BACKGROUND/AIMS: The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT). METHODS: Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC0-12) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT. RESULTS: In the first part of study, AUC0-12 was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively. CONCLUSIONS: A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.
Adult ; Aged ; Area Under Curve ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Gastrointestinal Diseases/etiology ; Graft Rejection/prevention & control ; Humans ; Immunosuppressive Agents/blood/*pharmacokinetics ; Leukopenia/etiology ; Liver/pathology ; Liver Failure/*therapy ; *Liver Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/adverse effects/*analogs & derivatives/blood/pharmacokinetics ; ROC Curve ; Retrospective Studies ; Tacrolimus/therapeutic use ; Tissue Donors

This paper is aimed to study the bioavailability and bioequivalence of Cyclosporin Soft Capsules (test preparation and reference preparation) in Chinese healthy volunteers. A high performance liquid chromatography-ultraviolet (HPLC-UV) method for determining the concentration of Cyclosporin A in human whole blood was developed and methodological validated. In accordance with the randomized two-period self crossover study, 24 volunteers received a single oral dose of 400 mg of test preparation or reference preparation. Multiple blood samples were collected post dose and then the concentration of Cyclosporin A in human whole blood samples was determined using the validated assay. The pharmacokinetic parameters including AUC0-t, Cmax, Tmax, and T1/2 were calculated using the non-compartmental method. The bioequivalence of the two preparations was evaluated. After receiving single dose of 400 mg of Cyclosporine A, the pharmacokinetic parameters of T1/2, Cmax, Tmax, and AUC0-t, of Cyclosporin A were (10.114 +/- 6.329) h and (9.717 +/- 4.076) h, (2021.235 +/- 298.581) ng x ml(-1) and (1992.192 +/- 1286.923) ng x ml(-1) (1.729 +/- 0.361) h and (1.813 +/- 0.323) h, (9824.811 +/- 1633.026) ng x h x ml(-1) and (10316.514 +/- 1395.955) ng x h x ml(-1) for test preparation and reference preparation, respectively. The statistical results suggested that these parameters were comparable between the two preparations. The results showed that the test preparation was bioequivalent with the reference preparation in healthy volunteers.
Area Under Curve ; Biological Availability ; Capsules ; Chemistry, Pharmaceutical ; Chromatography, High Pressure Liquid ; methods ; Cross-Over Studies ; Cyclosporine ; administration & dosage ; blood ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; administration & dosage ; blood ; pharmacokinetics ; Therapeutic Equivalency

A high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the determination of mizoribine in human serum using thiamphenicol as internal standard (IS). The serum samples of mizoribine were precipitated with acetonitrile and separated by HPLC on a reversed phase C18 column with a mobile phase of 0.1% ammonium acetate water solution-methanol (47:53, v/v). Mizoribine and IS were detected in the multiple reaction monitoring mode with precursor/product ion transitions of m/z 258.2/126.0 and 354.1/185.2, respectively. The calibration curves were linear over the range of 0.02-2 microg mL(-1) for mizoribine. The limit of quantification (LOQ) was 0.02 microg mL(-1) with acceptable precision and accuracy. The validated method was successfully applied for the evaluation of a bioequivalence study on Chinese healthy volunteers. The main pharmacokinetics parameters after oral administration of 100 mg mizoribine test or reference formulation were as follows: Cmax (1.00 +/- 0.21), (1.00 +/- 0.22) microg mL(-1); AUC(0-infinity) (6.72 +/- 1.39), (6.48 +/- 1.44) microg h mL(-1); t1/2 (2.77 +/- 0.26), (2.66 +/- 0.29) h; tmax (2.95 +/- 0.78), (2.84 +/- 0.50) h.
Adult ; Area Under Curve ; Asian Continental Ancestry Group ; Chromatography, High Pressure Liquid ; methods ; Confidence Intervals ; Enzyme Inhibitors ; blood ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; blood ; pharmacokinetics ; Male ; Ribonucleosides ; blood ; pharmacokinetics ; Spectrometry, Mass, Electrospray Ionization ; methods ; Therapeutic Equivalency ; Young Adult

