Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

AIM: To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. METHODS: Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. RESULTS: The best base model was a two-compartment model with a lag time (apparent oral clearance was 27 l h(-1), and apparent volume of the central compartment 98 l). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. CONCLUSIONS: The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.     

Population pharmacokinetic estimation of tacrolimus apparent clearance in adult liver transplant recipients

The goal was to study the factors affecting tacrolimus apparent clearance (CL/F) in adult liver transplant recipients. Tacrolimus dose and concentration data (n = 694) were obtained from 67 liver transplant recipients (22 female and 45 male), and the data were analyzed using a nonlinear mixed-effect modeling (NONMEM) method. A 1-compartment pharmacokinetic model with first-order elimination, an absorption rate constant fixed at 4.5 hours, and first-order conditional estimation was used to describe tacrolimus disposition. The predictive performance of the final model was evaluated using data splitting and assessing bias and precision of the estimates. The population estimate of tacrolimus CL/F and apparent volume of distribution (V/F) were found to be 21.3 L/h (95% confidence interval, CI, 18.0-24.6 L/h) and 316.1 L (95% CI 133-495 L), respectively. Neither patient's age, weight, gender, nor markers of liver function influenced tacrolimus CL/F. The final model was TVCL = 21.3 + 9.8 x (1 - HEM) + 3.4 x (1 - ALB) - 2.1 x (1 - DIL) - 7.4 x (1 - FLU), where TVCL, typical estimate of apparent clearance, HEM = 0 if hematocrit <35%, otherwise 1; ALB = 0 if albumin <3.5 g/dL, otherwise 1; DIL = 0 if diltiazem is coadministered, otherwise 1; FLU = 0 if fluconazole is coadministered, otherwise 1. This study identified the factors that significantly affect tacrolimus disposition in adult liver transplant recipients during the early posttransplantation period. This information will be helpful to clinicians for dose individualization of tacrolimus in liver transplant recipients with different clinical conditions including anemia or hypoalbuminemia or in those patients receiving diltiazem or fluconazole.     

A supratherapeutic dose of the Janus kinase inhibitor tasocitinib (CP-690,550) does not prolong QTc interval in healthy participants

Tasocitinib (CP-690,550), a selective inhibitor of the Janus kinase (JAK) family, is being developed for the treatment of several autoimmune diseases and prevention of allograft rejection. The aim of this study was to characterize the effect of tasocitinib on QT interval. Sixty male and female healthy adults were enrolled in a single-dose, randomized, 3-period, crossover study of a supratherapeutic dose of tasocitinib (100 mg), placebo, and moxifloxacin 400 mg. Triplicate electrocardiograms were performed at predose baseline and serially over 24 hours postdose in each treatment period. The upper limits of the 2-sided 90% confidence intervals (CIs) for the difference in QTc interval, corrected using Fridericia correction (QTcF), between tasocitinib and placebo were less than 5 ms at all time points. Concentration-QTcF analysis showed that the predicted mean change (90% CI) in QTcF at the observed mean C(max) was -0.12 (-1.18, 0.94) ms. For moxifloxacin, mean (90% CI) estimates of the change in QTcF from placebo were 11.3 (9.4, 13.1) and 12.5 (10.7, 14.4) ms at 2 and 4 hours, respectively, thereby establishing study sensitivity. A single supratherapeutic dose of tasocitinib 100 mg was well tolerated and not associated with QTc prolongation.     

