Evidence map›Paper›PMID 28321893›Full record

ArticleBiometrical journal. Biometrische Zeitschrift2017

Dose-finding methods for Phase I clinical trials using pharmacokinetics in small populations.

Moreno Ursino, Sarah Zohar, Frederike Lentz, Corinne Alberti, Tim Friede, Nigel Stallard, Emmanuelle Comets

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biometrical journal. Biometrische Zeitschrift, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed, 1 pooled it
–field-weighted citation impact
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

27 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pharmacological evidence of medicinal cannabis in oncology: a systematic review.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2019
    Pooled it
  2. Article
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  5. Review
  6. Moving the needle for oncology dose optimization: A call for action.CPT: pharmacometrics & systems pharmacology · 2024
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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

7 authors.

Moreno UrsinoINSERM, UMRS 1138, team 22, CRC, University Paris 5, University Paris 6, Paris, France.ORCID http://orcid.org/0000-0002-5709-4322
Sarah ZoharINSERM, UMRS 1138, team 22, CRC, University Paris 5, University Paris 6, Paris, France.
Frederike LentzFederal Institute for Drugs and Medical Devices, Bonn, Germany.
Corinne AlbertiINSERM, UMR 1123, Hôpital Robert-Debré, APHP, University Paris 7, Paris, France.
Tim FriedeDepartment of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
Nigel StallardStatistics and Epidemiology, Division of Health Sciences, Warwick Medical School, The University of Warwick, Warwick, UK.
Emmanuelle CometsINSERM, CIC 1414, University Rennes-1, Rennes, France.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The aim of phase I clinical trials is to obtain reliable information on safety, tolerability, pharmacokinetics (PK), and mechanism of action of drugs with the objective of determining the maximum tolerated dose (MTD). In most phase I studies, dose-finding and PK analysis are done separately and no attempt is made to combine them during dose allocation. In cases such as rare diseases, paediatrics, and studies in a biomarker-defined subgroup of a defined population, the available population size will limit the number of possible clinical trials that can be conducted. Combining dose-finding and PK analyses to allow better estimation of the dose-toxicity curve should then be considered. In this work, we propose, study, and compare methods to incorporate PK measures in the dose allocation process during a phase I clinical trial. These methods do this in different ways, including using PK observations as a covariate, as the dependent variable or in a hierarchical model. We conducted a large simulation study that showed that adding PK measurements as a covariate only does not improve the efficiency of dose-finding trials either in terms of the number of observed dose limiting toxicities or the probability of correct dose selection. However, incorporating PK measures does allow better estimation of the dose-toxicity curve while maintaining the performance in terms of MTD selection compared to dose-finding designs that do not incorporate PK information. In conclusion, using PK information in the dose allocation process enriches the knowledge of the dose-toxicity relationship, facilitating better dose recommendation for subsequent trials.

Indexed as

Maximum Tolerated DosePharmacokineticsResearch DesignClinical Trials, Phase I as TopicComputer SimulationHumansPopulation DensityDose-findingDose-toxicity relationshipMaximum tolerated dosePharmacokineticsPhase I clinical trials

Identifiers

PMID28321893
PMCPMC5573988

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Registered trials

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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.