Rapid and simplified HPLC-UV method with on-line wavelengths switching for determination of capecitabine in human plasma.

Capecitabine is an important oral fluoropyrimidine anticancer drug. The purpose of this study was to overcome limitations of previously reported methods and propose an optimized and widely available tool for analysis of capecitabine in human plasma. The simplification of the liquid-liquid extraction procedure involved elimination of unnecessary addition of phosphoric acid and reduction of the extraction solvent volume. The use of voriconazole as the internal standard, combined with gradient elution and on-line wavelength switching, assured very high within- and between-run precision of results (relative standard deviation < 7.1% for lower limit of quantification) and enabled the reduction of the total chromatographic run time to 8 min. The calibration curve was linear within the range of 0.05-10.00 microg/mL and the method selectivity was confirmed in the presence of capecitabine metabolites. All validation parameters met the acceptance criteria set by international regulatory guidances, which proves that the method leads to reliable results. The method may be applied in human pharmacokinetic studies, for the regulatory purposes and therapeutic drug monitoring.

A limited sampling strategy for estimating mycophenolic acid area under the curve in adult heart transplant patients treated with concomitant cyclosporine.

OBJECTIVE: Heart transplantation studies have shown a relationship between the mycophenolic acid area under the curve (AUC) 0-12 h (MPA AUC(0-12h)) values and risk of acute rejection episodes and fewer side-effects in patient receiving cyclosporine during the first year post-transplant. However, measurement of full AUC is costly and time consuming and in this case it is an impractical approach to drug monitoring. Therefore, the authors describe a limited sampling strategy to estimate the MPA AUC(0-12h) value in adult heart transplant recipients. METHODS: Ninety MPA pharmacokinetic (PK) profiles were studied. The samples were collected immediately before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12 h after the morning dose of mycophenolate mofetil (MMF) following an overnight fast. PK profiles were determined at 6-8 weeks, 6, 12 months and more than 1 year after transplantation. Using stepwise multiple linear regression analysis a sampling strategy from 60 of PK profiles was obtained and next the bias and precision of the model were evaluated in another 30 PK profiles. RESULTS: The three-point model using C(0.5h), C(1h), C(2h) was found to be superior to all other models tested (r(2) = 0.841). The regression equation for AUC estimation which gave the best fit to this model is: 9.69 + 0.63C(0.5) + 0.61C(1) + 2.20C(2). Using that model 63 of the 90 (70%) full AUC values were estimated within 15% of their actual value. For the best-fit model, the mean prediction error was 3.2%, with 95% confidence intervals for prediction error to range from -42.2% to 40.3%. All other models which use one, two or three time-points over the first 2 h are poorer predictors of the full AUC than the model above. CONCLUSION: The proposed three time-point equation to estimate AUC will be helpful in optimizing immunosuppressive therapy in heart transplantation.

The weight of pharmacokinetic parameters for mycophenolic acid in prediction of rejection outcome: the receiver operating characteristic curve analysis.

Often the clinical researcher is confronted with the question of how accurate a particular laboratory test is to identify disease. To confirm the ability of pharmacokinetic (PK) parameters to discriminate between patients with or without acute rejection after kidney transplantation, an analysis of receiver operating characteristic (ROC) curves was performed in 51 adult patients, among whom nearly 50% experienced biopsy-proven acute rejection episodes during the first 90 days posttransplant. All patients received cyclosporine or tacrolimus, prednisone, and mycophenolate mofetil (MMF). The following PK variables were determined for mycophenolic acid, an active metabolite of MMF: predose (C(0)), maximum concentration (C(max)), and area under the concentration-time curve (AUC(0-12h)). ROC plots of sensitivity versus 1-specificity were generated to determine whether a particular PK parameter could discriminate renal transplant recipients with an acute rejection from those who experienced no rejection. Area under the ROC curves and the 95% confidence interval limits were calculated using the method of Hanley and McNeil. The C(0) and C(max) were less predictive values for acute rejection than AUC(0-12h). The AUC parameter appeared the most effective to discriminate an acute rejection episode during MMF therapy. This study indicated the utility of ROC curve analysis to select PK parameters to predict acute rejection episodes.

Comparison of mycophenolic acid pharmacokinetic parameters in kidney transplant patients within the first 3 months post-transplant.

OBJECTIVE: The aim of this study was to investigate the effect of time on pharmacokinetic (PK) parameters of mycophenolic acid (MPA) in the early post-transplant period in kidney recipients. MPA is the active metabolite of mycophenolate mofetil (MMF), which was introduced into clinical practice ten years ago. METHOD: Mycophenolate mofetil was co-administered with cyclosporin (CsA) in a subgroup of 23 patients and with tacrolimus (Tac) in a subgroup of 10 patients. MPA plasma concentration profiles were measured by a validated high performance liquid chromatography method 1 week, 2 and 3 months after transplantation. RESULTS: Despite a comparable MMF dose, a large inter-patient variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.03-135.4 microg h/mL) and in predose concentrations (0.31-6.09 microg/mL) was observed. Patients with AUC > 35 microg h/mL showed better (P < 0.1) renal function than patients with AUC < 20 microg h/mL (mean creatinine concentration 1.48 +/- 0.12 vs. 3.35 +/- 0.4 mg/dL respectively). The total MPA trough and AUC did not correlate with biochemical parameters: leucocyte cell count and haematocrit. A higher trough level of the metabolite MPA glucuronide (MPAG) in the 1 week after transplantation was found when compared with the 3-month level (mean 150.1 +/- 146.7; range 17.1 to 560 vs. 75.8 +/- 40.0; range 27.3 to 174.2 microg/mL). The concentration of MPA, and MPA AUC values were significantly lower in patients receiving MMF and CsA than those receiving MMF and Tac during all three periods studied (P < 0.02). The influence of C(0) and MPA AUC values on the risk of graft rejection was investigated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for AUC was 0.847, whereas that of C(0) was 0.632. CONCLUSIONS: The MPA AUC(0-12h) appeared to be the more effective PK parameter for predicting acute rejection. We recommend that routine MPA and MPAG therapeutic drug level monitoring should be an important part of MMF therapy.

Gravimetric and spectrophotometric determination of some drugs--tertiary amine hydrochlorides in coated tablets.

Four drugs in the form of coated tablets: Amitryptylinum (Amitryptyline) (1), Imipramin (Imipramine) (2), Chloropyribenzaminum (Chloropyramine) (3), and Phenazolinum (Antazoline) (4) were determined gravimetrically and spectrophotometrically in the same process by using complexes with ammonium molybdate. Stoichiometry of the complexes was established by elemental analysis and analysis of the incineration residue (MoO3). The complexes were characterized by IR and UV spectra and melting points. Contents of the drugs in the complexes were also determined spectrophotometrically. In this method Beer's law was found to obey over the concentration ranges 10-80 micrograms/ml (complex of 1), 10-100 micrograms/ml (complexes of 2 and 3), and 10-60 micrograms/ml (complex of 4). This method was validated in terms of precision, linearity, limit of detection and limit of quantitation. The two methods of the drug determination used in a single process of analysis, verify each other.