Evidence map›Paper›PMID 30327943›Full record

ArticleClinical pharmacokinetics2019

Population Pharmacokinetics of Fludarabine in Children and Adults during Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.

Jurgen B Langenhorst, Thomas P C Dorlo, Erik M van Maarseveen, Stefan Nierkens, Jürgen Kuball, Jaap Jan Boelens, Charlotte van Kesteren, Alwin D R Huitema

Open access · hybridAbstract read
In one paragraph

Article in Clinical pharmacokinetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
59citing papers in PubMed, 2 pooled it
4.8field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

59 citing papers in PubMed, 2 syntheses or guidelines pooled it, 67 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 2 countries.

Jurgen B LangenhorstPediatric Blood and Marrow Transplant Program, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Thomas P C DorloDepartment of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands.
Erik M van MaarseveenDepartment of Clinical Pharmacy, University Medical Centre, Utrecht, Utrecht University, Heidelberglaan 100: D.00.X, 3584 CX, Utrecht, The Netherlands.
Stefan NierkensLaboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Jürgen KuballLaboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Jaap Jan BoelensPediatric Blood and Marrow Transplant Program, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Charlotte van KesterenPediatric Blood and Marrow Transplant Program, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Alwin D R HuitemaDepartment of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands. a.d.r.huitema-2@umcutrecht.nl.
Utrecht University · NLThe Netherlands Cancer Institute · NLUniversity Medical Center Utrecht · NL

Funding

X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4M
NCI NIH HHS P30 CA008748
6 · The paper itself

Abstract

backgroundFludarabine 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.

objectiveWe sought to describe the population PK of fludarabine in HCT recipients of all ages.

methodsFrom 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.

resultsVariability 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.

conclusionBW 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.

Indexed as

Models, BiologicalAdolescentAdultAgedChildChild, PreschoolFemaleHematopoietic Stem Cell TransplantationHumansInfantMaleMiddle AgedMyeloablative AgonistsTransplantation ConditioningVidarabineYoung AdultfludarabineMyeloablative AgonistsVidarabine

Identifiers

PMID30327943
PMCPMC6451721
OpenAlexW2896086864

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.