Abstract
Aims
To characterize the pharmacokinetics of mycophenolic acid (MPA) in Chinese renal transplant patients.
Methods
Thirty-one renal transplant patients (17 male, 14 female) receiving mycophenolate mofetil (MMF) 1.0 g twice daily were included in this study. A pharmacokinetic study was performed during an interval in dosing after steady state had been reached within 2 months after transplantation. The plasma MPA concentration were measured by high-performance liquid chromatography (HPLC) at 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the administration of a single dose. Pharmacokinetic parameters were calculated with 3P97 software. SAS® software was used for statistical analysis. Multiple linear regression analysis was used to determine limited sampling approaches.
Results
The mean peak plasma concentration (Cmax) and area under the concentration–time curve (AUC0–12) were 19.67 ± 8.21 µg ml−1 and 52.16 ± 12.50 µg h ml−1, but there was large variability in these pharmacokinetic parameters. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that each of the concentrations at 0.5, 1, 4 and 10 h was positively correlated with AUC (r = 0.60, P = 0.0004; r = 0.60, P = 0.0003; r = 0.61, P = 0.0003; r = 0.64, P = 0.0001, respectively). The combined use of these four samples explained over 90% of the variance in the total (nine-point) AUC0–12. A formula was obtained for the assessment of MPA AUC based on four samples: MPA AUC = 12.61 + 0.37 × C0.5 + 0.49 × C1 + 3.22 × C4 + 8.17 × C10.
Conclusions
Chinese renal transplant patients had higher median AUCs than caucasians and African-Americans. As in other studies, there was large interindividual variability. A limited four-point AUC was in good agreement with the 12-h AUC and provided the basis of a predictive formula.
Keywords: Chinese, mycophenolate mofetil, mycophenolic acid, pharmacokinetics, renal transplant patients
Introduction
Mycophenolate mofetil (MMF), an ester prodrug, is completely hydrolysed presystemically to form the active immunosuppressive agent mycophenolic acid (MPA). MPA reversibly inhibits inosine monophosphate dehydrogenase, resulting in a decrease in lymphocyte purine synthesis and proliferation [1]. MMF has been shown to be effective in the suppression of acute allograft rejection following cadaveric renal transplantation when given orally on a twice-daily schedule in combination with ciclosporin and steroids [2–4]. Following oral administration, the plasma profile of MPA in healthy subjects and renal transplant patients shows a rapid rise to achieve a peak plasma MPA concentration at about 1 h postdosing. A secondary plasma MPA peak is seen at 6–12 h after oral administration of MMF, suggesting enterohepatic circulation [5]. The correlation between the pharmacokinetics of MMF and its pharmacodynamics has been confirmed in renal transplant patients [6, 7]. Many studies have shown that more frequent withdrawals for adverse events occurred in the high-AUC groups, also corresponding to the highest doses. Higher MPA concentrations (AUC and concentrations at specific times, including C0) were found in patients with toxicity than in those who did not experience adverse effects [8–10]. When MMF is given at a fixed dose of 1 or 1.5 g twice daily in accordance with the recommended dosage by the manufacturer, adverse effects (e.g. gastrointestinal and haematological, etc.) and infection are very common in Chinese renal transplant patients [11, 12]. The pharmacokinetics of MPA in such patients has not previously been fully characterized. The objective of this study was to characterize the pharmacokinetics of MPA in Chinese renal transplant patients who receive ciclosporin and corticosteroids as the primary combined immunosuppressants. A secondary objective was to examine patients’ characteristics which are associated with pharmacokinetics and find the time points that best correlate with an abbreviated MPA AUC.
Methods
Study patients
Thirty-one Chinese renal transplant patients (17 male, 14 female) were included in this study. Inclusion criteria were male or female patients aged 18–70 years who had undergone renal transplantation at the Organ Transplantation Centre in Ruijin Hospital, Shanghai Second Medical University, and were being treated with MMF in combination with ciclosporin and corticosteroids as immunosuppressants. Exclusion criteria were systemic bacterial, fungal or viral infection, current treatment for acute rejection, delayed graft function, pregnancy and severe gastrointestinal disorders.
