITE; EVEROLIMUS; GLUCURONOSYLTRANSFERASE 1A9; GLUCURONOSYLTRANSFERASE 2B7; METHYLPREDNISOLONE; MYCOPHENOLIC ACID; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; PREDNISOLONE; PREDNISONE; RAPAMYCIN; TACROLIMUS;

AREA UNDER THE CURVE; AUTOIMMUNE DISEASE; BILE; CLINICAL FEATURE; CLINICAL TRIAL; DRUG ABSORPTION; DRUG CLEARANCE; DRUG EXPOSURE; DRUG MEGADOSE; DRUG METABOLISM; DRUG TRANSFORMATION; DRUG TRANSPORT; ENTEROHEPATIC CIRCULATION; GALLBLADDER EMPTYING; GRAFT REJECTION; HUMAN; INTESTINE FLORA; LOW DRUG DOSE; NONHUMAN; ORGAN TRANSPLANTATION; POPULATION MODEL; PRIORITY JOURNAL; REVIEW; SYSTEMIC LUPUS ERYTHEMATOSUS;

AUTOIMMUNE DISEASES; ENTEROHEPATIC CIRCULATION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MODELS, BIOLOGICAL; MYCOPHENOLIC ACID; ORGAN TRANSPLANTATION;

EID: 78649948343     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.2165/11536640-000000000-00000     Document Type: Review

References (102)

1. Port FK, Dykstra DM, Merion RM, et al. Trends and results for organ donation and transplantation in the United States, 2004. Am J Transplant 2005; 5: 843-9.
2. Cellcept®: US prescribing information. South San Francisco (CA): Genene- tech, Inc., 2010 Feb [online]. Available from URL: http://www.gene.com/ gene/products/information/cellcept/pdf/pi.pdf [Accessed 2010 Nov 5].
3. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005; 14 Suppl. 1: s2-8.
4. Knoll GA, MacDonald I, Khan A, et al. Mycophenolate mofetil dose re- duction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003; 14: 2381-6.
5. Pelletier RP, Akin B, Henry ML, et al. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 2003; 17: 200-5.
6. Van Gelder T, Le Meur Y, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006; 28:145-54.
7. Kuypers DR, Le Meur Y, Cantarovich M, et al. Consensus report on ther- apeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol 2010; 5: 341-58.
8. Kuypers DR. Immunosuppressive drug monitoring: what to use in clinical practice today to improve renal graft outcome. Transpl Int 2005; 18: 140-50.
9. Kaplan B. Mycophenolic acid trough level monitoring in solid organ trans- plant recipients treated with mycophenolate mofetil: association with clinical outcome. Curr Med Res Opin 2006; 22: 2355-64.
10. Nicholls AJ. Opportunities for therapeutic monitoring of mycophenolate mofetil dose in renal transplantation suggested by the pharmacokinetic/ pharmacodynamic relationship for mycophenolic acid and suppression of rejection. Clin Biochem 1998; 31: 329-33.
11. Oellerich M, Shipkova M, Schutz E, et al. Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: implications for therapeutic drug monitoring. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. Ther Drug Monit 2000; 22: 20-6.
12. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of myco- phenolate in solid organ transplant recipients. Clin Pharmacokinet 2007; 46:13-58.
13. Shaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003; 3: 534-42.
14. Armstrong VW, Tenderich G, Shipkova M, et al. Pharmacokinetics and bioavailability of mycophenolic acid after intravenous administration and oral administration of mycophenolate mofetil to heart transplant recipients. Ther Drug Monit 2005; 27: 315-21.
15. Bullingham R, Monroe S, Nicholls A, et al. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol 1996; 36: 315-24.
16. Hale MD, Nicholls AJ, Bullingham RE, et al. The pharmacokinetic- pharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 1998; 64: 672-83.
17. Kuypers DR, Naesens M, Vermeire S, et al. The impact of uridine diphos- phate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in denovo renal allograft recipients. Clin Pharmacol Ther 2005; 78: 351-61.
