| 1. |
- Wallin, Johan E, et al.
(författare)
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Population pharmacokinetics of tacrolimus in pediatric hematopoietic stem cell transplant recipients: new initial dosage suggestions and a model-based dosage adjustment tool.
- 2009
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Ingår i: Therapeutic drug monitoring. - 1536-3694. ; 31:4, s. 457-66
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Tidskriftsartikel (refereegranskat)abstract
- The population pharmacokinetics of tacrolimus was described in 22 pediatric hematopoietic 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 (IV) infusion (0.03 mg x kg(-1) x d(-1)) starting 2 days before transplantation, with conversion to oral therapy 2-3 weeks after transplant. Population pharmacokinetic analysis was performed using NONMEM. A Bayesian dosage adjustment tool that searches for individual parameter estimates to describe concentration measurements, counterbalanced by the final population model, was created in Excel. Typical clearance was 106 mL x h(-1) x kg(-0.75), 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 postoperative day. A Bayesian dosage adjustment tool capable of suggesting an initial infusion rate based on patient covariate values and devising a further individualized dosage regimen as drug concentration measures become available was developed. Predictions from the model showed that current IV dose recommendations of 0.03 mg x kg(-1) x d(-1) may potentially produce toxic drug concentrations in this patient population, whereas current oral conversion of 4 times the adjusted IV dose may lead to subtherapeutic concentrations. A more suitable infusion rate to obtain a steady state concentration of 12 ng/mL was predicted to be 0.035 mg x kg(-0.75) x (-1)d. An additional loading dose of 0.07 mg x kg(-1) x d(-1) (total dose: 0.07 mg x kg(-1) x d(-1) + 0.035 mg x kg(-0.75) x d(-1)) during the first 24 hours of therapy should allow rapid achievement of steady state concentrations. A conversion factor of 6 from IV to enteric therapy may be more suitable. Such dosage recommendations may be site specific. The appropriateness of targets was not investigated in this study. The Bayesian dosing adjustment tool and suggested dose recommendations need to be evaluated in a prospective study before they can be applied in the clinical setting.
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| 2. |
- Wallin, Johan E, et al.
(författare)
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Population pharmacokinetics of tacrolimus in pediatric liver transplantation : early posttransplantation clearance
- 2011
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 33:6, s. 663-672
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology. METHODS: The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients. RESULTS: An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h·kg immediately after transplantation, increasing to a maximum of 1.37 L·h·kg. Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time. CONCLUSIONS: A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.
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| 3. |
- Hennig, Stefanie, et al.
(författare)
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Population Pharmacokinetics of Tobramycin in Patients With and Without Cystic Fibrosis
- 2013
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 52:4, s. 289-301
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives While several studies have examined the pharmacokinetics of tobramycin in patients with cystic fibrosis (CF), there is no consensus on whether they differ in patients with and without CF. The objectives of this study were to identify covariates which explain pharmacokinetic variability and to examine whether having the disease CF in itself alters these relationships and drug dose requirements. Methods To investigate this issue, a population pharmacokinetic meta-analysis of data from eight centres was undertaken. NONMEM (R) 7.2 was used to analyse the data, which comprised 4,514 concentration-time measurements from 465 adults and children with CF and 1,095 concentration-time measurements from 267 adults and children without CF. Results Tobramycin disposition was well described by a two-compartment model with first-order elimination. Patient age, fat-free mass, serum creatinine concentration and sex were identified as significant covariates in the final model. Fat-free mass was superior to total bodyweight as a descriptor of clearance, volume of distribution of the central and peripheral compartments and inter-compartmental clearance. CF as an independent disease-specific factor had no significant influence on the pharmacokinetics of tobramycin at any stage during covariate model building. An optimal dose of 11 mg/kg every 24 h was defined for CF patients using a utility function approach. Conclusion The pharmacokinetics of tobramycin do not differ significantly in CF patients compared with patients without CF when subject age, fat-free mass, sex and renal function are taken into consideration. Variations in tobramycin dosing between CF and non-CF patients should therefore reflect target concentrations or exposures based on differences in expected pathogen sensitivity and not the presence of CF.
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| 4. |
- Hooker, Andrew C., et al.
(författare)
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Conditional weighted residuals (CWRES) : a model diagnostic for the FOCE method
- 2007
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 24:12, s. 2187-2197
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Population model analyses have shifted from using the first order (FO) to the first-order with conditional estimation (FOCE) approximation to the true model. However, the weighted residuals (WRES), a common diagnostic tool used to test for model misspecification, are calculated using the FO approximation. Utilizing WRES with the FOCE method may lead to misguided model development/evaluation. We present a new diagnostic tool, the conditional weighted residuals (CWRES), which are calculated based on the FOCE approximation. Materials and Methods CWRES are calculated as the FOCE approximated difference between an individual’s data and the model prediction of that data divided by the root of the covariance of the data given the model. Results Using real and simulated data the CWRES distributions behave as theoretically expected under the correct model. In contrast, in certain circumstances, the WRES have distributions that greatly deviate from the expected, falsely indicating model misspecification. CWRES/WRES comparisons can also indicate if the FOCE estimation method will improve the results of an FO model fit to data. Conclusions Utilization of CWRES could improve model development and evaluation and give a more accurate picture of if and when a model is misspecified when using the FO or FOCE methods.
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