First‐Time‐in‐Human Dose Selection: Allometric Thoughts and Perspectives

@article{Boxenbaum1995FirstTimeinHumanDS,
  title={First‐Time‐in‐Human Dose Selection: Allometric Thoughts and Perspectives},
  author={Harold G. Boxenbaum and Clifford Dilea},
  journal={The Journal of Clinical Pharmacology},
  year={1995},
  volume={35}
}
Some of the many factors that influence dose selection in first‐time‐in‐human studies are examined. These include animal toxicology, toxicokinetics, allometric scaling, pharmacokinetics, body surface area correlations, and integration of preclinical pharmacologic and toxicologic data. Appropriate preclinical evaluation and analysis may reduce the frequency and severity of unexpected toxic events arising during single‐dose, phase I testing. However, significant intrinsic uncertainties in this… 
View on Wiley
ncbi.nlm.nih.gov
153 Citations
Highly Influential Citations
4
Background Citations
32
Methods Citations
20

153 Citations

Citation Type

Citation Type

A Brief Survey of First‐in‐Human Studies
TLDR
Based on these examples, it appears that relatively conservative 2‐fold dose escalations are the most common escalation approach within FIH single ascending dose studies.
Selection of the First‐Time Dose in Humans: Comparison of Different Approaches Based on Interspecies Scaling of Clearance
TLDR
This work demonstrates that animal pharmacokinetic data can be used to estimate a suitable human starting dose, provided the data have been obtained from a dose that produces no adverse effects.
Inhaled efficacious dose translation from rodent to human: A retrospective analysis of clinical standards for respiratory diseases
  • J. Phillips
  • Biology, Medicine
    Pharmacology & therapeutics
  • 2017
Pharmacokinetic allometric scaling of antibodies: application to the first-in-human dose estimation.
  • I. Mahmood
  • Medicine, Biology
    Journal of pharmaceutical sciences
  • 2009
TLDR
The results of the study indicated that the clearance of antibodies can be predicted with reasonable accuracy in humans and a good estimate of first human dose can be obtained from the predicted human clearance.
Application of Preclinical Data to Initiate the Modified Continual Reassessment Method for Maximum Tolerated Dose—Finding Trials
  • I. Mahmood
  • Biology
    Journal of clinical pharmacology
  • 2001
TLDR
The results of the study indicate that MTD can be predicted with reasonable accuracy using interspecies scaling and can be applied to the modified continual reassessment method retrospectively for the selection of initial and subsequent doses of anticancer drugs in the patient population.
A novel Bayesian decision procedure for early-phase dose-finding studies.
TLDR
Software currently in development using mixed-effects modeling to define a maximum safe dose and to identify a range of acceptable doses for later drug development studies in patients is described and an example from a recent study is illustrated.
The Pharmacokinetic Principles Behind Scaling from Preclinical Results to Phase I Protocols
TLDR
It has been noted that the unbound clearance of a drug cannot be predicted any better than the total body clearance (CL), and there is a good correlation between bodyweight and volume of the central compartment (Vc); hence, Vc does not face the same complications as CL.
First Time in Human for GV196771: Interspecies Scaling Applied on Dose Selection
TLDR
The authors discuss the outcome of the prospective dose selection strategy for GV196771 compared to the actual concentration profiles observed in the FTIM study, using techniques of interspecies scaling.
Approaches for predicting human pharmacokinetics using interspecies pharmacokinetic scaling
TLDR
Various approaches developed for predicting pharmacokinetic parameters in humans using interspecies scaling are introduced and discussed, and methods to predict plasma concentration-time profiles in humans after intravenous and oral administration are reviewed.
Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans
TLDR
Two research tools are highlighted for analysing and interpreting disposition and pharmacokinetic data from multiple species and for extrapolating this data accurately in humans and strategies for applying these extrapolation tools in a complementary manner to perform dose predictions and in silico toxicity assessments in humans are explained.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 38 REFERENCES
Quantitative prediction of drug toxicity in humans from toxicology in small and large animals.
TLDR
If the starting dose in Phase 1 clinical trials had been selected by calculating one-third of the toxic dose low (in mg/sq m) in the most sensitive large animal species, 5 of the 30 drugs would have produced significant toxicity in the first patient.
Forecasting drug effects in man from studies in laboratory animals.
TLDR
It is shown that many of the most serious side effects that can result when a drug is given to man were not predictable from observations on dogs or rats.
Potential roles for preclinical pharmacology in phase I clinical trials.
TLDR
Retrospective analyses indicate that 20%-50% savings in the total number of dose escalations are possible, and potential strategies for controlling the rate of dose escalation based upon pharmacokinetic determinations in mouse and man are explored.
Controversy V: Phase I, First Time in Man Studies
  • W. Colburn
  • Medicine
    Journal of clinical pharmacology
  • 1990
TLDR
The authors come from academia: Roger Williams, University of California, San Francisco; industry: Richard Bergstrom and Louis Lemberger, Eli Lilly and Company; contract laboratory: Denis O’Donnell, Medical and Technical Research Associates, Inc.
Dosage regimen design for pharmaceutical studies conducted in animals.
  • J. Mordenti
  • Medicine
    Journal of pharmaceutical sciences
  • 1986
TLDR
The power equation adequately described the relationship between toxic dose and animal weight for most of the compounds, demonstrating the utility of the power equation in the assessment of dosing regimens for toxicity studies as well.
Nonsteroidal anti-inflammatory drugs: an analysis of the relationship between laboratory animal and clinical doses, including species scaling.
TLDR
The pharmacologic activity of nonsteroidal anti-inflammatory drugs (NSAID) has generally been studied in multiple tests, and it was found that carrageenan edema test greater than UVE greater than PBQ greater than RWTH.
Similarity principles and intrinsic geometries: contrasting approaches to interspecies scaling.
We criticize standard allometric approaches on the grounds that they emphasize scaling to one variable at a time, whereas chemically reactive hydrodynamic systems involved in pharmacokinetic…
Scaling of blood parameters in mammals
Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat.
TLDR
A considerably higher extraction ratio than the unbound fraction of diazepam exists in these animal species, and blood clearance exceeds liver blood flow, giving reason to assume a much higher ability of the liver to metabolize D, and a species-dependent extrahepatic metabolism.
New Drugs: First Time in Man
TLDR
Essai clinique en phase I chez l'homme pour une nouvelle molecule medicamenteuse permet une transition facilitee a l'etude sur la population de malades.
...
1
2
3
4
...