In this study, we evaluated the influence of different variance from each of the parameters on the output of tacrolimus population pharmacokinetic (PopPK) model in Chinese healthy volunteers, using Fourier amplitude sensitivity test (FAST). Besides, we estimated the index of sensitivity within whole course of blood sampling, designed different sampling times, and evaluated the quality of parameters' and the efficiency of prediction. It was observed that besides CL1/F, the index of sensitivity for all of the other four parameters (V1/F, V2/F, CL2/F and k(a)) in tacrolimus PopPK model showed relatively high level and changed fast with the time passing. With the increase of the variance of k(a), its indices of sensitivity increased obviously, associated with significant decrease in sensitivity index for the other parameters, and obvious change in peak time as well. According to the simulation of NONMEM and the comparison among different fitting results, we found that the sampling time points designed according to FAST surpassed the other time points. It suggests that FAST can access the sensitivities of model parameters effectively, and assist the design of clinical sampling times and the construction of PopPK model.
Administration, Oral ; Adult ; Asian Continental Ancestry Group ; Fourier Analysis ; Humans ; Immunosuppressive Agents ; administration & dosage ; blood ; pharmacokinetics ; Models, Biological ; Nonlinear Dynamics ; Sensitivity and Specificity ; Tacrolimus ; administration & dosage ; blood ; pharmacokinetics ; Young Adult

The present study is to establish the population pharmacokinetic (PPK) model of tacrolimus and to estimate PPK parameters of tacrolimus for the individualization of tacrolimus administration in patients with hematopoietic stem cell transplant. A total of 671 blood samples were collected from 68 hematopoietic stem cell transplant patients and clinical data were retrospectively collected from the medical records of these patients. Population pharmacokinetical analysis was performed using the nonlinear mixed-effect model (NONMEM) program. The Bootstrap and data splitting were used simultaneously to validate the final population pharmacokinetical models. The basic structural model was best described as one-compartment pharmacokinetical model with first-order absorption and elimination. A number of covariates including demographic characteristic, biochemical and hematological index, combined drugs, inter-occasion variability (IOV) and other variables, e.g. primary disease, post operation days (POD), the type of transplantation and the sources of donor, were screened for their influence on the pharmacokinetic parameters of tacrolimus. The population typical values of tacrolimus CL, V, F were 12.1 L x h(-1), 686 L, 42.2%; and the inter-individual variability of these parameters were 23.5%, 96.4%, 43.8%, respectively. The absorption rate constant was fixed 4.3 h(-1). The residual error between observed and model- predicted concentration was 3.03 ng x mL(-1). The CYP enzyme inhibitor (INHI), POD and age were identified to be the main covariates that influence tacrolimus CL, and hemoglobulin (HGB) was the main covariate that may explain the variability in tacrolimus V. The IOV of CL, V, F were 22.2%, 6.23%, 30.3%, respectively. The population pharmacokinetic data obtained in the present study have significant clinical value for the individualization of tacrolimus therapy in hematopoietic stem cell transplant patients.
Adolescent ; Adult ; Child ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunosuppressive Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Metabolic Clearance Rate ; Middle Aged ; Models, Biological ; Nonlinear Dynamics ; Retrospective Studies ; Tacrolimus ; administration & dosage ; blood ; pharmacokinetics ; Young Adult

The paper is aimed to establish an artificial neural network (ANN) for predicting mycophenolic acid (MPA) area under the plasma concentration-time curve (AUC) in renal transplantation recipients. 64 Chinese renal transplantation recipients receiving mycophenolate mofetil (MMF) were investigated. 10 timed samples were drawn at different days after transplantation. Plasma MPA concentration was determined by HPLC method and area under curve over the period of 0 to 12 h (AUC(0-12 h)) was calculated using the linear trapezoidal rule. ANN was established after network parameters were optimized using momentum method in combination with genetic algorithm. Furthermore, the predictive performance of ANN was compared with that of multiple linear regression (MLR). When using plasma MPA concentration of 0, 0.5, 2 h after MMF administration to predict MPA AUC(0-12 h), mean prediction error and mean absolute prediction error were -1.53% and 9.12%, respectively. Accuracy and precision of prediction by ANN were superior to that of MLR prediction, and similar results could be found when using plasma MPA concentration of 0, 0.5 h to predict MPA AUC(0-12h). The accuracy and precision of ANN prediction were superior to that of MLR prediction, and ANN can be used to predict MPA AUC(0-12 h).
Administration, Oral ; Adolescent ; Adult ; Aged ; Area Under Curve ; Drug Monitoring ; methods ; Female ; Humans ; Immunosuppressive Agents ; administration & dosage ; pharmacokinetics ; Kidney Transplantation ; Linear Models ; Male ; Middle Aged ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; blood ; pharmacokinetics ; Neural Networks (Computer) ; Young Adult

