Elisabet Størset (1), Nick Holford (2), Stefanie Hennig (3,4), Troels K Bergmann (3,5), Stein Bergan (6), Sara Bremer (7), Anders Åsberg (1), Karsten Midtvedt (1), Christine E Staatz (3,4)
(1) Department of Transplant Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway, (2) Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand, (3) School of Pharmacy, University of Queensland, Brisbane, Australia, (4) Australian Centre of Pharmacometrics, (5) Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark, (6) Department of Pharmacology, Oslo University Hospital, Oslo, Norway, (7) Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
Objectives: We have previously developed a theory-based population pharmacokinetic model for tacrolimus in adult kidney transplant recipients [1]. The aim of this study was to examine the extent of target achievement using (i) standard weight-based dosing, (ii) mechanism-based dosing and (iii) Bayesian dosing.
Methods: Dosing strategies were evaluated by simulating the concentration-time profiles of 1000 subjects during the first five days post-transplant with covariate values sampled from the original dataset. For each subject, dosing strategies were based on (i) total body weight (0.04 mg/kg/12 hours) or (ii) standard population pharmacokinetic parameter values and mechanism-based covariates (fat free mass, CYP3A5 genotype and prednisolone dose, p<0.001). Dosing strategy (iii) was designed to imitate the effect of Bayesian forecasting on prediction of individual parameters by tapering between-subject variability to zero over the first five days without a change in between-occasion variability. The target was set to an average steady-state concentration of 14.2 mcg/L (standardized to a hematocrit of 45 %) [2] with an acceptable range defined as 80-125 % of the target concentration [3]. The percentage of concentrations within this range was calculated for each dosing strategy. Modeling, simulation and Bayesian dosing was performed using NONMEM 7.2.
Results: Total weight-based dosing, mechanism-based dosing and Bayesian dosing led to 32 % (95 % CI 29 % to 35 %), 37 % (95 % CI 34 % to 40 %) and 65 % (95 % CI 62 % to 68 %), respectively, of simulated average steady-state concentrations within the suggested acceptable range.
Conclusions: Mechanism-based dosing is of little additional value to improve target achievement of tacrolimus after kidney transplantation compared with weight-based dosing. Bayesian dosing improves target achievement. However, even with ideal Bayesian dose adaptation, 35% of concentrations were outside the acceptable range. To reduce this percentage, efforts should be directed to reducing the between-occasion variability associated with tacrolimus oral bioavailability.
References:
[1] Størset E, Holford N, Hennig S et al. Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modeling. Br J Clin Pharmacol. Accepted Feb 2014.
[2] Saint-Marcoux F, Woillard J-B, Jurado C, Marquet P. Lessons from routine dose adjustment of tacrolimus in renal transplant patients based on global exposure. Ther Drug Monit 2013;35:322–7.
[3] Holford NHG, Buclin T. Safe and effective variability-a criterion for dose individualization. Ther Drug Monit 2012;34:565–8.
Reference: PAGE 23 () Abstr 3130 [www.page-meeting.org/?abstract=3130]
Poster: Drug/Disease modeling - Other topics