Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients |
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Authors: | Antignac Marie Barrou Benoit Farinotti Robert Lechat Philippe Urien Saïk |
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Institution: | Pharmacy Department, PitiéSalpêtrière Hospital,;Pharmacology Department, Centre RenéHuguenin, Saint-Cloud,;Pharmacology Department, PitiéSalpêtrière Hospital and;Department of Urology Surgery, PitiéSalpêtrière Hospital, AP HP-47 Bd de l'hôpital, 75013 Paris, France |
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Abstract: | What is already known about this subject- In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability.
- Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.
What this study adds- Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.
- Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.
AimsThe use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.MethodsThe database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.ResultsA one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h?1. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h?1. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg?1) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.ConclusionsThe number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance. |
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Keywords: | kidney population pharmacokinetics tacrolimus transplantation |
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