The goal of this study is to investigate the population pharmacokinetics of oral tacrolimus in Chinese renal transplant patients and to identify possible relationship between covariates and population parameters. Details of drug dosage history, sampling time and concentration of 802 data points in 58 patients were collected retrospectively. Before analysis, the 58 patients were randomly allocated to either the model building group (n=41) or the validation group (n=17). Population pharmacokinetic data analysis was performed using the nonlinear mixed-effects model (NONMEM) program on the model building group. The pharmacokinetics of tacrolimus was best described by a one compartment model with first-order absorption and elimination. Typical values of apparent clearance (CL/F), apparent volume of distribution (V/F) were estimated. A number of covariates including demographic index, clinical index and coadministration of other drugs were evaluated statistically for their influence on these parameters. The final population model related clearance with POD (post operative days), HCT (haematocrit), AST (aspartate aminotransferase) and coadministration of nicardipine and diltiazem. Predictive performance of the final model evaluated with the validation group showed insignificant bias between observed and model predicted concentrations. Typical value of CL/F and V/F was 21.7 L x h(-1) and 241 L, inter-patient variability (RSD) in CL/F and V/F was 41.6% and 49.7%, respectively. The residual variability (SD) between observed and model-predicted concentrations was 2.19 microg x L(-1). The population pharmacokinetic model of tacrolimus in Chinese renal transplant patients was established and significant covariates on the tacrolimus model were identified.
Administration, Oral ; Adolescent ; Adult ; Aged ; Asian Continental Ancestry Group ; Female ; Humans ; Immunosuppressive Agents ; administration & dosage ; blood ; pharmacokinetics ; Kidney Transplantation ; Male ; Metabolic Clearance Rate ; Middle Aged ; Models, Statistical ; Nonlinear Dynamics ; Retrospective Studies ; Tacrolimus ; administration & dosage ; blood ; pharmacokinetics ; Young Adult

OBJECTIVETo study the distribution of 5-FU in rat plasma and liver tissue following systemic or local 5-FU infusion.

METHODS5-FU was administered at the dose of 20 mg/kg systemically via bolus injection through the jugular vein or locally via infusion through the hepatic artery and portal vein of the rats. High-performance liquid chromatography was used to measure 5-FU concentration in the plasma and liver tissue, and the pharmacokinetic parameters, penetration rate and therapeutic dominance of 5-FU were calculated.

RESULTSSystemic administration of 5-FU resulted in the peak 5-FU concentration (Cmax) and area under curve (AUC) in the liver tissue of 13.79-/+4.56 microg/g and 342.20-/+108.20 microg.min(-1).g(-1)g-1, with the plasma Cmax and AUC of 36.85-/+5.96 microg/g and 842.00-/+158.00 microg.min(-1).ml(-1), respectively. Local 5-FU administration through the hepatic artery resulted in Cmax and AUC in the liver tissue of 29.58-/+4.30 microg/g and 794.60-/+115.40 microg.min(-1).g(-1) and Cmax and AUC in the plasma of 24.39-/+4.63 microg/g and 639.70-/+133.80 microg.min(-1).ml(-1), respectively. After administration through the portal vein, the Cmax and AUC of 5-FU was 28.21-/+4.46 microg/g and 733.60-/+180.3 microg.min(-1).g(-1) in the liver tissue, and 21.02-/+4.06 microg/ml and 529.80-/+111.50 microg.min(-1).ml(-1) in the plasma, respectively.