Study design, dosing and blood sampling
The study was an open-label evaluation of the pharmacokinetics of MPA in renal transplant patients. Cyclosporine A (CsA; Neoral®; Novartis Pharma, Beijing, China) was initially administered at 7 mg kg−1 day−1 in two divided doses, starting 3 days after surgery when the renal function of the patients was at a stage of rapid recovery. Thereafter, doses of CsA were adjusted to achieve 12-h trough concentrations of 200–250 ng ml−1 and 2-h concentrations (C2 h) of 1200–1500 ng ml−1, as measured by whole-blood monoclonal fluorescence polarization immunoassay (FPIA). Intravenous methylprednisolone sodium succinate (500 mg) was administered on the day of transplant surgery and the dose was then progressively tapered and maintained at a low dose of oral prednisone. MMF (Cellcept®) was administered orally at 2.0 g day−1 in two divided doses starting 24 h before surgery.
The pharmacokinetics of MPA was studied in patients taking 2.0 g of MMF twice daily regularly for at least 7 days within 2 months of renal transplantation. Multiple blood samples of patients taking MMF were collected in vacutainer tubes containing EDTA before dosing and 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after dosing. Plasma samples were obtained immediately after centrifugation and were frozen at −35 °C until the day of analysis. Biochemical parameters such as serum creatinine (Scr), blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, serum albumin and complete blood count were monitored on the day of the pharmacokinetic study.
Determination of plasma MPA concentration
Plasma MPA concentrations were determined by a validated high-performance liquid chromatography (HPLC) method [13]. The specified amounts of stock solutions were added to filtered drug-free plasma to prepare calibrators in the concentration range 0.5–45.0 µg ml−1 as follows and mixed for 1 h. These calibrators were assayed and a calibration curve was obtained from the results. Two hundred microlitres of each plasma sample was added to 1.5-ml polystyrene centrifuge tubes, then 4 µl of internal standard solution (300 µg ml−1 carbamazepine in methanol) was added to labelled tubes and vortexed for 30 s. Then 500 µl of acetonitrile was added to each tube and vortexed for another 30 s to deproteinize the plasma samples. Plasma concentrations of MPA were determined by reverse-phase HPLC using a µBondapak C18 column (3.9 × 300 mm; Waters, Milford, MA, USA) maintained at 45 °C. The mobile phase was composed of 40 mmol l−1 tetrabutyl ammonium bromide (TBA) and acetonitrile at the ratio of 65 : 35; the pH value was adjusted with phosphoric acid at 3.0. It was pumped in isocratic mode for elution of the column and the flow rate was 1.4 ml min−1. MPA was detected by UV absorbance at a wavelength of 210 nm. Concentrations were calculated by peak area values. The calibration factor was calculated by dividing the concentration of the calibrator (2.0 µg ml−1) by the peak area ratio, which was the ratio of the peak area of MPA and internal standard. The concentration of each sample was calculated by multiplying its peak ratio by the calibration factor.
Pharmacokinetic data analysis
Pharmacokinetic analysis was performed using 3P97® software. Noncompartmental analysis was used to determine several pharmacokinetic parameters such as area under the concentration–time curve (AUC) from 0 to 12 h, area under the moment curve (AUMC), mean residence time (MRT), time to maximum concentration (tmax), peak concentration (Cmax), and apparent clearance (CL/F). Cmax and tmax were obtained directly from the plasma concentration–time data and AUC was calculated by the trapezoidal rule. AUMC, MRT and CL/F were calculated using standard pharmacokinetic formulae.
Statistical analysis
SAS® software was used for statistical analysis (SAS Inc., Chicago, IL, USA). Correlation analysis between MPA pharmacokinetic parameters and patient characteristics was performed using Spearman’s correlation program. The MPA AUC was evaluated from the correlation of demographic factors such as age, sex, weight, body surface area and physiological parameters such as serum creatinine, creatinine clearance and serum albumin. Differences in pharmacokinetic parameters between male and female patients were evaluated using the independent-samples t-test program. To identify predictors of MPA AUC and develop a limited sampling strategy for the assessment of MPA AUC, Spearman’s correlation coefficient was used. Multiple linear regression analysis was used to determine limited sampling approaches and an abbreviated AUC was calculated from predictable time points. Results are expressed as the mean ± SD. A P-value of <0.05 was considered to be statistically significant, of <0.01 was considered to be highly significant and of <0.001 was considered to be very significant.
