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Computational Predictions of Mycophenolic Acid Exposure after Oral Administration using a Joined In Vitro–In Vivo Extrapolation and Physiologically-Based Pharmacokinetic Modeling Approach in Caucasian and Chinese Healthy Volunteers and Patients With Varying Degree of Renal Impairment

Joshi, Rujuta2; Venkataramanan, Raman1,2; Kalluri, Hari Varun2

doi: 10.1097/01.tp.0000520312.63960.a6
116.8
Free

1Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; 2Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.

Purpose: Mycophenolate Mofetil (MMF) is an immunosuppressive prodrug used as a prophylactic agent for graft rejection in solid organ and hematopoietic stem cell transplant patients. It undergoes immediate hydrolysis to the active form mycophenolic acid (MPA). The drug exhibits a large pharmacokinetic variability. There is poor correlation between trough concentration and MPA exposure measured as area under the plasma concentration -time curve (AUC). Our objective is to understand the physiological factors that influence the mycophenolic acid exposure using a validated physiologically based pharmacokinetic (PBPK) model in order to optimize therapy in transplant patients.

Methods: Simcyp Simulator V15 was used to perform PBPK analysis. Physicochemical properties for mycophenolic acid were obtained from literature and a model was build and validated across doses of 500–1500 mg IV and oral of MMF in population cohorts of healthy volunteers, Chinese healthy volunteers and renal impairment. Pharmacokinetic parameters like Cmax, Tmax, AUC and Clearance were assessed and compared with the observed data. A full PBPK model was considered using an Advanced Dissolution Absorption Model (ADAM) to build the model. Parameter estimation using non-linear mixed effects was used to optimize tissue partitioning. The simulated clinical trials was carried out in the 100 virtual subjects from population groups of Simcyp’s platform: i) healthy volunteers, ii) renal impairment with GFR values between 30–60 iii) renal impairment with GFR below 30. Intrinsic clearance for each of the UGT enzymes was extrapolated from recombinant UGT data as reported by Picard et al using rUGT scalar.

Results: The developed mechanistic models adequately described the pharmacokinetics mycophenolic acid after IV and oral doses in healthy volunteers, Chinese healthy volunteers and patients with varying degree of renal impairment. The predicted pharmacokinetic parameters for all the model naive data were within 1. 5 fold of the observed data.

Conclusions: The top down bottom up PBPK-based approach showed a good correlation with the literature related to MPA pharmacokinetic parameters. This model has the potential to predict pharmacokinetics in other solid organ transplant recipients and thereby individualize MMF dosing.

Dr. Sibylle Neuhoff.

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References:

1. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P. Identification of the UDP‐glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 2005;33:139–146.

2. Bullingham R, Monroe S, Nicholls A, Hale M. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol. 1996;36:315–324.

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