Whole-Body PBPK Modeling of Tacrolimus in Healthy Volunteers
Stefan Zeiser (1), Nicoline Treijtel (1), Edwin Spaans (1)
(1) Kinesis Pharma B.V.
Objectives: To describe disposition of Tacrolimus (TAC) in healthy volunteers by a whole-body PBPK model based on literature data. Furthermore, to determine blood:plasma partitioning in terms of logP and fu by using plasma and whole blood concentrations simulateneously, and to estimate the fraction of hepatic clearance and intestinal first pass effect.
Methods: Physico-chemical and PK parameters of patients and healthy volunteers were gathered in a literature review. Whole blood and plasma concentrations after IV and PO administration were taken from three studies in literature [1], [2], [3]. The model was implemented in the PBPK platform PK-Sim® [4]. Elimination of TAC was described by hepatic and intestinal CYP3A4/5 together with intestinal efflux pump Pgp. The major driver of blood partitioning, FKBP12 in erythrocytes [5], [6], was implemented by a protein binding partner. Physico-chemical and PK parameters were optimized with data from [1] using a simulated annealing algorithm implemented in PK-Sim®. Estimates of logP, fu, CLint of CYP3A4/5 and binding parameters for FKBP12 are based on plasma and whole blood IV concentrations. Estimates of intestinal concentration of CYP3A4/5 and kinetic parameters of Pgp are based on plasma and whole blood PO data.
Results: Whole blood and plasma mean concentrations from [1] could simultaneously be described well. Predictions of mean plasma and whole blood concentrations were within a two-fold range of observed concentrations of European and Asian healthy volunteers from two independent studies, [2], [3]. Results from patient studies could not be reproduced without any adaptations, [7], [8]. Based on data from Möller et al., logP and fu values were determined equal to 5.82 and 0.0129, respectively. Bioavailability F with and without intestinal first pass effect were calculated to 30% and 61%, respectively.
Conclusions: TAC plasma and whole blood concentrations from [1] could simultaneously be described well. Despite the reported high variability of PK parameters whole blood concentrations in white Americans and Asian population could be predicted in an acceptable manner in a dose range from 2–5 mg. Prediction of patient data from [7] needs further investigation. Using whole blood and plasma concentrations simultaneously the estimated value of logP was at the high end of reported range, [9], [10]. Based on model prediction, intestinal first pass effect reduces bioavailability by 50% compared to hepatic clearance alone.
References:
[1] Möller A, Iwasaki K, Kawamura A, Teramura Y, Shiraga T, Hata T, Schäfer A, Undre NA. The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects. Drug Metab Dispos. 1999;27(6):633-6.
[2] Mancinelli LM, Frassetto L, Floren LC, Dressler D, Carrier S, Bekersky I, Benet LZ, Christians U. The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther. 2001; 69(1):24-31.
[3] Xin HW, Wu XC, Li Q, Yu AR, Zhu M, Shen Y, Su D, Xiong L, Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. Br J Clin Pharmacol. 2007; 64(4): 469–475.
[4] Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W. 2003. PK-Sim: A physiologically based pharmacokinetic ‘whole-body’ model. Biosilico 1:121–124.
[5] Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell, 1991; 66 (4): 807–15.
[6] Siekierka, JJ and Wiederrecht, G and Greulich, H and Boulton, D and Hung, SHY and Cryan, J and Hodges, P J and Sigal, NH. The cytosolic-binding protein for the immunosuppressant FK-506 is both a ubiquitous and highly conserved peptidyl-prolyl cis-trans isomerase. J. Biol. Chem. 1990; 265: 21011-15.
[7] Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I. Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant. 2003; 18(4):819-22.
[8] Jusko W J, Thomson A W, Fung J, McMaster P, Wong S H, Zylber-Katz E, Christians U, Winkler M, Fitzsimmons W E, Lieberman R. Consensus document: therapeutic monitoring of tacrolimus (FK-506). Ther Drug Monit. 1995, 17: 606-614.
[9] Billich A, Aschauer H, Aszodi A, Stuetz A. Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus. Int J Pharma 2004, 269: 29–35.
[10] Bos JD. Non-steroidal topical immunomodulators provide skin-selective, self-limiting treatment in atopic dermatitis. Eur J Dermatol 2003, 13: 455–61.