18. Baldelli S, Merlini S, Perico N, et al. C-440T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics 2007; 8: 1127-41.
19. Betonico GN, Abbud-Filho M, Goloni-Bertollo EM, et al. Influence of UDP- glucuronosyltransferase polymorphisms on mycophenolate mofetil-induced side effects in kidney transplant patients. Transplant Proc 2008; 40: 708-10.
20. Girard H, Court MH, Bernard O, et al. Identification of common poly- morphisms in the promoter of the UGT1A9 gene: evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver. Pharmacogenetics 2004; 14: 501-15.
21. Kuypers DR, de Jonge H, Naesens M, et al. Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients. Clin Ther 2008; 30: 673-83.
22. Levesque E, Benoit-Biancamano MO, Delage R, et al. Pharmacokinetics of mycophenolate mofetil and its glucuronide metabolites in healthy volunteers. Pharmacogenomics 2008; 9: 869-79.
23. Naesens M, Kuypers DR, Verbeke K, et al. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 2006; 82: 1074-84.
24. Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 2007; 63: 1161-9.
25. Wang J, Yang JW, Zeevi A, et al. IMPDH1 gene polymorphisms and asso- ciation with acute rejectionin renal transplant patients. Clin Pharmacol Ther 2008; 83: 711-7.
26. Jiao Z, Ding JJ, Shen J, et al. Population pharmacokinetic modelling for en- terohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9. Br J Clin Pharmacol 2008; 65: 893-907.
27. Bernard O, Tojcic J, Journault K, et al. Influence of nonsynonymous poly- morphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronidesofmycophenolic acid. Drug Metab Dispos 2006; 34: 1539-45.
28. Picard N, Cresteil T, Premaud A, et al. Characterization of a phase 1 meta- boliteofmycophenolic acid produced by CYP3A4/5.Ther Drug Monit 2004; 26: 600-8.
29. ShipkovaM,Armstrong VW, Wieland E, et al. Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Br J Pharmacol 1999; 126: 1075-82.
30. Shipkova M, Strassburg CP, Braun F, et al. Glucuronide and glucoside conjugation of mycophenolic acid by human liver, kidney and intestinal microsomes. Br J Pharmacol 2001; 132: 1027-34.
31. Feichtiger H, Wieland E, Armstrong VW, et al. The acyl glucuronide meta- bolite of mycophenolic acid induces tubulin polymerization in vitro. Clin Biochem 2010; 43: 208-13.
32. Gensburger O, Picard N, Marquet P. Effect of mycophenolate acyl- glucuronide on human recombinant type 2 inosine monophosphate dehy-drogenase. Clin Chem 2009; 55: 986-93.
33. Mackenzie PI. Identification of uridine diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid. Ther Drug Monit 2000; 22: 10-3.
34. Picard N, Ratanasavanh D, Premaud A, et al. Identification of the UDP- glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 2005; 33: 139-46.
35. Basu NK, Kole L, Kubota S, et al. Human UDP-glucuronosyltransferases show atypical metabolism of mycophenolic acid and inhibition by curcumin. Drug Metab Dispos 2004; 32: 768-73.
36. Bowalgaha K, Miners JO. The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes. Br J Clin Pharmacol 2001; 52: 605-9.
37. Bernard O, Guillemette C. The main role of UGT1A9 in the hepatic metab- olism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos 2004; 32: 775-8.
38. Filler G. Drug interactions between mycophenolate and cyclosporine. Pediatr Transplant 2004; 8: 201-4.
39. Westley IS, Brogan LR, Morris RG, et al. Role of MRP2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites: effect of cyclosporine. Drug Metab Dispos 2006; 34: 261-6.
40. Kobayashi M, Saitoh H, Tadano K, et al. Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats. J Pharmacol Exp Ther 2004; 309: 1029-35.
41. Picard N, Yee SW, Woillard JB, et al. The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clin Pharmacol Ther 2010; 87: 100-8.
