WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Tacrolimus trough concentration is being currently used for dose individualization.• Limited sampling strategies (LSS) have been developed and validated for renal transplant patients.• Earlier literature has suggested that measurement of tacrolimus AUC is more reliable than trough with respect to both rejection and nephrotoxicity. WHAT THIS STUDY ADDS• Four thousand renal transplants take place annually in India, with many patients prescribed tacrolimus in combination with mycophenolate and steroid.• In this study a LSS with two points, i.e. trough and 1.5 h postdose was developed and validated to estimate AUC0-12.• The added benefit of only a single additional sample with completion of blood collection in 1.5 h and minimum additional cost makes this a viable LSS algorithm in renal transplant patients.• In patients having tacrolimus trough concentrations outside the recommended range (<3 and >10 ng ml -1 in the treatment protocol in our institution) or having side-effects in spite of trough concentrations in the desired range, we can estimate AUC using this LSS for a better prediction of exposure. AIMSTo develop and validate limited sampling strategy (LSS) equations to estimate area under the curve (AUC0-12) in renal transplant patients. METHODSTwenty-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 AUC0-12. 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. RESULTSThree models were identified, all with R 2 Ն 0.907. Two point models included one with trough (C0) and 1.5 h postdose (C1.5), 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 AUC0-12. 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). CONCLUSIONThe two-point LSS equation .C0) + (3.33.C1.5)] can be used as a predictable and accurate measure of AUC0-12 in stable renal transplant patients prescribed prednisolone and mycophenolate.
BackgroundUse of antibiotic-loaded acrylic bone cement to treat orthopaedic infections continues to remain popular, but resistance to routinely used antibiotics has led to the search for alternative, more effective antibiotics. We studied, in vitro, the elution kinetics and bio-activity of different concentrations of meropenem-loaded acrylic bone cement.MethodsMeropenem-loaded bone cement cylinders of different concentrations were serially immersed in normal saline. Elution kinetics was studied by measuring the drug concentration in the eluate, collected at pre-determined intervals, by high-performance liquid chromatography. Bio-activity of the eluate of two different antibiotic concentrations was tested for a period of 3 weeks against each of the following organisms: Staphylococcus aureus ATCC 2593 (MSSA), Enterococcus faecalis ATCC 29212, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, S. aureus ATCC 43300 (MRSA) and Klebsiella pneumoniae ATCC 700603 (ESBL).ResultsMeropenem elutes from acrylic bone cement for a period of 3–27 days depending on the concentration of antibiotic. Higher doses of antibiotic concentration resulted in greater elution of the antibiotic. The eluate was found to be biologically active against S. aureus ATCC 2593 (MSSA), P. aeruginosa ATCC 27853, E. coli ATCC 25922 and K. pneumoniae ATCC 700603 (ESBL) for a period of 3 weeks.ConclusionsThe elution of meropenem is in keeping with typical antibiotic-loaded acrylic bone cement elution characteristics. The use of high-dose meropenem-loaded acrylic bone cement seems to be an attractive option for treatment of resistant Gram-negative orthopaedic infections but needs to be tested in vivo.
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 (r = 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.
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