Effects of gastric emptying on oral mycophenolic acid pharmacokinetics in stable renal allograft recipients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Strategies that are more elaborate than measuring predose plasma concentrations are required for the therapeutic monitoring of mycophenolic acid (MPA). * Previous studies in healthy subjects and diabetes patients have suggested that MPA pharmacokinetics are influenced by gastric emptying, but this has not been demonstrated directly. WHAT THIS STUDY ADDS: * This study has investigated the relationship between gastric emptying, measured directly (using the (14)C octanoate and (13)C glycine breath tests) and the steady-state plasma concentration-time profile of MPA. * Delayed gastric emptying was associated with a longer t(max) and lower C(max), but total exposure to MPA was not affected. * The findings suggest that it could be misleading to rely fully on short-term (<2 h) limited sampling strategies for MPA therapeutic monitoring in recipients with gastric emptying disorders, the latter occurring relatively frequently in solid organ transplantation. AIM: To investigate the effect of gastric emptying on the pharmacokinetics of mycophenolic acid (MPA) in renal transplant patients. METHODS: We assessed the effect of gastric emptying on the disposition of MPA in 27 stable renal allograft recipients at 2 years after transplantation. Gastric emptying was measured by the (14)C-octanoate and (13)C-glycine breath test. RESULTS: Delayed gastric emptying was associated with a significantly longer MPA t(max)[1.0 (0.33-2.0) h vs. 0.5 (0.33-1.0) h; mean difference 0.39 h, 95% confidence interval (CI) 0.03, 0.75; P = 0.0289] and with a significant decrease in the maximum MPA concentration after dosing [10.6 (6.5-21.3) mg l(-1)vs. 20.1 (10.7-28.5) mg l(-1); mean difference 6.5 mg l(-1), 95% CI 2.1, 10.9; P = 0.0075]. Despite the substantial effect of delayed gastric emptying rates on MPA C(max) and t(max), total dose-interval exposure, measured by the MPA AUC(0-4), was not affected by the rate of gastric emptying [20.4 (13.9-43.0) mg h(-1) l(-1)vs. 22.4 (13.1-29.8) mg h(-1) l(-1)]. CONCLUSION: Delayed gastric emptying was associated with a slower absorption of MPA, a longer time to reach peak concentrations and lower maximum concentrations. These effects should be taken into account when validating limited (<2 h) sampling strategies to estimate total MPA exposure, which could be unreliable when monitoring patients with gastric emptying disorders.     

Impact of changing from cyclosporine to tacrolimus on pharmacokinetics of mycophenolic acid in renal transplant recipients with diabetes

The rate of mycophenolic acid (MPA) absorption after oral administration of mycophenolate mofetil (MMF) is delayed in patients with diabetes. Cyclosporine (CsA) decreases MPA exposure by inhibiting enterohepatic recirculation of MPA/MPA glucuronide, and tacrolimus (TRL) may alter the rate and extent of MPA absorption due to its prokinetic properties especially in patients with diabetic gastroparesis. This study evaluated the effect of changing from CsA to TRL on pharmacokinetics of MPA in stable renal transplant recipients with long-standing diabetes. Eight patients were switched from a stable dose of CsA to TRL while taking MMF 1 g twice daily. The 12-hour steady-state total plasma concentration-time profiles of MPA and MPA glucuronide were obtained after oral administration of MMF on 2 occasions: first while taking CsA and second after changing to TRL. Pharmacokinetic parameters of MPA were calculated by the noncompartmental method. Changing from CsA to TRL resulted in significantly increased MPA exposure (area under the concentration-time curve from 0 to 12 hours, AUC0-12) by 46 +/- 32% (P = 0.012) and MPA predose concentration (C0) by 121 +/- 67% (P = 0.008). The magnitude of change in MPA exposure did not correlate well with MPA-C0 or CsA trough concentration. Switching to TRL had minimal impact on peak concentration of MPA (15.0 +/- 6.9 mg/L with CsA versus 16.1 +/- 9.7 mg/L with TRL, P = 0.773) and time to reach the peak concentration (1.0 +/- 0.4 hours with CsA versus 1.2 +/- 0.8 hours with TRL, P = 0.461). Highly variable and unpredictable changes in MPA exposure among renal transplant patients with diabetes do not support a strategy of preemptively adjusting MMF dose when switching calcineurin inhibitors in this population.     