Results
Patient characteristics
This study was approved by the independent ethics committee of Ruijin Hospital affiliated to Shanghai Second Medical University and the written consent of all patients was obtained. A total of 31 renal transplant recipients (17 male, 14 female) completed the study. Characteristics of these patients are listed in Table 1. All patients had received cadaveric donor grafts. There was no case of retransplantation. The mean age was 42.55 ± 9.71 years and the mean body weight was 60.3 ± 9.27 kg. No patient had delayed graft function or severely impaired renal function. The mean serum creatinine of the 31 patients was 1.16 ± 0.28 mg dl−1 and the mean creatinine clearance was 59.33 ± 20.62 ml min−1. The mean serum albumin was 3.41 ± 0.25 g dl−1. The mean ciclosporin dose administered on the day of the pharmacokinetic study was 422.18 ± 87.92 mg day−1, the mean ciclosporin trough concentration (C0 h) was 221.5 ± 61.38 ng ml−1 and the 2-h concentration (C2 h) was 1301.5 ± 121.7 ng ml−1. All patients took the same dose (1.0 g twice daily) of MMF on the day of the study. Of these patients, five experienced acute rejection within 1 month after transplantation and were treated with high-dose steroid therapy. A few patients complained of mild adverse gastrointestinal events, but no patient experienced any serious side-effect due to MMF.
Table 1.
Patient demographics
| Demographics | |
| Number of study patients | 31 |
| Sex (male, female) | 17, 14 |
| Age (years, mean ± SD) | 42.55 ± 9.71 |
| Weight (kg, mean ± SD) | 60.3 ± 9.27 |
| Body surface area (m2, mean ± SD) | 1.68 ± 0.19 |
| Retransplant | _ |
| Biochemical parameters (mean ± SD) | |
| Serum creatinine (mg dl−1) | 1.16 ± 0.28 |
| Creatinine clearance (ml min−1) | 59.33 ± 20.62 |
| Aspartate aminotransferase (IU l−1) | 24.9 ± 5.63 |
| Alanine aminotransferase (IU l−1) | 41.6 ± 21.78 |
| Total bilirubin (mg dl−1) | 0.83 ± 0.32 |
| Serum albumin (g dl−1) | 3.41 ± 0.25 |
| Dose of immunosuppressants (mean ± SD) | |
| Dose of MMF (g day−1) | 2.0 |
| Dose of ciclosporin (mg day−1) | 422.18 ± 87.92 |
| C0 h of ciclosporin (ng ml−1) | 221.5 ± 61.38 |
| C2 h of ciclosporin (ng ml−1) | 1301.5 ± 121.7 |
Analysis of MPA plasma concentrations
Reverse-phase chromatography showed that MPA was well resolved and the internal standard was clearly separated. The retention times observed were 8.17 ± 0.13 min for MPA and 6.08 ± 0.21 min for the internal standard.
The assay for plasma MPA was linear throughout the range of 0.50–45.0 µg ml−1. The coefficient of correlation (r) between the concentration of the calibrator and the peak area ratio of MPA and internal standard was 0.99.
Pharmacokinetics
The mean plasma MPA concentration–time curve in 31 renal transplant patients is depicted in Figure 1. The pharmacokinetic profiles of MPA are characterized by an early and sharp increase of MPA concentration, with the first peak concentration being reached at 0.5–1.5 h after dosing. These profiles were consistent with rapid absorption and rapid conversion of MMF to MPA, followed by rapid distribution and metabolism of MPA. Small secondary increases in plasma MPA concentrations occurred in 10 patients at 4–12 h after dosing, consistent with previously described enterohepatic circulation of MPA glucuronide (MPAG), which undergoes deglucuronidation and reabsorption as MPA. Because these increases interfered with the accurate calculation of the terminal half-life of MPA, the values for half-life were not determined in this study. The pharmacokinetic parameters of MPA in 31 individual renal transplant patients are depicted in Table 2. There was a substantial interindividual variation of MPA AUC, Cmax and tmax values among the patients. The mean MPA AUC after oral administration of MMF 1.0 g bid in Chinese renal transplantation recipients was 48.34 ± 12.32 µg h−1 ml−1 in males and 56.80 ± 11.47 µg h−1 ml−1 in females. The mean value of MRT was 3.67 ± 0.56 h in males and 3.62 ± 0.54 h in females. The peak concentration of MPA was reached (tmax) at 1.15 ± 0.39 h in males and at 1.0 ± 0.39 h in females after dosing. The mean maximal MPA concentration (Cmax) was 16.99 ± 6.35 µg ml−1 in males and 22.92 ± 9.23 µg ml−1 in females. The mean oral clearance (CL/F) was 19.59 ± 2.98 l h−1 in males and 10.92 ± 6.12 l h−1 in females.
Figure 1.
Mean plasma concentration–time profile in 31 Chinese renal transplant patients. Male (♦), female (▪), total (▴)
Table 2.
