In this study, the pharmacokinetic profiles of the Chinese renal transplant recipients receiving EC-MPS were analyzed with LSS using EMIT. Compared with high-performance liquid chromatography, which was considered as the “gold standard” for drug concentration measurement, EMIT was reported for higher results. However, EMIT had a good linear correlation with high-performance liquid chromatography, making it a practical method for drug monitoring.25–28 More importantly, due to the high efficiency, convenience, and automation of EMIT, it has been more widely used in clinical setting. In this study, all samples were tested with EMIT, which should be considered when adjusting drug doses.
In accordance with the previous studies, large interindividual variability was shown in MPA exposure.20,29 MPA is metabolized by the UDP-glucuronosyltransferase (UGT) to a major metabolite, 7-O-glucuronide, and 7-O-glucuronide undergoes biliary excretion into the intestine via multidrug resistance protein 2 and solute carrier organic anion transporter.30 A series of studies have proven that the genetic polymorphisms of UGT and SLCO influence the pharmacokinetics of MPA.31 Food intake time, types of food ingestion, and gastric emptying may also have influence on it.9 Although for EC-MPS drug concentration monitoring is more difficult, it still highlights the value and importance of TDM. Various studies have shown the relationship between the MPA AUC and the risk of rejection and side effects. With TDM, the patients could receive personalized prescription.
Despite the interindividual variability, it shared the same trend within each group. The concentration of MPA increased sharply between 2.5 and 3 hours postdose, and the maximum occurred about 4 hours after the oral administration (peak time point: 4 hours postdose and mean MPA-Tmax: 4.8 hours postdose), which was in accordance with the majority of the individual profiles of patients. It was delayed compared with a previous study, which has reported that the median time to maximum MPA concentration was 2.0 hours.32 This result might reflect the metabolic characteristics of EC-MPS in Chinese population. There was only 1 obvious peak in the curves of our study. This may be due to the limitations of LSS. Within the range of 3–6 hours postdose, the inadequate sample points may conceal the second peak, which was also seen in other research.15
The results of univariate correlation analysis suggested that the predose MPA concentration was poor at predicting the systemic exposure of MPA (R 2 = 0.187). Only the concentration at 4 hours postdose, which was also the peak of the concentration, had a relatively higher correlation, but it was still not reliable enough (R 2 = 0.553). As a result, 3 time point (C 0, C 3, and C 4) and 4 time point (C0, C3, C4, and C8) equations were developed. Although the frequency of sampling was acceptable, the time span needed was still impractical for outpatients. In our study, the same multiple regression method was performed with the variables within 2 hours postdose (C0, C0.5, C1, C1.5, and C2) so that it might have better practicability, but all parameters were excluded except C1.5 because of high P value (P > 0.10, data not shown). Fleming et al15 did the same effort, but the R 2 for the early 4 points within 2 hours was only 0.292. De Winter et al and Pawinski et al also wanted to develop an equation using the time points within 3 hours postdose, but they failed because of biased and imprecise results.16,33 When C8 was added into the 3 time point equation in our study, it had a much better performance in the validation group. Because the reported enterohepatic recirculation was about 3–12 hours postdose and caused the second peak of MPA, the C8 was related to this phenomenon so that it greatly increased the precision of the equation.2,32 It is the pharmacokinetic characteristics of EC-MPS that decreases the convenience for TDM, especially for the outpatients.
A series of studies with similar parameters to evaluate the equations are shown in Table 6.9,15,16,19,22,33 It is in accordance with our results that a relatively feasible and precise equation should contain time points at a later stage. Compared with the results in Table 6, the equations developed in our study have a relatively better predictive performance, especially for the 4 time point equation, whose bias and precision for the validation group were 0.505 and 13.370, respectively. Considering that the SE of estimation was only 4.444, and about 80% of the estimated AUC was within 85%–115% of the measured AUC, this equation could be the reference for the treatment of inpatients in clinical setting.
