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Confidence Interval Criteria for Assessment of Dose Proportionality

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Abstract

Purpose. The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs.

Methods. Statistical estimation is used to derive a (1-α)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (Rdnm) of a pharmacokinetic variable (PK). An acceptance interval for Rdnm defining the clinically relevant, dose-proportional region is established a priori. Proportionality is declared if the CI for Rdnm is completely contained within the critical region. The approach is illustrated with mixed-effects models based on a power function of the form PK = β0 • Doseβ1; however, the logic holds for other functional forms.

Results. It was observed that the dose-proportional region delineated by a power model depends only on the dose ratio. Furthermore, a dose ratio (ρ1) can be calculated such that the CI lies entirely within the pre-specified critical region. A larger ratio (ρ2) may exist such that the CI lies completely outside that region. The approach supports inferences about the PK response that are not constrained to the exact dose levels studied.

Conclusion. The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.

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Authors and Affiliations

  1. Lilly Laboratory for Clinical Research, 550 North University Boul- evard, Indianapolis, Indiana, 46202-5250

    Brian P. Smith

  2. Lilly Development Centre, 11 rue Granbonpre, B-1348, Mont-Saint-Guibert, Belgium

    Francois R. Vandenhende

  3. Lilly Laboratory for Clinical Research, 550 North University Boul- evard, Indianapolis, Indiana, 46202-5250

    Karl A. DeSante, Pamela A. Welch, John T. Callaghan & S. Thomas Forgue

  4. Department of Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, 46202

    Karl A. DeSante & John T. Callaghan

  5. Drug Disposition Department, Lilly Research Laboratories, Indi- anapolis, Indiana, 46285

    Nagy A. Farid

  6. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202

    Pamela A. Welch

  7. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202

    John T. Callaghan

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  1. Brian P. Smith
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  2. Francois R. Vandenhende
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  3. Karl A. DeSante
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  4. Nagy A. Farid
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  5. Pamela A. Welch
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  6. John T. Callaghan
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  7. S. Thomas Forgue
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Smith, B.P., Vandenhende, F.R., DeSante, K.A. et al. Confidence Interval Criteria for Assessment of Dose Proportionality. Pharm Res 17, 1278–1283 (2000). https://doi.org/10.1023/A:1026451721686

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  • DOI: https://doi.org/10.1023/A:1026451721686

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