Pharmacokinetic parameters of mycophenolic acid in renal transplant patients given mycophenolate mofetil 1.0 g bid
| Sex | AUC (µg h−1 ml−1) | AUMC (µg h−1 ml−1) | tmax (h) | Cmax (µg ml−1) | MRT (h) | CL/F (l h−1) |
|---|---|---|---|---|---|---|
| Male | 48.34 ± 12.32 | 179.98 ± 58.31 | 1.15 ± 0.39 | 16.99 ± 6.35 | 3.67 ± 0.56 | 19.59 ± 2.98 |
| Female | 56.80 ± 11.47 | 204.45 ± 45.79 | 1.0 ± 0.39 | 22.92 ± 9.23 | 3.62 ± 0.54 | 10.92 ± 6.12 |
| Total | 52.16 ± 12.50 | 191.03 ± 53.62 | 1.08 ± 0.39 | 19.67 ± 8.21 | 3.64 ± 0.54 | 15.67 ± 11.19 |
| P-value | 0.06 | 0.21 | 0.30 | 0.04 | 0.82 | 0.02 |
AUC, Area under the concentration–time curve; AUMC, area under the moment curve; tmax, time to maximum concentration; Cmax, maximum concentration; MRT, mean residence time; CL/F, apparent clearance.
Correlation of MPA AUC and patient characteristics
Correlation analysis between MPA AUC and patients’ baseline characteristics was performed to identify factors affecting the AUC value. The patients’ age, sex, weight and body surface area had no correlation with MPA AUC (P = 0.41, 0.06, 0.63 and 0.71, respectively). The serum albumin concentration showed no correlation with MPA AUC (P = 0.27) and renal function seemed to have no effect on AUC since serum creatinine and creatinine clearance did not correlate with AUC (P = 0.56 and 0.22, respectively).
Predictors of MPA AUC for an abbreviated sampling strategy for MMF monitoring
Many studies show that the efficacy and tolerability of MMF can be improved by incorporating MPA therapeutic drug monitoring into routine clinical practice [14–16]. A target range of 30–60 mg h−1 l−1 for MPA AUC has been proposed for the optimal MMF dosage in renal transplant patients [15, 16]. However, the routine measurement of the full 12-h dose interval MPA AUC is very impractical and would be cost-prohibitive. In order to develop an abbreviated sampling scheme for the estimation of MPA AUC0–12, analysis was performed to identify the predictable time points of AUC. When the plasma concentration of each time point was analysed based on correlation with the AUC value, concentrations at 0.5 h postdose (C0.5 h), 1 h postdose (C1 h), 4 h postdose (C4 h) and 10 h postdose (C10 h) showed a positive relationship (Table 3). Spearman’s correlation coefficients for C0.5 h, C1 h, C4 h and C10 h were 0.60 (P = 0.0004), 0.60 (P = 0.0003), 0.61 (P = 0.0003) and 0.64 (P = 0.0001), respectively.
Table 3.
Correlation coefficient (r) between mycophenolic acid (MPA) AUC and each MPA concentration
| C0 h | C0.5 h | C1 h | C1.5 h | C2 h | C4 h | C6 h | C8 h | C10 h | C12 h | |
|---|---|---|---|---|---|---|---|---|---|---|
| r | 0.19 | 0.60 | 0.60 | 0.19 | 0.36 | 0.61 | 0.53 | 0.52 | 0.64 | 0.47 |
| P-value | 0.3108 | 0.0004 | 0.0003 | 0.3104 | 0.0499 | 0.0003 | 0.0020 | 0.0025 | 0.0001 | 0.0070 |
Multiple linear regression analysis was used to determine limited sampling approaches and a formula was obtained for the assessment of MPA AUC: MPA AUC = 12.61 + 0.37 × C0.5 h + 0.49 × C1 h + 3.22 × C4 h + 8.17 × C10 h. We compared the limited sampling strategy with the model proposed by Filler et al. [17]. These authors proposed sampling times at 1, 2 and 6 h. We also calculated an abbreviated AUC from C0 h, C0.5 h and C2 h; and C0 h, C1 h and C6 h. Sampling times and correlation coefficients are summarized in Table 4. The ability of each model to predict MPA AUC is depicted in Figure 2.
Table 4.
