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Population pharmacokinetics of tacrolimus in paediatric haematopoietic stem cell transplant recipients: New initial dosage suggestions and a model based dosage adjustment tool
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Department of Paediatrics, University of Gothenburg, Gothenburg, Sweden. (Immunology)
School of Pharmacy, University of Queensland, Brisbane, Australia..
2009 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, no 4, 457-466 p.Article in journal (Refereed) Published
Abstract [en]

The population pharmacokinetics of tacrolimus was described in 22 paediatric haematopoietic stem cell transplant recipients and a model-based dosage adjustment tool that may assist with therapy in new patients was developed.  Patients received tacrolimus by continuous intravenous infusion (0.03mg/kg/day) starting two days before transplantation, with conversion to oral therapy 2-3 weeks post-transplant.  Population pharmacokinetic analysis was performed using NONMEM.  A dosage adjustment tool that searches for individual parameter estimates to describe concentration measurements, counter-balanced by the final population model, was created in Excel.  Typical clearance was 106 mL/h/kg0.75, typical distribution volume was 3.71 L/kg and typical bioavailability was 15.7%.  Tacrolimus clearance decreased with increasing serum creatinine and bioavailability decreased with post-operative day.  Predictions from the model showed that current intravenous dose recommendations of 0.03 mg/kg/day may produce potentially toxic drug concentrations in the patient population, whereas current oral conversion of four times the adjusted intravenous dose may lead to subtherapeutic concentrations. We suggest a dose of 0.035mg/kg0.75/day to ensure satisfactory levels, and an oral conversion factor of six times the intravenous dose.  A dosage adjustment tool was developed that is capable of suggesting an initial infusion rate based on patient weight and serum creatinine and of devising a further individualised dosage as individual drug concentration measurements become available.  The tool also allows the clinicia to graphically examine the concentration-time profile of tacrolimus under different infusion rates, with or without a loading dose.

Place, publisher, year, edition, pages
Philadelphia PA, US: Lippincott Williams & Wilkins , 2009. Vol. 31, no 4, 457-466 p.
Keyword [en]
tacrolimus, pediatric hematopoietic stem cell transplant, population pharmacokinetics, Bayesian forecasting, dosage prediction
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-100505ISI: 000268567400006OAI: oai:DiVA.org:uu-100505DiVA: diva2:210449
Available from: 2009-04-01 Created: 2009-04-01 Last updated: 2011-05-11Bibliographically approved
In thesis
1. Dose Adaptation Based on Pharmacometric Models
Open this publication in new window or tab >>Dose Adaptation Based on Pharmacometric Models
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
Model Based Dose Adaptation
Abstract [en]

Many drugs exhibit major variability in both pharmacokinetic (PK) and pharmacodynamic (PD) parameters that prevents the use of the same dose for all patients. Variability can occur both between patients (IIV) as well as within patients over the course of time (IOV). In a drug with narrow therapeutic range and substantial IIV, dose selection may require individual adaptation. Adaptation can either be made before (a priori) or after (a posteriori) first drug administration. The former implies basing the dose on prior information known to be influential, such as kidney function indicators, weight or concomitant medication, whereas a posteriori dose adaptations are based on post-treatment observations. Often individualization cannot be based on the clinical outcome itself. In such cases, drug concentrations or biomarkers may be valuable for dose individualisation.

In this thesis two therapeutic areas where dosing is critical have been investigated regarding the possibilities of a priori and a posteriori dose adaptation; anticancer treatment where myelosuppression is dose limiting, and tacrolimus used for immunosuppression in paediatric transplantation. In tacrolimus previously published models were found to be of little value for dose adaptation in the early critical days post-transplantation. New PK models were developed and used to suggest new dosing regimens tailored for the paediatric population, recognizing the changing pharmacokinetics in the early time post-transplantation.

For several anticancer drugs covariates were identified that partly explained IIV in myelosuppression. IOV were found to be lower than IIV which implies that individual dose adaptations a posteriori can be valuable. Dose adaptation, using Bayesian principles in order to simultaneously minimise the risk of severe toxicity or subtherapeutic levels, was evaluated using simulations. Type and amount of data needed, as well as variability parameters influential on the outcome, were evaluated. Results show drug concentrations being of little value, if neutrophil counts are available.

The models discussed in this thesis have been implemented in MS Excel macros for Bayesian forecasting, to allow widespread distribution to clinical settings without necessitating access to specific statistical software.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 94
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100569 (URN)978-91-554-7488-1 (ISBN)
Public defence
2009-05-15, B41, BMC, Dag Hammarsköldsväg, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-02 Last updated: 2011-05-11Bibliographically approved

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Wallin, JohanFriberg, Lena

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