This study has a number of limitations that should be considered. All cases were from a Chinese population, and the genetic polymorphism for MPA metabolism was not analyzed. Blood samples were stored at 4°C overnight for the practicability. This could cause a measurement error. The number of sampling time points for the measured AUC is limited, especially between 2 and 4 hours postdose, in which the MPA concentration increased sharply. Renal function of kidney transplant recipient achieves a stable condition mostly 2 weeks after the transplantation, and the pharmacokinetics of EC-MPS is relatively stable at this time point as well. Additionally, inappropriate MPA exposure in early stage after the kidney transplantation correlated to allograft rejection, infection, and myelosuppression; thus, MPA pharmacokinetic monitoring at an early stage after the kidney transplantation is of great importance. Based on these considerations, we chose 2 weeks after transplantation for the study time point. However, beyond 2 weeks after the transplantation, there are still important changes in dose-corrected MPA exposure, which could potentially change the overall performance of the currently obtained 4 point LSS at other (later) time points after the transplantation. Further validation is needed before LSS calculated by this predictive equation can be applied to patients receiving long-term EC-MPS. Moreover, the relatively small number of patients involved in this study amplified the bias. The models should thus be further tested with larger patient groups in more centers.
1. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351:2715–2729.
2. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics
of mycophenolate mofetil. Clin Pharmacokinet. 1998;34:429–455.
3. Bunnapradist S, Ambuhl PM. Impact of gastrointestinal-related side effects on mycophenolate mofetil dosing and potential therapeutic strategies. Clin Transpl. 2008;22:815–821.
4. Johnston A, He X, Holt DW. Bioequivalence of enteric-coated mycophenolate sodium
and mycophenolate mofetil: a meta-analysis of three studies in stable renal transplant recipients. Transplantation. 2006;82:1413–1418.
5. Budde K, Bauer S, Hambach P, et al.. Pharmacokinetic and pharmacodynamic comparison of enteric-coated mycophenolate sodium
and mycophenolate mofetil in maintenance renal transplant patients. Am J Transpl. 2007;7:888–898.
6. Burg M, Saemann MD, Wieser C, et al.. Enteric-coated mycophenolate sodium
reduces gastrointestinal symptoms in renal transplant patients. Transpl Proc. 2009;41:4159–4164.
7. Ortega F, Sanchez-Fructuoso A, Cruzado JM, et al.. Gastrointestinal quality of life improvement of renal transplant recipients converted from mycophenolate mofetil to enteric-coated mycophenolate sodium
drugs or agents: mycophenolate mofetil and enteric-coated mycophenolate sodium
. Transplantation. 2011;92:426–432.
8. Langone AJ, Chan L, Bolin P, et al.. Enteric-coated mycophenolate sodium
versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicenter, double-blind, randomized study. Transplantation. 2011;91:470–478.
9. Yao X, Huang H, Wei C, et al.. Limited sampling strategy
for mycophenolic acid
in Chinese kidney transplant recipients receiving enteric-coated mycophenolate sodium
and tacrolimus during the early posttransplantation phase. Ther Drug Monit. 2015;37:516–523.
10. Shaw LM, Holt DW, Oellerich M, et al.. Current issues in therapeutic drug monitoring of mycophenolic acid
: report of a roundtable discussion. Ther Drug Monit. 2001;23:305–315.
11. Kuypers DR, Le Meur Y, Cantarovich M, et al.. Consensus report on therapeutic drug monitoring of mycophenolic acid
in solid organ transplantation. Clin J Am Soc Nephrol. 2010;5:341–358.
12. Kuypers DR, De Jonge H, Naesens M, et al.. Current target ranges of mycophenolic acid
exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients. Clin Ther. 2008;30:673–683.
13. Van Gelder T, Le Meur Y, Shaw LM, et al.. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. 2006;28:145–154.
14. Sommerer C, Muller-Krebs S, Schaier M, et al.. Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium
: limited sampling strategies and clinical outcome in renal transplant patients. Br J Clin Pharmacol. 2010;69:346–357.
15. Fleming DH, Mathew BS, Prasanna S, et al.. A possible simplification for the estimation of area under the curve (AUC(0)(-)(1)(2)) of enteric-coated mycophenolate sodium
in renal transplant patients receiving tacrolimus. Ther Drug Monit. 2011;33:165–170.