42. Cremers S, Schoemaker R, Scholten E, et al. Characterizing the role of en- terohepatic recycling in the interactions between mycophenolate mofetil and calcineurin inhibitors in renal transplant patients by pharmacokinetic modelling. Br J Clin Pharmacol 2005; 60: 249-56.
43. Filler G,Bendrick-Peart J, Christians U. Pharmacokinetics of mycophenolate mofetil and sirolimus in children. Ther Drug Monit 2008; 30: 138-42.
44. Filler G, Lepage N, Delisle B, et al. Effect of cyclosporine on mycophenolic acid area under the concentration-time curve in pediatric kidney transplant recipients. Ther Drug Monit 2001; 23: 514-9.
45. Kiberd BA, Puthenparumpil JJ, Fraser A, et al. Impact of mycophenolate mofetil loading on drug exposure in the early posttransplant period. Transplant Proc 2005; 37: 2320-3.
46. Cattaneo D, Perico N, Gaspari F, et al. Glucocorticoids interfere with my- cophenolate mofetil bioavailability in kidney transplantation. Kidney Int 2002; 62: 1060-7.
47. Usui T, Kuno T, Mizutani T. Induction of human UDP-glucuronosyl- transferase 1A1 by cortisol-GR. Mol Biol Rep 2006; 33: 91-6.
48. Kanou M, Usui T, Ueyama H, et al. Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone. Mol Biol Rep 2004; 31: 151-8.
49. Soars MG, Petullo DM, Eckstein JA, et al. An assessment of UDP-glucur- onosyltransferase induction using primary human hepatocytes. Drug Metab Dispos 2004; 32: 140-8.
50. Roberts MS, Magnusson BM, Burczynski FJ,et al. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmaco-kinet 2002; 41: 751-90.
51. Lee WA, Gu L, Miksztal AR, et al. Bioavailability improvement of myco- phenolic acid through amino ester derivatization. Pharm Res 1990; 7: 161-6.
52. Bullingham RES, Nicholls AJ, Kanmm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34: 429-55.
53. Wu CY, Benet LZ. Predicting drug disposition via application of BCS: trans- port/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 2005; 22: 11-23.
54. Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/ elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev 2008; 60: 717-33.
55. Lecureur V, Courtois A, Payen L, et al. Expression and regulation of hepatic drug and bile acid transporters. Toxicology 2000; 153: 203-19.
56. Miura M, Satoh S, Inoue K, et al. Influence of lansoprazole and rabeprazole on mycophenolic acid pharmacokinetics one year after renal transplantation. Ther Drug Monit 2008; 30: 46-51.
57. Wang J, Figurski M, Shaw LM, et al. The impact of P-glycoprotein and Mrp2 on mycophenolic acid levels in mice. Transpl Immunol 2008; 19 (3-4): 192-6.
58. Sawamoto T, Van Gelder T, Christians U, et al. Membrane transport of mycophenolate mofetil and its active metabolite, mycophenolic acid in MDCK and MDR1-MDCK cell monolayers. J Heart Lung Transplant 2001; 20: 234-5.
59. Strassburg CP, Kneip S, Topp J, et al. Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. J Biol Chem 2000; 275: 36164-71.
60. Radominska-Pandya A, Little JM, Pandya JT, et al. UDP-glucuronosyl- transferases in human intestinal mucosa. Biochim Biophys Acta 1998; 1394: 199-208.
61. Marzolini C, Tirona RG, Kim RB. Pharmacogenomics of the OATP and OAT families. Pharmacogenomics 2004; 5: 273-82.
62. Zamek-Gliszczynski MJ, Hoffmaster KA, Nezasa K, et al. Integration of hepatic drug transporters and phase II metabolizing enzymes: mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur J Pharm Sci 2006; 27: 447-86.
63. Ghibellini G, Leslie EM, Brouwer KL. Methods to evaluate biliary excretion of drugs in humans: an updated review. Mol Pharm 2006; 3: 198-211.
