| 1. |
- Fanta, Samuel, et al.
(författare)
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Developmental pharmacokinetics of ciclosporin : a population pharmacokinetic study in paediatric renal transplant candidates
- 2007
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 64:6, s. 772-784
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Tidskriftsartikel (refereegranskat)abstract
- Aims To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin. Methods Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg−1) and orally (10 mg kg−1) on separate occasions followed by blood sampling for 24 h. Results A three-compartment model with first-order absorption without lag-time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age-related changes in oral bioavailability or in BW-normalized V were seen. The BW-normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW3/4) removed its relationship to age. Conclusion The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.
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| 2. |
- Abrantes, João A., et al.
(författare)
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Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
- 2019
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Ingår i: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 85:6, s. 1326-1336
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.
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| 3. |
- Frobel, Anne-Kristina, et al.
(författare)
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A time-to-event model for acute rejections in paediatric renal transplant recipients treated with ciclosporin A
- 2013
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 76:4 SI, s. 603-615
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Tidskriftsartikel (refereegranskat)abstract
- AimsCiclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUCs) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome. MethodsPatient records at the Children's Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling, bootstrap-stepwise covariate modelling and cross-validated stepwise covariate modelling. The clinical relevance of the effects was assessed with the time at which 90% of the patients were AR free (t(90)). ResultsData from 87 patients (0.7-19.8 years old, 54 experiencing an AR) were analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90% interval 1.13-8.40hmgl(-1)), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median t(90) was 5.8days (90% confidence interval 5.1-6.8) for long dialysis times (90th percentile) and 7.4days (6.4-11.7) for short dialysis times (10th percentile). ConclusionsA survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help to avoid unnecessarily high CsA dosing in children.
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| 4. |
- Niebecker, Ronald, et al.
(författare)
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Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism-the Hokusai-VTE phase 3 study
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 80:6, s. 1374-1387
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism in the Hokusai-VTE phase 3 study. The impact of the protocol-specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CLcr ) of 30 to 50 ml min(-1) or concomitant P-glycoprotein inhibitor on edoxaban exposure was assessed using simulations.METHODS: The sparse data from Hokusai-VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.RESULTS: A linear two-compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non-renal and renal. The latter increased non-linearly with increasing CLcr . Compared with healthy volunteers, inter-compartmental clearance and the CLcr covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co-administration of P-glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model-based simulations revealed lower exposure in dose-reduced compared with non-dose-reduced patients.CONCLUSIONS: The adopted dose-reduction strategy resulted in reduced exposure compared with non-dose-reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.
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