Vellaichamy M Annapandian

A limited sampling strategy for tacrolimus in renal transplant patients

AIMS To develop and validate limited sampling strategy (LSS) equations to estimate area under the curve (AUC(0-12)) in renal transplant patients. METHODS Twenty-nine renal transplant patients (3-6 months post transplant) who were at steady state with respect to tacrolimus kinetics were included in this study. The blood samples starting with the predose (trough) and collected at fixed time points for 12 h were analysed by microparticle enzyme immunoassay. Linear regression analysis estimated the correlations of tacrolimus concentrations at different sampling time points with the total measured AUC(0-12). By applying multiple stepwise linear regression analysis, LSS equations with acceptable correlation coefficients (R(2)), bias and precision were identified. The predictive performance of these models was validated by the jackknife technique. RESULTS Three models were identified, all with R(2) > or = 0.907. Two point models included one with trough (C(0)) and 1.5 h postdose (C(1.5)), another with trough and 4 h postdose. Increasing the number of sampling time points to more than two increased R(2) marginally (0.951 to 0.990). After jackknife validation, the two sampling time point (trough and 1.5 h postdose) model accurately predicted AUC(0-12). Regression coefficient R(2) = 0.951, intraclass correlation = 0.976, bias [95% confidence interval (CI)] 0.53% (-2.63, 3.69) and precision (95% CI) 6.35% (4.36, 8.35). CONCLUSION The two-point LSS equation [AUC(0-12) = 19.16 + (6.75.C(0)) + (3.33.C1.5)] can be used as a predictable and accurate measure of AUC(0-12) in stable renal transplant patients prescribed prednisolone and mycophenolate.

A Reliable Limited Sampling Strategy for the Estimation of Mycophenolic Acid Area Under the Concentration Time Curve in Adult Renal Transplant Patients in the Stable Posttransplant Period

In renal transplant patients, there is an established relationship between mycophenolate area under the curve and clinical outcome. The authors have developed and validated a limited sampling strategy to estimate mycophenolic acid area under the curve to 12 hours (MPA AUC0-12) in a stable renal transplant Indian population prescribed a formulation of mycophenolate mofetil (Mofilet) along with prednisolone and tacrolimus. Intensive pharmacokinetic sampling was performed in 29 patients to measure mycophenolate concentration from trough to 12 hours postdose. Subsets of different timed concentrations against total measured 12-hour area under the curve were analyzed by linear regression. Three models were identified and linear regression analysis done. After all subset regression analysis, three, four, and five time point limited sampling strategies (LSS) were developed having correlation coefficients above 0.92. Validation of the models was performed using the jackknife method and their predictive performances were tested. After validation, the correlation coefficients for all three models were above 0.901. The five-point LSS had the best predictive performance with a bias (95% confidence interval) of 0.67% (-3.45 to 4.79) and mean precision 7.73%. In all patients except one, the five-point LSS estimation for total area under the curve was within ± 20% of the total measured AUC0-12. Trough concentration had a significant correlation with AUC0-12 (r2 = 0.69). However, if dosing in routine clinical practice was adjusted based only on trough concentration, 41% of our patients would require a different dose compared with monitoring using AUC0-12. The five-point LSS uses half-hourly samples from trough to 1.5 hour postdose with an additional sample at 3 hours. Ninety-three percent of our patients had a Cmax within 1.5 hour and inclusion of all the time points up to1.5 hour gave a better estimate of AUC0-12. This model simplifies area under the curve measurement with high precision in stable adult renal transplant patients.

A possible simplification for the estimation of area under the curve (AUC₀₋₁₂) of enteric-coated mycophenolate sodium in renal transplant patients receiving tacrolimus.

Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplantation. With a delayed absorption profile, it has not been possible to develop limited sampling strategies to estimate area under the curve (mycophenolic acid [MPA] AUC0-12), which have limited time points and are completed in 2 hours. We developed and validated simplified strategies to estimate MPA AUC0-12 in an Indian renal transplant population prescribed EC-MPS together with prednisolone and tacrolimus. Intensive pharmacokinetic sampling (17 samples each) was performed in 18 patients to measure MPA AUC0-12. The profiles at 1 month were used to develop the simplified strategies and those at 5.5 months used for validation. We followed two approaches. In one, the AUC was calculated using the trapezoidal rule with fewer time points followed by an extrapolation. In the second approach, by stepwise multiple regression analysis, models with different time points were identified and linear regression analysis performed. Using the trapezoidal rule, two equations were developed with six time points and sampling to 6 or 8 hours (8hrAUC[0-12exp]) after the EC-MPS dose. On validation, the 8hrAUC(0-12exp) compared with total measured AUC0-12 had a coefficient of correlation (r2) of 0.872 with a bias and precision (95% confidence interval) of 0.54% (-6.07-7.15) and 9.73% (5.37-14.09), respectively. Second, limited sampling strategies were developed with four, five, six, seven, and eight time points and completion within 2 hours, 4 hours, 6 hours, and 8 hours after the EC-MPS dose. On validation, six, seven, and eight time point equations, all with sampling to 8 hours, had an acceptable r2 with the total measured MPA AUC0-12 (0.817-0.927). In the six, seven, and eight time points, the bias (95% confidence interval) was 3.00% (-4.59 to 10.59), 0.29% (-5.4 to 5.97), and -0.72% (-5.34 to 3.89) and the precision (95% confidence interval) was 10.59% (5.06-16.13), 8.33% (4.55-12.1), and 6.92% (3.94-9.90), respectively. Of the eight simplified approaches, inclusion of seven or eight time points improved the accuracy of the predicted AUC compared with the actual and can be advocated based on the priority of the user.

Mycophenolic acid area under the curve recovery time following rifampicin withdrawal.

Renal transplant patients prescribed mycophenolate mofetil (MMF) may require treatment for tuberculosis with a regimen including the tuberculocidal drug rifampicin. MMF is an ester prodrug which is rapidly hydrolysed to the active compound, mycophenolic acid (MPA). Therapeutic drug monitoring of mycophenolate involves the measurement of MPA area under the curve (MPA-AUC0-12). Rifampicin is known to increase the metabolism and decrease enterohepatic recirculation of mycophenolic acid, (MPA). When MPA is monitored after the discontinuation of rifampicin, an important factor is the time required for the MPA area under the curve to return to the pre-rifampicin value. At present this is not known. This report describes one such renal allograft patient, on long term MMF and prescribed rifampicin by a local physician. As expected there was a clinically significant decrease in MPA-AUC0-12 Three weeks after rifampicin was discontinued the MPA-AUC0-12 was still only 65% of the pre-rifampicin value and only 55% of the steady state MPA-AUC0-12 measured six months later.

Can mycophenolic acid dose requirement during the first transplant help predict dosing for the second transplant

We describe the pharmacokinetic profile of mycophenolic acid (MPA) in a patient receiving Mycophenolate mofetil (MMF) during her first and second renal transplantations. The MMF dose required to achieve a therapeutic range of MPA-AUC(0)(-)(12)(h) early following the second transplantation was 10 times greater than that required late following the first transplantation. Her MMF requirement then declined and continued to decrease even beyond 1 year. Intra-individual variability in MPA profiles precluded the ability to predict MMF dosing for the second transplant based on that during the first. Therapeutic drug monitoring of MMF should be continued beyond 1 year of transplantation.

Spectrum of biopsy proven renal disease in South Asian children: Two decades at a tropical tertiary care centre

We report findings from a large single centre paediatric renal biopsy cohort in South Asia.