64. Cosson VF, Fuseau E. Mixed effect modeling of sumatriptan pharmaco- kinetics during drug development: II. From healthy subjects to phase 2 dose ranging in patients. J Pharmacokinet Biopharm 1999; 27: 149-71.
65. Ilett KF, Tee LB, Reeves PT, et al. Metabolism of drugs and other xenobiotics in the gut lumen and wall. Pharmacol Ther 1990; 46: 67-93.
66. Bullingham R, Shah J, Goldblum R, et al. Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients. Br J Clin Pharmacol 1996; 41: 513-6.
67. Funaki T. Enterohepatic circulation model for population pharmacokinetic analysis. J Pharm Pharmacol 1999; 51: 1143-8.
68. Payen S, Zhang D, Maisin A, et al. Population pharmacokinetics of myco- phenolic acid in kidney transplant pediatric and adolescent patients. Ther Drug Monit 2005; 27: 378-88.
69. Yau W-P, Vathsala A, Lou H-X, et al. Mechanism-based enterohepatic circulation model of mycophenolic acid and its glucuronide metabolite: assessment of impact of cyclosporine dose in Asian renal transplant patients. J Clin Pharmacol 2009; 49: 684-99.
70. Sam WJ, Akhlaghi F, Rosenbaum SE. Population pharmacokinetics of my- cophenolic acid and its 2 glucuronidated metabolites in kidney transplant recipients. J Clin Pharmacol 2009; 49: 185-95.
71. de Winter B, Neumann I, van Hest RM, et al. Limited sampling strategies for therapeutic drug monitoring of mycophenolate mofetil therapy in patients with autoimmune disease. Ther Drug Monit 2009; 31: 382-90.
72. Le Meur Y, Buchler M, Thierry A, et al. Individualized mycophenolate mo- fetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant 2007; 7: 2496-503.
73. Woltosz W. Weibull absorption models. In: PharmPK discussion [discussion list on the Internet]. 2009 Jun 22 at 21:00 [online]. Available from URL: http:// www.boomer.org/pkin/PK09/PK2009395.html [Accessed 2010 Oct 13].
74. Woltosz W. Weibull absorption models. In: PharmPK discussion [discussion list on the Internet]. 2009 Jun 23 at 09:30 [online]. Available from URL: http:// www.boomer.org/pkin/PK09/PK2009395.html [Accessed 2010 Oct 13].
75. Sun YN, Jusko WJ. Transit compartments versus gamma distribution func- tion to model signal transduction processes in pharmacodynamics. J Pharm Sci 1998; 87: 732-7.
76. Savic RM, Jonker DM, Kerbusch T, et al. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn 2007; 34: 711-26.
77. Steimer JL, Plusquellec Y, Guillaume A, et al. A time-lag model for pharma- cokinetics of drugs subjecttoenterohepatic circulation. J Pharm Sci 1982; 71: 297-302.
78. Peris-Ribera JE, Torres-Molina F, Garcia-Carbonell MC, et al. General treatment of the enterohepatic recirculation of drugs and its influence on the area under the plasma level curves, bioavailability, and clearance. Pharm Res 1992; 9: 1306-13.
79. Matis JH, Wehrly TE. Generalized stochastic compartmental models with Erlang transit times. J Pharmacokinet Biopharm 1990; 18: 589-607.
80. Saint-Marcoux F, Marquet P, Jacqz-Aigrain E, et al. Patient characteristics influencing ciclosporin pharmacokinetics and accurate Bayesian estimation of ciclosporin exposure in heart, lung and kidney transplant patients. Clin Pharmacokinet 2006; 45: 905-22.
81. Rousseau A, Leger F, Le Meur Y, et al. Population pharmacokinetic mod- eling of oral cyclosporin using NONMEM: comparison of absorption pharmacokinetic models and design of a Bayesian estimator. Ther Drug Monit 2004; 26: 23-30.