Automated determination of free mycophenolic acid and its glucuronide in plasma from renal allograft recipients

Mycophenolic acid, the active moiety of mycophenolate mofetil, inhibits the enzyme inosine monophosphate dehydrogenase. The main metabolite, mycophenolic acid glucuronide, has no immunosuppressive effect. Reported protein bindings are 97% for mycophenolic acid and 82% for mycophenolic acid glucuronide. Considerable intraindividual and interindividual variability in mycophenolic acid pharmacokinetics has been observed. Data on the variability of mycophenolic acid free fraction in plasma are sparse but may be relevant when discussing whether therapeutic drug monitoring of this drug is warranted. The authors describe a fully automated method for the determination of free concentrations by dialysis across a membrane followed by concentration of the dialysate on a trace enrichment column and liquid chromatography. Total concentrations are measured by protein precipitation and direct injection on the trace enrichment column. Plasma concentrations as low as 6 ng/mL free mycophenolic acid and 1 microg/mL free mycophenolic acid glucuronide can be measured with between-day coefficient of variation less than 15% and 6%, respectively. Stability testing confirmed that plasma samples could be stored for 14 days at 4 degrees C or -20 degrees C and at room temperature for approximately 12 hours without significant changes in free concentrations. Predose total and free concentrations of mycophenolic acid and mycophenolic acid glucuronide were determined in 27 samples from stable renal allograft recipients treated with mycophenolate mofetil, cyclosporin, and steroids. Total concentrations ranged from 0.57 to 16.2 microg/mL mycophenolic acid and 36 to 199 microg/mL mycophenolic acid glucuronide. Free concentrations ranged from 13 to 210 ng/mL mycophenolic acid and 8 to 58 microg/mL mycophenolic acid glucuronide. The method presented here has been successfully applied to measure free mycophenolic acid and free mycophenolic acid glucuronide in clinical samples. Further investigations may provide important data to support the identification of principles and target ranges for the monitoring of mycophenolic acid in the immunosuppressive therapy of organ transplant recipients.     

Long-term pharmacokinetic study of the novel combination of tacrolimus and sirolimus in de novo renal allograft recipients

It was recently shown in two randomized studies that combining sirolimus (rapamycin) and tacrolimus is very efficient in renal transplantation. However, little is known about the long-term pharmacokinetics of this combination. We performed simultaneous AUC measurements (area under the concentration curves) of sirolimus and tacrolimus at 1, 3, and 12 months posttransplantation in nine de novo recipients treated with this drug combination to characterize the evolution of the pharmacokinetics of both drugs and to investigate possible interactions between the two compounds. Patients were treated with a standard-dose tacrolimus or with a reduced-dose tacrolimus in combination with sirolimus and corticosteroids. This long-term pharmacokinetic study has shown that when sirolimus is combined with tacrolimus, dose changes of sirolimus are reflected by pharmacokinetic exposure parameters. Patients taking a low dose of sirolimus in combination with a standard dose tacrolimus might require sirolimus dose increments over time to maintain constant exposure to sirolimus. Further prospective dose-controlled studies are necessary to investigate a possible effect of a standard-dose tacrolimus on long-term sirolimus bioavailability and/or metabolism. Dose reductions of tacrolimus in both study groups were reflected by concordant decreasing pharmacokinetic exposure parameters, which illustrates the common clinical practice of reducing the dose of calcineurin inhibitor as time elapses after transplantation.     

Population pharmacokinetic modeling for mycophenolic acid and its main glucuronide metabolite in Chinese kidney transplant recipients

OBJECTIVE To develop an integrated model of MPA and MPAG in kidney recipients, and to evaluate the effect of clinical covariates and genotypes on mycophenolic acid(MPA) and 7-O-mycophenolic acid glucuronide(MPAG) disposition. METHODS Data were collected from 191 adult Chinese mycophenolic acid,including 24 patients with full concentration-time profiles and 167 with trough concentrations. They contained 962 MPA measurements and 746 MPAG measurements.Population pharmacokinetic analysis was performed using NONMEM~?. RESULTS The PK of MPA and MPAG were best described by a three-chain compartment model. Significant correlations were found between the clearance of MPA(CLMPA) and albumin levels(ALB), and between the clearance of MPAG(CLMPAG) and the creatinine clearance(CCR).CLMPA was 13.7 L·h-1 and the CLMPAG was 1.3 L · h~(-1) for the Chinese kidney transplant recipients with ALB 42 g · L~(-1) and CCR 72 m L · min~(-1).CONCLUSION The MPA data was described adequately by a 2-compartment model with linear elimination, while MPAG was described using a 1-compartment model.ALB, CCR affected CLMPA and CLMPAG respectively.The impact of gene polymorphisms of enzymes and transporters did not affect pharmacokinetic of MMF in kidney transplant recipients in our study, including UGT1 A9,UGT1 A8, UGT2 B7, OATP1 B3, MRP2.     

