OJNeph  Vol.2 No.4 , December 2012
Mycophenolic Acid Absorption Profiles in Patients with Kidney or Combined Pancreas-Kidney Transplantation
Abstract: Background: Mycophenolate Mofetil (MMF) is widely used in organ transplant patients to avoid calcineurine inhibittor-associated side effects. Therapeutic monitoring of MMF is up to now perform by using trough level measurements (measurements before drug administration). The present study was designed to characterize potential differences in MMF absorption kinetics between patients with allogenic kidney transplantation [kidney Tx] and simultaneous pancreas kidney transplantation [PK Tx], which might for example occur due to diabetic gastrointestinal atony. Methods: A total of 64 pharmacokinetic profiles were prospectively studied in 44 adult kidney Tx and 20 PK Tx patients. To calculate AUC by the trapezoidal rule, mycophenolic acid (MPA) levels were measured in EDTA-plasma by an EMIT assay at 0, 0.5, 1, 2, 3, 4 6, and 12h after oral MMF administration between postoperative day 14 to 28 instable patients. Results: Substantial differences between kidney Tx and PK Tx patients were evident concerning: donor age, recipient age, number of mismatches, and kidney function (serum creatinine). Despite these dissimilarities pharmacokinetic absorption profiles did not significantly differ between patient groups as measured by AUC, C2, maximum MPA concentration (Cmax), and time until maximum absorption (Tmax). Astonishingly, concomitant cyclosporine and tacrolimus medication did not influence adsorption profiles. Only MPA concentrations 6h post administration correlated closely with AUC in both patient groups, whereas trough levels failed to be predictive for AUC. Conclusions: In our study population, MMF absorption kinetics did not differ between kidney and PK Tx patients and did not seem influenced by concomitant immunosuppressive medication. Therefore, MPA measurements during the absorption phase could be useful to better estimate AUC in patients with kidney Tx and PK Tx.
Cite this paper: J. Fertmann, H. Arbogast, W. Illner, W. Land, K. Jauch and J. Hoffmann, "Mycophenolic Acid Absorption Profiles in Patients with Kidney or Combined Pancreas-Kidney Transplantation," Open Journal of Nephrology, Vol. 2 No. 4, 2012, pp. 116-122. doi: 10.4236/ojneph.2012.24019.

[1]   L. M. Shaw, B. Kaplan, D. DeNofrio, et al., “Pharmacokinetics and Concentration-Control Investigations of Mycophenolic Acid in Adults after Transplantation,” Therapeutic Drug Monitoring, Vol. 22, No. 1, 2000, pp. 14-19. HUdoi:10.1097/00007691-200002000-00003U

[2]   T. van Gelder, L. B. Hilbrands, Y. Vanrenterghem, et al., “A Randomized Double-Blind, Multicenter Plasma Concentration-Controlled Study of the Safety and Efficacy of Oral Mycophenolate Mofetil for the Prevention of Acute Rejection after Kidney Transplantation,” Transplantation, Vol. 68, No. 2, 1999, pp. 261-266. HUdoi:10.1097/00007890-199907270-00018U

[3]   H. W. Sollinger, S. Cho, G. Danowitch, et al., “Mycophenolate Mofetil for the Prevention of Acute Rejection in Primary Cadaveric Renal Allograft Recipients,” Transplantation, Vol. 60, No. 3, 1995, pp. 225-232. HUdoi:10.1097/00007890-199508000-00003U

[4]   G. Filler, M. Zimmering and I. Mai, “Pharmacokinetics of Mycophenolate Mofetil Are Influenced by Concomittant Immunosuppression,” Pediatric Nephrology, Vol. 14, No. 2, 2000, pp. 100-104. HUdoi:10.1007/s004670050021U

[5]   M. Oellerich, M. Shipkova, E. Schütz, et al., “Pharmacokinetic and Metabolic Investigations of Mycophenolic Acid in Pediatric Patients after Renal Transplantation: Implications for Therapeutic Drug Monitoring,” Therapeutic Drug Monitoring, Vol. 22, No. 4, 2000, pp. 20-26. HUdoi:10.1097/00007691-200002000-00004U