CONCLUSIONCompared with systemic venous bolus injection, administration through the hepatic artery and portal vein can significantly increase 5-FU concentration in the liver, and decrease its concentration in the peripheral blood.

Animals ; Area Under Curve ; Female ; Fluorouracil ; administration & dosage ; blood ; pharmacokinetics ; Hepatic Artery ; Immunosuppressive Agents ; administration & dosage ; blood ; pharmacokinetics ; Infusions, Intra-Arterial ; Infusions, Intravenous ; Liver ; metabolism ; pathology ; Liver Neoplasms, Experimental ; blood ; drug therapy ; Male ; Metabolic Clearance Rate ; Portal Vein ; Rats ; Rats, Wistar

AIMTo develop a pharmacokinetic model for the enterohepatic circulation of mycophenolic acid (MPA).

METHODSTwenty healthy volunteers were orally given a single dose of 500 mg mycophenolate mofetil. Plasma samples were collected during 48 hours and MPA concentration was measured by HPLC method. Pharmacokinetic (PK) model was established based on physiological and biopharmaceutical consideration and PK parameters were obtained using nonlinear mixed effect model.

RESULTSThe proposed model included an intestinal compartment and gall bladder compartment in addition to the central compartment. The predicted time-concentration curve and AUC0-t, Cmax, Tmax estimated by the established model were in agreement with the observations.

CONCLUSIONThe established model was well defined for the MPA disposition and could afford a useful approach for the further clinical investigation.

Adult ; Area Under Curve ; Enterohepatic Circulation ; physiology ; Glucuronides ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; pharmacokinetics ; Male ; Models, Biological ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; blood ; pharmacokinetics

AIMTo investigate the possible effect of tetramethylpyrazine (TMP), an active ingredient of a commonly used Chinese herb, on the pharmacokinetics of cyclosporine A (CsA) by intragastric administration in rats.

METHODSForty male Sprague-Dawley rats were equally divided into four groups by randomized block design according to weight. On the first day, after each fasting rat was intragastrically administered CsA (10 mg x kg(-1)), blood samples (0.2 - 0.25 mL) were collected from the tail vein at 0, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h. From day 4 to day 8, each group began to undergo different pretreatments with intragastric administration of water, verapamil (Ver), low and high dose TMP, separately. On day 9, each group intragastrically co-administered CsA (10 mg x kg(-1)) and different pretreatment compounds mentioned above, then blood samples were collected according to the schedule of the first day. The whole blood concentration of CsA was determined by HPLC. Main pharmacokinetic parameters were calculated and compared by statistic analysis.

RESULTSIn the group of water pretreated and co-administrated with CsA, no significantly different pharmacokinetic parameters of CsA were found. After Ver pretreatment and co-administration with CsA, AUC(0-48 h) and C(max) were increased significantly (P < 0.01 and P < 0.05); T(1/2) beta and CL were markedly prolonged and decreased (P < 0.05); T(max) and V were not apparently influenced. After low dose TMP pretreatment and co-administration with CsA, there was no significant difference in the pharmacokinetic parameters of CsA, in spite of the increasing trends of AUC(0-48 h) and C(max). After high dose TMP pretreatment and co-administration with CsA, AUC(0-48 h) and C(max) of CsA were increased significantly (P < 0.01), but there was no significant change in other parameters.

CONCLUSIONIt was indicated that the high dose of TMP could apparently increase the intragastric absorption extent of CsA, while almost had no effect on its elimination process.

Administration, Oral ; Animals ; Area Under Curve ; Biological Availability ; Calcium Channel Blockers ; pharmacology ; Cyclosporine ; administration & dosage ; blood ; pharmacokinetics ; Dose-Response Relationship, Drug ; Drug Administration Routes ; Immunosuppressive Agents ; administration & dosage ; blood ; pharmacokinetics ; Ligusticum ; chemistry ; Male ; Plants, Medicinal ; chemistry ; Pyrazines ; administration & dosage ; isolation & purification ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Stomach ; Verapamil ; pharmacology