82. Yu LX, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm 1999; 186: 119-25.
83. Shum B, Duffull SB, Taylor PJ, et al. Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil. Br J Clin Pharmacol 2003; 56: 188-97.
84. Le Guellec C, Bourgoin H, Buchler M, et al. Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients. Clin Pharmacokinet 2004; 43: 253-66.
85. Staatz CE, Duffull SB, Kiberd B, et al. Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation. Eur J Clin Pharmacol 2005; 61: 507-16.
86. van Hest RM, van Gelder T, Vulto AG, et al. Population pharmacokinetics of mycophenolic acid in renal transplant recipients. Clin Pharmacokinet 2005; 44: 1083-96.
87. Premaud A, Debord J, Rousseau A, et al. A double absorption-phase model adequately describes mycophenolic acid plasma profiles in de novo renal transplant recipients given oral mycophenolate mofetil. Clin Pharmacokinet 2005; 44: 837-47.
88. van Hest RM, van Gelder T, Bouw R, et al. Time-dependent clearance of myco- phenolic acid in renal transplant recipients. Br J Clin Pharmacol 2007; 63: 741-52.
89. deWinter BC, van Gelder T, Glander P, etal, Population pharmacokinetics of mycophenolic acid: a comparison between enteric-coated mycophenolate sodium and mycophenolate mofetil in renal transplant recipients. Clin Pharmacokinet, 2008, 47, 827-38.
90. Zahr N, Amoura Z, Debord J, et al. Pharmacokinetic study of mycophenolate mofetil in patients with systemic lupus erythematosus and design of Bayesian estimator using limited sampling strategies. Clin Pharmacokinet 2008; 47: 277-84.
91. Musuamba FT, Rousseau A, Bosmans JL,et al. Limited sampling models and Bayesian estimation for mycophenolic acid area under the curve prediction in stable renal transplant patients co-medicated with ciclosporin or siro-limus. Clin Pharmacokinet 2009; 48: 745-58.
92. de Winter BC, van Gelder T, Sombogaard F, et al. Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. J Pharmacokinet Pharmacodyn 2009; 36: 541-64.
93. Saint-Marcoux F, Royer B, Debord J, et al. Pharmacokinetic modelling and development of Bayesian estimators for therapeutic drug monitoring of mycophenolate mofetil in reduced-intensity haematopoietic stem cell transplantation. Clin Pharmacokinet 2009; 48: 667-75.
94. Satoh S, Tada H, Murakami M, et al. Circadian pharmacokinetics of mycophenolic acid and implication of genetic polymorphisms for early clinical events in renal transplant recipients. Transplantation 2006; 82: 486-93.
95. Kagaya H, Inoue K, Miura M, et al. Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 2007; 63: 279-88.
96. Prausa SE, Fukuda T, Maseck D, et al. UGT genotype may contribute to adverse events following medication with mycophenolate mofetil inpediatric kidney transplant recipients. Clin Pharmacol Ther 2009; 85: 495-500.
97. Goo RH, Moore JG, Greenberg E, et al. Circadian variation in gastric emptying of meals in humans. Gastroenterology 1987; 93: 515-8.
98. de Winter BC, Mathot RA, van Hest RM, et al. Therapeutic drug monitoring of mycophenolic acid: does it improve patient outcome? Expert Opin Drug Metab Toxicol 2007; 3: 251-61.
99. Zahir H, McCaughan G, Gleeson M, et al. Factors affecting variability in distribution of tacrolimus in liver transplant recipients. Br J Clin Pharmacol 2004; 57: 298-309.
100. Zhou H. Pharmacokinetic strategies in deciphering atypical drug absorption profiles. J Clin Pharmacol 2003; 43: 211-27.
101. Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of 'bottom-up' vs 'top-down' recognition of covariates. Drug Metab Pharmacokinet 2009; 24: 53-75.
102. Parrott N, LukacovaV, Fraczkiewicz G, etal. Predicting pharmacokinetics of drugs using physiologically based modeling: application to food effects. AAPS J 2009; 11: 45-53