Time-dependent clearance of mycophenolic acid in renal transplant recipients

AIMS: Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects. METHODS: One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation. RESULTS: The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL. CONCLUSIONS: By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofetil.     

Limited sampling strategy for simultaneous estimation of the area under the concentration-time curve of tacrolimus and mycophenolic acid in adult renal transplant recipients

The aim of this study was to develop a limited sampling strategy to allow the simultaneous estimation of the area under the concentration-time curves (AUCs) of tacrolimus and mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil, using a small number of samples from patients undergoing renal transplantation. Fifty Japanese patients were enrolled. On day 28 after transplantation, samples were collected just before and 1, 2, 3, 4, 6, 9, and 12 hours after tacrolimus and mycophenolate mofetil administration at 9:00 am and 9:00 pm. The full pharmacokinetic profiles obtained from these timed concentration data were used to choose the best sampling times. Three error indices (percent mean error, percent mean absolute error, and percent relative mean square error) were used to evaluate the predictive bias, accuracy, and precision. The predicted AUC0-12 of MPA calculated at the three time points of C2h-C4h-C9h best approximated the actual AUC0-12 of MPA (r = 0.877), and the AUC0-12 of tacrolimus calculated at the same time points predicted a good correlation with the actual AUC (r = 0.928). When the three sampling times of trough level (C0h) and two other points within 4 hours after administration were used, the three points of C0h-C2h-C4h were the best points for estimation of the AUC0-12 tacrolimus and MPA (AUC0-12 = 7.04.C0 + 1.71.C2 + 3.23.C4 + 15.19, r = 0.799, P < 0.001 and AUC0-12 = 0.26.C0 + 2.06.C2 + 3.82.C4 + 20.38, r = 0.693, P < 0.001, respectively). The percent mean error, percent mean absolute error, and percent relative mean square error of the prediction formula using the three time points of C0h-C2h-C4h were -0.3%, 8.8%, and 13.5% for tacrolimus and 2.9%, 17.1%, and 21.5% for MPA, respectively. A limited sampling strategy using C2h-C4h-C9h provides the most reliable and accurate simultaneous estimation of the AUC0-12 of tacrolimus and MPA in patients undergoing renal transplantation. In addition, a limited sampling strategy using C0h-C2h-C4h is recommended for the simultaneous estimation of the AUC0-12 of tacrolimus and MPA when focused on samples collected within 4 hours after administration for clinical expediency.     

Validation of an abbreviated pharmacokinetic profile for the estimation of mycophenolic acid exposure in pediatric renal transplant recipients

The pharmacokinetics of mycophenolic acid (MPA), the active moiety of the immunosuppressant mycophenolate mofetil (MMF), exhibits large inter-individual variability. Concentration-controlled dosing of MMF based on therapeutic drug monitoring may therefore be advantageous compared to a fixed-dose regimen. Because full AUC(0-12) monitoring is not practical and predose MPA concentrations correlate only moderately with the corresponding AUC(0-12), the estimation of MPA exposure by a limited sampling strategy has been suggested. However, before such an algorithm is transferred to clinical practice, it is compulsory to prospectively validate it in a different data set, in order to avoid biased results. The aim of this investigation was therefore to prospectively validate an algorithm based on an abbreviated pharmacokinetic (PK) profile for the estimation of MPA exposure in 54 pediatric renal transplant recipients (169 PK profiles) on MMF in conjunction with CsA and prednisone on a second data set in a different group of patients with a similar immunosuppressive regimen (25 patients, 119 PK profiles). An algorithm based on three PK sampling timepoints during the first 2 hours after MMF dosing (estimated AUC(0-12) = 18.6 + 4.3 x C(0) + 0.54 x C(0.5) + 2.15 x C(2)) was able to predict the corresponding MPA-AUC(0-12) with a low percentage prediction error (10.7%) and an acceptable coefficient of determination (r = 0.76). The performance of this algorithm was comparable among different pediatric age groups. By ROC curve analysis, the calculated MPA-AUC(0-12) based on this algorithm was able to differentiate between rejecters and non-rejecters with a comparable prognostic sensitivity (66.7%) and specificity (61.9%) as the full-time MPA-AUC(0-12). In conclusion, the use of this validated algorithm for the estimation of MPA exposure based on a limited sampling strategy during the first 2 hours after MMF dosing has the potential to optimize MMF therapy in pediatric renal transplant recipients.     

Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia

The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total mycophenolic acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose samples) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC(0-6)) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = -0.54, P < 0.0001). Receiver operating characteristic (ROC) curve analysis was performed on the albumin versus percentage free MPA data. The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA (defined as > or = 3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin < or = 31 g/L), clinicians should consider monitoring the free MPA concentration.     

Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil

BACKGROUND: The establishment of a rationale for therapeutic drug monitoring for mycophenolic acid (MPA) and outlining a therapeutic window remains a challenging task in renal transplantation. Furthermore, the pharmacokinetic characteristics of free and total MPA and its glucuronides depend directly or indirectly on graft function and the type of co-administered calcineurin-inhibitor. METHODS: The authors conducted a prospective 12-month multicenter pharmacokinetic study on MPA (MPA, free MPA, free fraction MPA) and its metabolites (MPAG, Acyl-MPAG). The aim of this study was to examine the long-term pharmacokinetic characteristics of MMF when combined with tacrolimus in renal allograft recipients and to identify a possible relationship between these pharmacokinetic parameters and clinical outcome parameters. RESULTS: They have demonstrated that in renal transplant recipients MPA, free MPA, Acyl-MPAG and MPAG have a particular pharmacokinetic profile when combined with tacrolimus which differs from the combination with CsA. They could not establish a relationship between pre-dose trough concentration of MPA and its metabolites and clinical efficacy endpoints and drug-related adverse events, except for anemia. CONCLUSIONS: These findings suggest that trough plasma concentration monitoring of MPA and its metabolites might not provide a useful clinical tool for guiding MMF dose adjustments to avoid drug-related toxicity. More extensive pharmacokinetic measurements like area under the concentration curves might be necessary for routine therapeutic drug monitoring of MMF.     

Pharmacokinetics of mycophenolic acid and estimation of exposure using multiple linear regression equations in Chinese renal allograft recipients

OBJECTIVES: To investigate the pharmacokinetics of mycophenolic acid (MPA) in Chinese adult renal allograft recipients, and to generate the validated model equations for estimation of the MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) with a limited sampling strategy. PATIENTS AND METHODS: The pharmacokinetics in 75 Chinese renal allograft recipients treated with mycophenolate mofetil 2 g/day in combination with cyclosporin and corticosteroids were determined. The MPA concentration was assayed by high-performance liquid chromatography at pre-dose (C(0)) and at 0.5 (C(0.5)), 1 (C(1)), 1.5 (C(1.5)), 2 (C(2)), 4 (C(4)), 6 (C(6)), 8 (C(8)), 10 (C(10)) and 12 (C(12)) hours after dosing on day 14 post-transplant. Patients were randomly divided into: (i) a model group (n = 50) to generate the model equations by multiple stepwise regression analysis for estimation of the MPA AUC by a limited sampling strategy; and (ii) a validation group (n = 25) to evaluate the predictive performance of the model equations. RESULTS: The mean MPA AUC(12) was 52.97 +/- 15.09 mg . h/L, ranging from 24.0 to 102.3 mg . h/L. The patient's age and serum albumin level had a significant impact on the MPA AUC(12). The correlation between the pre-dose MPA trough level (C(0)) and the MPA AUC(12) was poor (r(2) = 0.02, p = 0.33). Model equations 7 (MPA AUC(12) = 14.81 + 0.80 . C(0.5) + 1.56 . C(2) + 4.80 . C(4), r(2) = 0.70) and 11 (MPA AUC(12) = 11.29 + 0.51 . C(0.5) + 2.13 . C(2) + 8.15 . C(8), r(2) = 0.88) were selected for MPA AUC calculation in Chinese patients, resulting in good agreements between the estimated MPA AUC and the full MPA AUC(12), with a mean prediction error of +/-10.1 and +/-6.9 mg . h/L, respectively. CONCLUSION: In Chinese renal allograft recipients, MPA pharmacokinetics manifest substantial interindividual variability, and the MPA AUC(12) tends to be higher than that in Caucasian patients receiving the same dose of mycophenolate mofetil. Two validated model equations with three sampling timepoints are recommended for MPA AUC estimation in Chinese patients.     