[6]   L. T. Weber, T. Lamersdorf, M. Shipkova, et al., “Area under Curve Concentration-Time Curve for Total, But Not for Free, Mycophenolic Acid Increases in the Stable Phase after Enal Transplantation: A Longitudinal Study in Pediatric Patients,” Therapeutic Drug Monitoring, Vol. 21, No. 5, 1999, pp. 498-506. HUdoi:10.1097/00007691-199910000-00002U

[7]   K. P. Braun, P. Glander, P. Hambach, et al., “Pharmacokinetics and Pharmacodynamics of Mycophenolate Mofetil under Oral and under Intravenous Therapy,” Transplantation Proceedings, Vol. 34, No. 5, 2002, pp. 1745-1747. HUdoi:10.1016/S0041-1345(02)03051-8U

[8]   G. Filler, N. Lepage, B. Delisle, et al., “Effect of Cyclosporine on Mycophenolic Acid Area under the Concentration-Time Curve in Pediatric Kidney Transplant Recipients,” Therapeutic Drug Monitoring, Vol. 23, No. 5, 2001, pp. 514-519. HUdoi:10.1097/00007691-200110000-00003U

[9]   C. Mignat, “Clinically Significant Drug Interactions with New Immunosuppressive Agents,” Drug Safety, Vol. 16, No. 4, 1997, pp. 267-278. HUdoi:10.2165/00002018-199716040-00004U

[10]   D. Kuypers, K. Claes, P. Evenepoel, et al., “Long-Term Changes in Mycophenolic Acid Exposure in Combination with Tacrolimus and Corticosteroids Are Dose Dependent and Not Reflected by Trough Plasma Concentration: A Prospective Study in 100 De Novo Renal Allograft Recipients,” Journal of Clinical Pharmacology, Vol. 43, No. 8, 2003, pp. 866-880. HUdoi:10.1177/0091270003256151U

[11]   R. E. S. Bullingham, A. Nicholls and M. D. Hale, “Pharmacokinetics of Mycophenolate Mofetil: A Short Review,” Transplantation Proceedings, Vol. 28, No. 2, 1996, pp. 925-929.

[12]   R. E. S. Bullingham, A. Nicholls and B. R. Kamm, “Clinical Pharmacokinetics of Mycophenolate Mofetil,” Clinical Pharmacokinetics, Vol. 34, No. 6, 1998, pp. 429-455. HUdoi:10.2165/00003088-199834060-00002U

[13]   L. M. Shaw, A. Nawrocki, M. Korecka, et al., “Using Established Immunosuppressant Therapy Effectively: Lessons from the Measurement of Mycophenolic Acid Plasma Concentrations,” Therapeutic Drug Monitoring, Vol. 26, No. 2, 2004, pp. 347-351. HUdoi:10.1097/00007691-200408000-00002U

[14]   B. Krumme, K. Wollenberg, G. Kirste, et al., “Drug Monitoring of Mycophenolic Acid in the Early Period after Renal Transplantation,” Transplantation Proceedings, Vol. 30, No. 5, 1998, pp. 1773-1774. HUdoi:10.1016/S0041-1345(98)00425-4U

[15]   Pillans PI, Rigby RJ, Kubler P, et al., “A Retrospective Analysis of Mycophenolic Acid and Cyclosporine Concentrations with Acute Rejection in Renal Transplant Recipients,” Clinical Biochemistry, Vol. 34, No. 1, 2001, pp. 77-81. HUdoi:10.1016/S0009-9120(00)00196-XU

[16]   L. M. Shaw, M. Korecka, R. Venkataramanan, et al., “Mycophenolic Acid Pharmacodynamics and Pharmacokinetics Provide a Basis for Rational Monitoring Strategies,” American Journal of Transplantation, Vol. 3, No. 5, 2003, pp. 534-542. doi:10.1034/j.1600-6143.2003.00079.xU

[17]   V. C. Cox and M. Ensom, “Mycophenolate Mofetil for Solid Organ Transplantation: Does the Evidence Support the Need for Clinical Pharmacokinetic Monitoring?” Therapeutic Drug Monitoring, Vol. 25, No. 2, 2003, pp. 137-157. HUdoi:10.1097/00007691-200304000-00003U

[18]   L. M. Shaw, M. Korecka, D. DeNofrio, et al., “Pharmacokinetic, Pharmacodynamic, and Outcome Investigations as the Basis for Mycophenolic Acid Therapeutic Drug Monitoring in Renal and Heart Transplant Patients,” Clinical Biochemistry, Vol. 34, No. 1, 2001, pp. 17-22. HUdoi:10.1016/S0009-9120(00)00184-3U

