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

ObjectivesTo: (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.MethodsTacrolimus 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.ResultsThe 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).ConclusionA 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.

[1]  S. Keam,et al.  Tacrolimus: a further update of its use in the management of organ transplantation. , 2003, Drugs.

[2]  T. Wagner,et al.  Tacrolimus for treatment of bronchiolitis obliterans syndrome after unilateral and bilateral lung transplantation. , 2002, Transplantation proceedings.

[3]  E. Arbustini,et al.  Efficacy of tacrolimus rescue therapy in refractory acute rejection after lung transplantation. , 2002, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[4]  Y. Tanigawara,et al.  Human P-glycoprotein transports cyclosporin A and FK506. , 1993, The Journal of biological chemistry.

[5]  S. Uemoto,et al.  Forecasting of Blood Tacrolimus Concentrations Based on the Bayesian Method in Adult Patients Receiving Living-Donor Liver Transplantation , 2003, Clinical pharmacokinetics.

[6]  J. Potter,et al.  The importance of area under the curve monitoring of cyclosporin in patients with cystic fibrosis after lung transplantation , 2002 .

[7]  S. Urien,et al.  Population pharmacokinetics of tacrolimus in full liver transplant patients: modelling of the post-operative clearance , 2005, European Journal of Clinical Pharmacology.

[8]  R. Jelliffe,et al.  Failure of Traditional Trough Levels to Predict Tacrolimus Concentrations , 2001, Therapeutic drug monitoring.

[9]  Atholl Johnston,et al.  Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. , 2002, Clinical therapeutics.

[10]  P. Marquet,et al.  Maximum A Posteriori Bayesian Estimation of Oral Cyclosporin Pharmacokinetics in Patients with Stable Renal Transplants , 2002, Clinical Pharmacokinetics.

[11]  H. Saito,et al.  Population pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation , 2001, European Journal of Clinical Pharmacology.

[12]  P. Marquet,et al.  Application of a Gamma Model of Absorption to Oral Cyclosporin , 2001, Clinical pharmacokinetics.

[13]  H. Reichenspurner,et al.  Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. , 2001, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[14]  D. Faulds,et al.  Tacrolimus. A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. , 1993, Drugs.

[15]  H. Saito,et al.  Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living‐donor liver transplantation , 2001, Clinical pharmacology and therapeutics.

[16]  David Z. D'Argenio,et al.  Optimal sampling times for pharmacokinetic experiments , 1981, Journal of Pharmacokinetics and Biopharmaceutics.

[17]  L. Benet,et al.  Can the Enhanced Renal Clearance of Antibiotics in Cystic Fibrosis Patients Be Explained by P-Glycoprotein Transport? , 2002, Pharmaceutical Research.

[18]  C. Staatz,et al.  Population pharmacokinetics of tacrolimus in adult kidney transplant recipients , 2002, Clinical pharmacology and therapeutics.

[19]  M. Estenne,et al.  Bayesian Forecasting of Oral Cyclosporin Pharmacokinetics in Stable Lung Transplant Recipients With and Without Cystic Fibrosis , 2003, Therapeutic drug monitoring.

[20]  C. Staatz,et al.  Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation , 2004, Clinical pharmacokinetics.

[21]  C. Staatz,et al.  Bayesian Forecasting and Prediction of Tacrolimus Concentrations in Pediatric Liver and Adult Renal Transplant Recipients , 2003, Therapeutic drug monitoring.

[22]  H. Reichenspurner,et al.  Long term follow-up of a prospective randomized trial comparing tacrolimus versus cyclosporine in combination with MMF after lung transplantation , 2003 .

[23]  E. Trulock,et al.  The registry of the international society for heart and lung transplantation: nineteenth official report-2002. , 2002, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[24]  P. Marquet,et al.  Limited sampling strategies using Bayesian estimation or multilinear regression for cyclosporin AUC0–12 monitoring in cardiac transplant recipients over the first year post-transplantation , 2003, European Journal of Clinical Pharmacology.

[25]  F. Morell,et al.  Preliminary results of rescue therapy with tacrolimus and mycophenolate mofetil in lung transplanted patients with bronchiolitis obliterans. , 2002, Transplantation proceedings.

[26]  A. McLachlan,et al.  Population Pharmacokinetic Estimation of Tacrolimus Apparent Clearance in Adult Liver Transplant Recipients , 2005, Therapeutic drug monitoring.

[27]  C. Staatz,et al.  Toward better outcomes with tacrolimus therapy: Population pharmacokinetics and individualized dosage prediction in adult liver transplantation , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.