Pharmacokinetic Study of Tacrolimus in Cystic Fibrosis and Non-Cystic Fibrosis Lung Transplant Patients and Design of Bayesian Estimators Using Limited Sampling Strategies

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Abstract
To: (i) test different pharmacokinetic models to fit full tacrolimus concentration-time profiles; (ii) estimate the tacrolimus pharmacokinetic characteristics in stable lung transplant patients with or without cystic fibrosis (CF); (iii) compare the pharmacokinetic parameters between these two patient groups; and (iv) design maximum a posteriori Bayesian estimators (MAP-BE) for pharmacokinetic forecasting in these patients using a limited sampling strategy. Tacrolimus blood concentration-time profiles obtained on three occasions within a 5-day period in 22 adult lung transplant recipients (11 with CF and 11 without CF) were retrospectively studied. Three different one-compartment models with first-order elimination were tested to fit the data: one with first-order absorption, one convoluted with a gamma distribution to describe the absorption phase, and one convoluted with a double gamma distribution able to describe secondary concentration peaks. Finally, Bayesian estimation using the best model and a limited sampling strategy was tested in the two groups of patients for its ability to provide accurate estimates of the main tacrolimus pharmacokinetic parameters and exposure indices. The one-compartment model with first-order elimination convoluted with a double gamma distribution gave the best results in both CF and non-CF lung transplant recipients. The patients with CF required higher doses of tacrolimus than those without CF to achieve similar drug exposure, and population modelling had to be performed in CF and non-CF patients separately. Accurate Bayesian estimates of area under the blood concentration-time curve from 0 to 12 hours (AUC12), AUC from 0 to 4 hours, peak blood concentration (Cmax) and time to reach Cmax were obtained using three blood samples collected at 0, 1 and 3 hours in non-CF patients (correlation coefficient between observed and estimated AUC12, R2 = 0.96), and at 0, 1.5 and 4 hours in CF patients (R2 = 0.91). A particular pharmacokinetic model was designed to fit the complex and highly variable tacrolimus blood concentration-time profiles. Moreover, MAP-BE allowing tacrolimus therapeutic drug monitoring based on AUC12 were developed.