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Development of In Vitro-In Vivo Correlation for Potassium Chloride Extended Release Tablet Formulation Using Urinary Pharmacokinetic Data

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Abstract

Purpose

To develop and validate a Level A in vitro-in vivo correlation (IVIVC) for potassium chloride extended-release (ER) formulations.

Methods

Three prototype ER formulations of potassium chloride with different in vitro release rates were developed and their urinary pharmacokinetic profiles were evaluated in healthy subjects. A mathematical model between in vitro dissolution and in vivo urinary excretion, a surrogate for measuring in vivo absorption, was developed using time-scale and time-shift parameters. The IVIVC model was then validated based on internal and external predictability.

Results

With the established IVIVC model, there was a good correlation between the observed fraction of dose excreted in urine and the time-scaled and time-shifted fraction of the drug dissolved, and between the in vitro dissolution time and the in vivo urinary excretion time for the ER formulations. The percent prediction error (%PE) on cumulative urinary excretion over the 24 h interval (Ae0–24h) and maximum urinary excretion rate (Rmax) was less than 15% for the individual formulations and less than 10% for the average of the two formulations used to develop the model. Further, the %PE values using external predictability were below 10%.

Conclusions

A novel Level A IVIVC was successfully developed and validated for the new potassium chloride ER formulations using urinary pharmacokinetic data. This successful IVIVC may facilitate future development or manufacturing changes to the potassium chloride ER formulation.

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Abbreviations

Ae :

Amount excreted in each interval

BE:

Bioequivalence

Ae0–24 :

Cumulative urinary excretion over the 24 h interval

ER:

Extended-release

IVIVC:

In vitro-in vivo correlation

Rmax :

Maximum urinary excretion rate

PE:

Prediction error

Tmax :

Time of maximal urinary excretion

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was sponsored by AbbVie Inc. AbbVie Inc. contributed to the study design; research; data interpretation, writing, review, and approval of the manuscript for publication. Rajendar K Mittapalli, Patrick Marroum, Yihong Qiu, Kathleen Apfelbaum, Hao Xiong are employees of AbbVie Inc. All authors may hold AbbVie stocks or options.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA

    Rajendar K. Mittapalli, Patrick Marroum & Hao Xiong

  2. Drug products, Operations Science and Technology, AbbVie Inc., North Chicago, Illinois, USA

    Yihong Qiu & Kathleen Apfelbaum

Authors
  1. Rajendar K. Mittapalli
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  2. Patrick Marroum
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  3. Yihong Qiu
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  4. Kathleen Apfelbaum
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  5. Hao Xiong
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Corresponding author

Correspondence to Hao Xiong.

Electronic supplementary material

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Supplemental Figure 1

Comparison of observed versus model predicted fraction dissolved for potassium chloride extended release formulations A (Fast), B (Intermediate), and C (Slow). (PNG 36 kb)

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Mittapalli, R.K., Marroum, P., Qiu, Y. et al. Development of In Vitro-In Vivo Correlation for Potassium Chloride Extended Release Tablet Formulation Using Urinary Pharmacokinetic Data. Pharm Res 34, 1527–1533 (2017). https://doi.org/10.1007/s11095-017-2179-2

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  • DOI: https://doi.org/10.1007/s11095-017-2179-2

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