16. Pawinski T, Luszczynska P, Durlik M, et al.. Development and validation of limited sampling strategies for the estimation of mycophenolic acid
area under the curve in adult kidney and liver transplant recipients receiving concomitant enteric-coated mycophenolate sodium
and tacrolimus. Ther Drug Monit. 2013;35:760–769.
17. De Winter BC, Van Gelder T, Glander P, et al.. Population pharmacokinetics
of mycophenolic acid
: a comparison between enteric-coated mycophenolate sodium
and mycophenolate mofetil in renal transplant recipients. Clin Pharmacokinet. 2008;47:827–838.
18. Yang SL, Gao X, Wang QH, et al.. Use of limited sampling strategy
for estimating area under concentration-versus-time curve of mycophenolate sodium in renal allograft recipients [in Chinese]. Zhonghua Yi Xue Za Zhi. 2013;93:3841–3846.
19. Sanchez Fructuoso AI, Perez-Flores I, Calvo N, et al.. Limited-sampling strategy for mycophenolic acid
in renal transplant recipients reciving enteric-coated mycophenolate sodium
and tacrolimus. Ther Drug Monit. 2012;34:298–305.
20. Qiu K, Tian H, Wang W, et al.. Pharmacokinetics
of enteric-coated mycophenolate sodium
in Chinese renal transplantation
recipients. Chin Med J (Engl). 2012;125:4226–4232.
21. Shah T, Tellez-Corrales E, Yang JW, et al.. The pharmacokinetics
of enteric-coated mycophenolate sodium
and its gastrointestinal side effects in de novo renal transplant recipients of Hispanic ethnicity. Ther Drug Monit. 2011;33:45–49.
22. Capone D, Tarantino G, Kadilli I, et al.. Evalutation of mycophenolic acid
systemic exposure by limited sampling strategy
in kidney transplant recipients receiving enteric-coated mycophenolate sodium
(EC-MPS) and cyclosporine. Nephrol Dial Transpl. 2011;26:3019–3025.
23. Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm. 1981;9:503–512.
24. Wong KM, Shek CC, Chau KF, et al.. Abbreviated tacrolimus area-under-the-curve monitoring for renal transplant recipients. Am J Kidney Dis. 2000;35:660–666.
25. Martiny D, Macours P, Cotton F, et al.. Reliability of mycophenolic acid
monitoring by an enzyme multiplied immunoassay technique. Clin Lab. 2010;56:345–353.
26. Chen B, Gu Z, Chen H, et al.. Establishment of high-performance liquid chromatography and enzyme multiplied immunoassay technology methods for determination of free mycophenolic acid
and its application in Chinese liver transplant recipients. Ther Drug Monit. 2010;32:653–660.
27. Irtan S, Azougagh S, Monchaud C, et al.. Comparison of high-performance liquid chromatography and enzyme-multiplied immunoassay technique to monitor mycophenolic acid
in paediatric renal recipients. Pediatr Nephrol. 2008;23:1859–1865.
28. Premaud A, Rousseau A, Le Meur Y, et al.. Comparison of liquid chromatography-tandem mass spectrometry with a commercial enzyme-multiplied immunoassay for the determination of plasma MPA in renal transplant recipients and consequences for therapeutic drug monitoring. Ther Drug Monit. 2004;26:609–619.
29. Li J, Liu Y, Huang J, et al.. Evaluation of mycophenolic acid
exposure using a limited sampling strategy
in renal transplant recipients. Am J Nephrol. 2013;37:534–540.
30. Bernard O, Tojcic J, Journault K, et al.. Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid
. Drug Metab Dispos. 2006;34:1539–1545.
31. Han N, Yun HY, Kim IW, et al.. Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium
in kidney transplant recipients. Eur J Clin Pharmacol. 2014;70:1211–1219.
32. Budde K, Glander P, Diekmann F, et al.. Review of the immunosuppressant enteric-coated mycophenolate sodium
. Expert Opin Pharmacother. 2004;5:1333–1345.
33. De Winter BC, Van Gelder T, Mathot RA, et al.. Limited sampling strategies drawn within 3 hours postdose poorly predict mycophenolic acid
area-under-the-curve after enteric-coated mycophenolate sodium
. Ther Drug Monit. 2009;31:585–591.