Pharmacokinetic modeling of plasma protein binding of mycophenolic acid in renal transplant recipients
van Hest, Reinier1, Teun van Gelder1,2, Arnold Vulto1, Leslie Shaw3, Ron Mathôt1
1Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, The Netherlands, 2Department of Internal Medicine, Renal Transplant Unit, Erasmus MC, Rotterdam, The Netherlands, 3Department of Pathology & Laboratoty Medicine, University of Pennsylvania, Philadelphia, USA
Background: Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal transplantation. In a previous population pharmacokinetic analysis, using total plasma MPA concentrations, it was shown that impaired renal function and low plasma albumin levels were significantly associated with an increased clearance (CL) of total MPA [1]. As hypothesis for the underlying mechanism it was proposed that low plasma albumin levels and accumulation of the glucuronide metabolite of MPA (MPAG), occurring during renal impairment, decrease the binding of MPA to albumin. The subsequent increase of MPA free fraction (fu) produces an increased total MPA CL, in line with the reported low hepatic extraction for MPA (< 0.4) [2]. Thus far, this hypothesis has not been evaluated on the basis of in vivo data.
Aim: The aim of this study was to develop a population pharmacokinetic model for total and unbound MPA plasma concentrations, as well as for total MPAG plasma concentrations to elucidate the mechanism of the effect of renal function and plasma albumin level on the pharmacokinetics of mycophenolate mofetil.
Patients and Methods: Retrospective pharmacokinetic data of unbound and total MPA, and total MPAG were obtained from 88 renal transplant recipients who participated in a previously performed randomised concentration controlled trial [3]. Data were available on day 11 and day 140 after transplantation. All patients were concurrently treated with cyclosporine and steroids. Data were analyzed using the non-linear mixed effects modelling program (NONMEM).
Results: 774 total MPA (Ct), 479 unbound MPA (Cu), and 772 total MPAG concentrations were avalaible. The data were adequately described by a 4 compartment model: a central and peripheral compartment for both Cu and total MPAG plasma concentrations with a link between the central compartments. Ct was modeled as follows (equation 1):
MPA Ct (mmol/L) = MPA Cu + MPA Cu * θprotein binding (Eq.1)
with MPA Cu * θprotein binding representing the bound MPA plasma concentration.
The following population parameters (CV%) were obtained: duration of absorption (zero order, D1): 0.85 h (9%), lag time: 0.09 h (55%) unbound MPA central volume of distribution (V1u): 3290 L (23%), unbound MPA CL (CLu): 1130 L/h (6%), unbound MPA peripheral volume: 5600 L (25%), unbound MPA intercompartmental clearance: 1180 L/h (16%), total MPAG central volume of distribution: 7.2 L (20%), total MPAG CL (CLmpag): 1.7 L/h (3%), total MPAG peripheral volume: 8.1 L (17%), total MPAG intercompartmental clearance: 7.7 L/h (50%). θprotein binding was estimated to be 33 (3%), corresponding to a fu of 2.9%. The between-subject variability for D1, V1u, CLu, CLmpag and θprotein binding was 85%, 97%, 31%, 26% and 12%, respectively. Within-patient variability for CLu was estimated to be 19%. θprotein binding significantly correlated with creatinine clearance (CrCl), plasma albumin level and the MPAG concentration (p<0.001): a reduction of CrCl from 60 to 10 mL/min correlated with an increase in fu from 2.7% to 4.6%, accumulation of total MPAG concentrations from 50 to 150 mg/L correlated with an increase in fu from 2.8% to 3.7%, and a change in plasma albumin level from 40 to 30 g/L correlated with an increases of fu from 2.6% to 3.4%. Furthermore, a decrease in cyclosporine daily dose from 600 to 300 mg corresponded with a decrease in CLu from 1218 to 943 L/h (p<0.001), and a change in CrCl from 60 to 10 mL/min correlated with a change in CLmpag from 2.0 to 0.5 L/h (p<0.001).
No significant correlations were detected between CLu and plasma albumin level, CrCl and MPAG concentration.
Conclusion: The model supports the hypothesis that low CrCl, low plasma albumin levels, and high MPAG concentrations decrease total MPA exposure by affecting MPA binding to albumin. The relationship between θprotein binding and MPAG concentrations provides evidence that MPAG displaces MPA from its albumin binding sites. Furthermore, the model is in accordance with the assumption that MPA is a drug with a low extraction ratio: a decrease in MPA protein binding (θprotein binding) leads to an increase of fu and a decrease of Ct, but leaves Cu unaffected. Because Cu is regarded as the pharmacologically active moiety, mycophenolate mofetil dose adjustments may not be indicated when renal function is impaired or when plasma albumin level is low.
References:
1. Van Hest RM, Van Gelder T, Vulto AG, Mathot RA. Population pharmacokinetics of mycophenolic acid in renal transplant recipients. Clin Pharmacokinet. 44:1083-1096, 2005.
2. Shaw LM, Korecka M, Vankataramanan R, Goldberg L, Bloom R, Brayman KL. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant. 3:534-542, 2003.
3. Hale MD, Nicholls AJ, Bullingham RE, Hene R, Hoitsma A, Squifflet JP, Weimar W, Vanrenterghem Y, Van de Woude FJ, Verpooten GA. The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther. 64:672-683, 1998.