Population pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation

OBJECTIVE: To characterize the pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation (LDLT). METHODS: Thirty-five patients were given tacrolimus as 18- to 60-h intravenous infusions after surgery, followed by a 4-week course of oral dose therapy (at 0900 hours and 2100 hours). Blood samples were collected daily in the morning (0800 hours) beginning the day after surgery. Whole blood concentration data were evaluated by nonlinear mixed-effect modeling using the program NONMEM and were characterized using a one-compartment model. RESULTS: The clearance (CL, l h(-1)) was related to the grafted hepatic weight, postoperative days (POD), and hepatic and renal dysfunction. Interindividual variabilities in CL, volume of distribution (V), and bioavailability (F) were 57.4%. 39.7%, and 63.0%, respectively, and the correlation between individual CL and F was 0.776. Residual intraindividual variability was 2.9 ng ml(-1). Based on the estimated final parameters, a typical recipient of LDLT with grafted hepatic weight of 600 g and normal hepatic and renal function would have a CL of 0.737 l h(-1) on POD 0 and 1.14 l h(-1) on POD 30, V of 1.52 l kg(-1) and F of 6.8%. CONCLUSIONS: Nonlinear mixed-effect modeling was useful for analysis of pharmacokinetic characteristics of tacrolimus in LDLT patients. Immediately after surgery, patients receiving LDLT showed a smaller CL value than other transplant patients, and CL value increased with POD within 30 days after surgery. The estimated population pharmacokinetic parameters can be applied for a priori dosage calculations in adult patients with LDLT.     

Population pharmacokinetic study of cyclosporine in Chinese renal transplant recipients

Purpose  

To establish the population pharmacokinetic (PPK) model of cyclosporine (CsA) in Chinese renal transplant recipients and evaluate the influence of various indexes including CYP3A5 and MDR1 genetic polymorphism on pharmacokinetic parameters.     

Concentrations of mycophenolic acid and glucuronide metabolites under concomitant therapy with cyclosporine or tacrolimus

Mycophenolate mofetil [MMF, the prodrug of mycophenolic acid (MPA)] is usually administered at double doses with cyclosporine than with tacrolimus because it is believed that MPA exposure is lower during cyclosporine therapy. This study aimed to compare 12 hour, steady-state concentration-time profiles of MPA and its phenol- and acyl-glucuronide metabolites (MPAG and AcMPAG, respectively) in stable kidney transplant recipients maintained either on cyclosporine (n = 12) or tacrolimus (n = 12). During the absorption phase in the cyclosporine group, dose-normalized concentrations of total and free MPA were significantly higher but the overall area under the concentration-time curve (AUC0-12) was not significantly different. Additionally, exposure to AcMPAG was higher in the cyclosporine group (P < 0.05). Ten of 12 patients in the cyclosporine group were on ketoconazole therapy; however, the exposure to MPA or MPAG was not different when MMF was given orally to Sprague-Dawley rats with or without ketoconazole. In conclusion, cyclosporine modulates the disposition of MPA and metabolites differently from tacrolimus; however, patients on cyclosporine may not require double doses of MMF to achieve the same exposure.