Elisabet Størset (1), Nick Holford (2), Karsten Midtvedt (3), Sara Bremer (4), Anders Åsberg (5)
(1) Centre for Pharmacy, Department of Public Health and Primary Health Care, University of Bergen, Norway; (2) Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand; (3) Department of Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; (4) Department of Medical Biochemistry, Oslo University Hospital, Rikshospitalet, Oslo, Norway; (5) Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway
Objectives: Tacrolimus is a potent immunosuppressive agent, frequently used after kidney transplantation. High variability between subjects and dosing occasions in addition to apparently time varying pharmacokinetics makes target concentration intervention (TCI) challenging. Initial doses are typically based only on total body weight. Tacrolimus is highly distributed into and bound to erythrocytes [1], but hematocrit is not used for TCI. Several population pharmacokinetic models have been developed [2-5], but few are reported to be in use for initial dosing or Bayesian forecasting, even though there is wide agreement of its potential clinical value. The aims of this study were (1) to identify predictable differences between kidney transplant recipients for initial dosing of tacrolimus, (2) to develop a population model suitable for Bayesian forecasting and (3) to evaluate the use of hematocrit for tacrolimus TCI [6].
Methods: A total of 1546 blood samples were collected from four independent studies. Twenty-nine patients contributed full pharmacokinetic profiles from 44 occasions, and 44 patients contributed trough concentrations from the first 10 weeks after transplantation. A two compartment model with first order absorption and lag time, using study specific absorption rate constants and residual error models was used to describe the data. Between occasion variability was tested on all parameters. The following covariates were examined: CYP3A5 genotype, hematocrit, age, weight, height, sex, albumin, serum creatinine, C-reactive protein, liver function tests, steroid dose, concomitant use of interactive drugs, acute rejection episodes and time after transplantation. Modeling was done with NONMEM 7.2, using the first order conditional method with interaction.
Results: Relative bioavailability was decreased by 53 % in CYP3A5 expressers, by 27 % in females, by up to 21 % with higher prednisolone doses and was 104 % higher immediately after transplantation. The two latter effects were best described by sigmoid Emax models (Pred50 16 mg/day, Day50 1.4 days). Allometric scaling to fat free mass revealed a relationship between PK and body size in kidney transplanted adults. Studies using total body weight have not found a relationship with size [2-5]. A linear hematocrit associated change in blood concentration explained the time related changes in pharmacokinetics after day 2 post-transplant. Assuming F=0.2 [7], the blood clearance of tacrolimus (2.7 L/h/60kg fat free mass) means it has a low extraction ratio. Pharmacologically active unbound drug clearance should not be affected by changes in hematocrit. Hematocrit based standardization of measured and target concentrations may lead to more consistent clinical effects.
Conclusions: Initial dosing may be improved if determined by CYP3A5 *1/*3 genotype, sex, prednisolone dose and allometric scaling to fat free mass. The model should be suitable for Bayesian forecasting during the first 10 weeks after transplantation. Measured blood concentrations should be adjusted using hematocrit to achieve a hematocrit standardized target concentration.
References:
[1] Chow, FS., et. al. Effect of hematocrit and albumin concentration on hepatic clearance of tacrolimus (FK506) during rabbit liver perfusion. Drug Metab Dispos 25(5): 610-616
[2] Press, R., et al. Explaining variability in Tacrolimus Pharmacokinetics to Optimize Early Exposure in Adult Kidney Transplant Recipients.Ther Drug Monit 2009; 31: 187-197
[3] Musuamba, FT. A simultaneous D-optimal designed study for population pharmacokinetic analyses of mycophenolic acid and tacrolimus early after renal transplantation, J Clin Pharmacol 2011 Dec 29 [Epub ahead of print]
[4] Staatz, C. et. al. Population pharmacokinetics of tacrolimus in adult kidney transplant recipients, Clin Pharmacol Ther. 2002 Dec; 72(6):660-9
[5] Antignac, M. et al. Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol 2007, 64(6):750-757
[6] Holford NH. Target concentration intervention: beyond Y2K. Br J Clin Pharmacol 1999; 48: 9-13.
[7] Venkataramanan, R. et. al.Clinical Pharmacokinetics of Tacrolimus, Clin Pharmacokinet. 1995; 29(6):404-430
Reference: PAGE 21 () Abstr 2306 [www.page-meeting.org/?abstract=2306]
Poster: Other Drug/Disease Modelling