L.C. Martial(1); M. Biewenga(2); B.N. de Ruijter(2); J.J. Swen(1); B. van Hoek(2*); D.J.A.R. Moes(1*).
(1)Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden; (2)Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden,* Shared senior authorship
Objectives: Meltdose tacrolimus (Envarsus®) is marketed as a tacrolimus formulation with a more consistent exposure. Due to the narrow therapeutic window, therapeutic drug monitoring is essential to maintain adequate exposure[1]. While trough monitoring is the current standard, the area under the concentration-time-curve over 24 hours (AUC) is the best link between exposure and response. The primary objective of this study was to develop a population pharmacokinetic (PK) model of Envarsus® and construct a limited sampling strategy (LSS). The secondary objective of this study was to find potential covariates suitable for initial dose individualization.
Methods: Stable adult liver transplant patients were converted from prolonged release tacrolimus (Advagraf®) to Envarsus® and AUC measurement (8 time points) was performed. Demographic factors, recipient and donor CYP3A4*22, CYP3A5*3, IL-6,-10 and-18 genotype were tested as covariates. Nonlinear-mixed-effects-modelling (NONMEM) and R statistics were used for analyses.
Results: 55 patients were converted to Envarsus® (median dose 2mg; range: 0.75-6mg) of which 53 (total 748 concentrations) could be included for PK analysis. Pharmacogenetic information of CYP-status was available for 54 patients and from 49 donors. IL-6,-10 and -18 -pharmacogenetic information was available for 53 patients and from 48 donors. The PK was best described by a two compartmental model with delayed absorption described with 1.6 transit compartments with mean transit time of 3.4h for absorption. The PK parameters along with their % interindividual variability (IIV) were as follows: clearance (CL): 3,27 L/h (34%); intercompartmental clearance (Q): 9,6 L/h (24%), volume of distribution of compartment 1: 95 L (141%); volume of distribution of compartment 2: 500 L.
Hematocrit and CYP3A5-genotype of the recipient were significantly correlated to CL in univariate analyses and reduced unexplained IIV of CL from 34% to 27%. Transplant recipients with a functional CYP3A5 enzyme had on average 43% higher CL than non-expressors. Hematocrit was negatively correlated with CL, i.e. a lower hematocrit led to higher CL. However, in a multi-variate analysis, these correlations failed to be statistically significant and were therefore not included in the PK model.
Two 4-point LSS (t=0,3,6,8 & 0,3,6,12) resulted in adequate AUC prediction with a median(range) bias of 0,6% (-8,9 – 7,2) and 1,4%(-7,5 – 6,2). The best 3-point LSS was t=0,4,8 with a median bias of 1,8% (-12,5 – 12,5). The correlation coefficient (Pearson, r2) was 0,89 between trough concentrations and AUC.
Conclusions: The PK of Envarsus® in stable adult liver transplant patients was adequately described by a 2-compartmental model with delayed absorption described with transit compartments. Variability in CYP3A4 and CYP3A5 status was of much less impact on CL of Envarsus® and could not reduce IIV of CL in a clinically significant way, as opposed to what is known for other tacrolimus-formulations[2]. A 3-point LSS predicted the AUC with maximal 12,5% bias. A 4-point LSS led to even lower bias. This LSS can be used in routine clinical care to adequately predict AUC with a reduced burden for both patients and the clinic.
References:
[1] Staatz CE et al. Clinical Pharmacokinetics. 2004;43:623–653.
[2] Moes DJAR et al. Eur J Clin Pharmacol. 2016; 72:163–174.
Reference: PAGE () Abstr 9332 [www.page-meeting.org/?abstract=9332]
Poster: Clinical Applications