[19]   A. G. Johnson, R. J. Rigby, P. J. Taylor, et al., “The Kinetics of Mycophenolic Acid and Its Glucuronide Metabolite in Adult Kidney Transplant Recipients,” Clinical Pharmacology & Therapeutics, Vol. 66, No. 5, 1999, pp. 492-500. HUdoi:10.1016/S0009-9236(99)70012-3U

[20]   K. Zucker, A. Rosen, A. Tsaroucha, et al., “Unexpected Augmentation of Mycophenolic Acid Pharmacokinetics in Renal Transplant Patients Receiving Tacrolimus and Mycophenolate Mofetil in Combination Therapy, and Analogous in Vitro Findings,” Transplant Immunology, Vol. 5, No. 3, 1997, pp. 225-232. HUdoi:10.1016/S0966-3274(97)80042-1U

[21]   P. J. Smak Gregoor, T. van Gelder, C. J. Hesse, et al., “Mycophenolic Acid Plasma Concentrations in Kidney Allograft Recipients with or without Cyclosporin: A Cross-Sectional Study,” Nephrology Dialysis Transplantation, Vol. 14, No. 3, 1999, pp. 706-708. Hdoi:10.1093/ndt/14.3.706U

[22]   L. Pou, M. Brunet, C. Cantarell, et al., “Mycophenolic Acid Plasma Concentrations: Influence of Comedication,” Therapeutic Drug Monitoring, Vol. 23, No. 1, 2000, pp. 35-38. HUdoi:10.1097/00007691-200102000-00007U

[23]   T. van Gelder, J. Klupp, M. J. Barten, et al., “Comparison of the Effects of Tacrolimus and Cyclosporin on the Pharmacokinetics of Mycophenolic Acid,” Therapeutic Drug Monitoring, Vol. 23, No. 2, 2001, pp. 119-128. HUdoi:10.1097/00007691-200104000-00005U

[24]   M. Glanemann, J. Klupp, J. M. Langrehr, et al., “Higher Immunosuppressive Efficacy of Mycophenolate Mofetil in Combination with FK 506 than in Combination with Cyclosporine A,” Transplantation Proceedings, Vol. 32, No. 3, 2000, pp. 522-523. HUdoi:10.1016/S0041-1345(00)00872-1U

[25]   D. Cattaneo, Perico N., F. Gaspari, et al., “Glucocorticoids Interfere with Mycophenolate Mofetil Bioavailability in Kidney Transplantation,” Kidney International, Vol. 62, No. 3, 2002, pp. 1060-1067. HUdoi:10.1046/j.1523-1755.2002.00531.xU

[26]   G. I. Hubner, R. Eismann and W. Sziegoleit, “Relationship between Mycophenolate Mofetil Side Effects and Mycophenolic Acid Plasma Trough Levels in Renal Transplant Patients,” Arzneimittelforschung, Vol. 50, No. 10, 2000, pp. 936-940.

[27]   I. Neumann, M. Haidinger, H. Jaeger, et al., “Pharmacokinetics of Mycophenolate Mofetil in Patients with Autoimmune Diseases Compared to Renal Transplant Recipients,” Journal of the American Society of Nephrology, Vol. 14, No. 3, 2003, pp. 721-727. HUdoi:10.1097/01.ASN.0000051598.12824.DAU

[28]   M. Brunet, J. Martorell, F. Oppenheimer, et al., “Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid in Stable Renal Transplant Recipients Treated with Low Doses of Mycophenolat Mofetil,” Transplant International, Vol. 13, No. S1, 2000, pp. S301-S305.

[29]   P. Belitsky, G. A. Levy and A. Johnston, “Neoral Absorption Profiling: An Evolution in Effectiveness,” Transplantation Proceedings, Vol. 32, No. 3A, 2000, pp. 45S- 52S. HUdoi:10.1016/S0041-1345(00)00863-0U

[30]   K. Mahalati, P. Belitsky, I. Sketris, et al., “Neoral Monitoring by Simplified Sparse Sampling Area under the Concentration-Time Curve,” Transplantation, Vol. 68, No. 1, 1999, pp. 55-62. HUdoi:10.1097/00007890-199907150-00011U