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- Langenhorst, Jurgen B, et al.
(författare)
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Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation.
- 2020
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 9:5, s. 272-281
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Tidskriftsartikel (refereegranskat)abstract
- Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m2 ) to either covariate-based or therapeutic drug monitoring (TDM)-guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of end points and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM-guided dosing to current practice with NRM as primary outcome (n = 70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible.
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| 2. |
- Langenhorst, Jurgen B, et al.
(författare)
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Population Pharmacokinetics of Fludarabine in Children and Adults during Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.
- 2019
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 58:5, s. 627-637
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Fludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used.OBJECTIVE: We sought to describe the population PK of fludarabine in HCT recipients of all ages.METHODS: From 258 HCT recipients aged 0.3-74 years, 2605 samples were acquired on days 1 (42%), 2 (17%), 3 (4%) and 4 (37%) of conditioning. Herein, the circulating metabolite of fludarabine was quantified, and derived concentration-time data were used to build a population PK model using non-linear mixed-effects modelling.RESULTS: Variability was extensive where area under the curve ranged from 10 to 66 mg h/L. A three-compartment model with first-order kinetics best described the data. Actual body weight (BW) with standard allometric scaling was found to be the best body-size descriptor for all PK parameters. Estimated glomerular filtration rate (eGFR) was included as a descriptor of renal function. Thus, clearance was differentiated into a non-renal (3.24 ± 20% L/h/70 kg) and renal (eGFR × 0.782 ± 11% L/h/70 kg) component. The typical volumes of distribution of the central (V1), peripheral (V2), and second peripheral (V3) compartments were 39 ± 8%, 20 ± 11%, and 50 ± 9% L/70 kg respectively. Intercompartmental clearances between V1 and V2, and V1 and V3, were 8.6 ± 8% and 3.8 ± 13% L/h/70 kg, respectively.CONCLUSION: BW and eGFR are important predictors of fludarabine PK. Therefore, current linear BSA-based dosing leads to highly variable exposure, which may lead to variable treatment outcome.
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