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.
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