Limited sampling strategies and correlation coefficient
| Model | Sampling times | Model equation | Pearson r2 correlation coefficients |
|---|---|---|---|
| 1 | 0.5, 1, 4 and 10 h | 12.61 + 0.37 × C0.5 + 0.49 × C1 + 3.22 × C4 + 8.17 × C10 | 0.92 |
| 2 | 1, 2 and 6 h | 10.75 + 0.98 × C1 + 2.38 × C2 + 4.86 × C6 | 0.70 |
| 3 | 0, 0.5 and 2 h | 15.79 + 2.05 × C0 + 0.95 × C0.5 + 3.73 × C2 | 0.62 |
| 4 | 0, 1 and 6 h | 14.57 + 1.62 × C0 + 1.5 × C1 + 5.15 × C6 | 0.65 |
Figure 2.
A comparison of the ability of each model to predict accurately the mycophenolic acid AUC
Discussion
Many studies on MPA pharmacokinetics have been performed in renal transplant patients and MPA pharmacokinetics are now better understood. However, MPA pharmacokinetics in Chinese renal transplant patients have not been previously well characterized. It was found in the clinic that when MMF was given at a fixed dose of 1.0 or 1.5 g twice daily in accordance with the manufacturer’s recommended dosage, adverse effects (e.g. gastrointestinal and haematological) and infection were more common. The recommended MMF regimen may be inappropriate for Chinese renal transplant patients and it was essential to carry out a pharmacokinetic study on MPA.
It was found that the pattern of the concentration–time profile of MPA was similar to the results of other studies performed in caucasians, with great interindividual variability in MPA AUC (15.05–76.52 µg h−1 ml−1), Cmax (5.88–39.57 µg ml−1) and tmax (0.5–1.5 h). A rapid increase in plasma concentration was observed within 1.5 h of dosing and a second peak was observed at 4–12 h in some patients, consistent with the results reported by Weber et al. [18]. The mean MPA AUC in Chinese patients who received MMF 1.0 g twice daily was calculated as 52.16 ± 12.50 µg h−1 ml−1, which is higher than that of caucasians (33.3 ± 13.7 µg h−1 ml−1) or African-American patients (26.8 ± 14.3 µg h−1 ml−1) who received the same dosage [19]. Moreover, it is higher in comparison with the target range of 30–60 µg h−1 ml−1 reported by Shaw et al. [20]. When patients in this study were given the recommended dosage (MMF 1.0 g, twice daily), 32% (10/31) reached the MPA AUC beyond the above expected range, with only one male patient below 30 µg h−1 ml−1 and 18% (3/17) of male patients and 43% (6/14) of female patients exceeding 60 µg h−1 ml−1. Although there appeared to be a difference in MPA AUC between men and women, this was not statistically significant. The mean (± SEM) AUC value was 56.8 ± 11.47 µg h−1 ml−1 in women vs. 48.34 ± 12.32 µg h−1 ml−1 in men (P = 0.06). The patient’s age, weight and body surface area were not related to the MPA AUC value.
MPAG concentration was not measured because no pharmacokinetic studies have shown that its concentration relates to either toxicity or acute rejection.
Most clinical trials have been performed using fixed doses (e.g. 1.0 g twice daily) of MMF. Recently, however, a growing number of investigators have suggested the individualization of MMF dose based on the plasma concentration of MPA. There are several rationales for the possible role of therapeutic drug monitoring as a therapeutic strategy with MMF. The pharmacokinetic and pharmacodynamic relationship between MPA exposure (MPA AUC) and acute rejection has been confirmed by randomized, double-blind studies [7]. Also, it is evident that the pharmacokinetics of MPA shows inter- and intra-individual variability in transplant recipients, especially in patients with renal dysfunction. Moreover, there exist clinically significant drug–drug interactions between MMF and concomitant immunosuppressants [21, 22], as well as antacids and certain antibiotics [23], affecting the pharmacokinetics of MMF. All these facts support the hypothesis that the optimization of the MMF dose based on individual MPA AUC has merit.
Another reason for monitoring MPA AUCs based on the findings in this study is the fact that almost 30% of Chinese subjects (9/31) had supratherapeutic concentrations. The large variability in MPA pharmacokinetics found in this study suggest that plasma MPA concentrations should be monitored routinely for the individualization of MMF administration. Since the relationship between MPA AUC and the efficacy or adverse effects of MPA in Chinese renal transplant patients has not been firmly established, it is necessary to use the target MPA AUC range of 30–60 µg h−1 ml−1 proposed by Shaw et al. as a reference standard. However, since routine measurement of the full (nine-point) 12-h dose interval MPA AUC0–12 h is impractical and cost-prohibitive, the predictable time point of MPA AUC0–12 h must be determined. Statistical analysis in this study has shown that an AUC based on concentrations at 0.5, 1, 4 and 10 h provides a useful prediction of the AUC0–12 h.
Competing interests: None declared.
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