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Dog Colonoscopy Model for Predicting Human Colon Absorption

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Purpose

This study was conducted to develop and validate a dog colon model that predicts colon permeability in humans.

Methods

The following compounds were studied: Class 1 highly soluble (HS)/highly permeable (HP): aminophylline, propranolol, CP-409092; Class 2 LS/HP: nifedipine; trovafloxacin, sertraline; Class 3 HS/LP: azithromycin, atenolol, CP-331684, CP-424391; Class 4 LS/LP: CJ-13610. Administration to dogs was made 30 cm cranial to the anal sphincter with a lubricated Schott Model VFS-5 flexible endoscope. The bioavailability of the compound following the colon administration in dogs, relative to the same formulation administered orally (relative bioavailability), was determined.

Results

Except for atenolol, a small hydrophillic molecule, the relative bioavailability from administration to the colon of the dog correlated well with the following compound properties: high solubility and high, passive permeability > high solubility, low permeability > low solubility, high, passive permeability ∼ low solubility, low permeability.

Conclusion

The dog colon model is proposed as a surrogate for human intubation studies when the controlled release candidate falls in BCS Classes 2 (LS/HP), 3 (HS/LP), and 4 (LS/LP). However, no human intubation or dog colon studies are required for Class 1 (HS/HP), as these compounds are likely to be well absorbed from the colon.

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Notes

  1. (4-(2-(2-(6-Aminopyridin-3-yl)-2(R)-hydroxyethylamino)-ethoxy)-phenyl)-acetic acid.

  2. CP-409092: 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide.

  3. 2-Amino-N-[2-(3′R-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxo-ethyl]-isobutyramide l-tartrate.

  4. 4-[3-{4-(2-Methylimidazol-1-yl)phenylthio}]phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide methanesulfonate.

  5. The clinical studies are the subject of a manuscript in preparation.

  6. The clinical studies are the subject of a manuscript in preparation.

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Acknowledgments

We wish to acknowledge the following for their assistance in the compound analysis: F. Nelson (analysis of CP-409092 in pooled dog plasma); L. D. Kendall, D. Zhang, (oral administration and analysis of CJ-13610 in dog plasma); F. Lombardo, G. Foulds (analysis of azithromycin in dog serum, retired), J. Miceli, T. Smolarek, R. Polzer (analysis of trovafloxacin in dog serum). We wish to acknowledge C. A. Oksanen and N. Tierney (trovafloxacin formulations) and M. Biron, A. Campeta, J. Timpano, L. Yuhas, E. Greer, and E. Fiese (retired) for the pH solubility data and D. Salotti (now at Merck) for permeability data collected from the rat SPIP model. We also thank all the veterinarians, animal handlers and staff who assisted in the dog studies. Finally, we wish to acknowledge S. M. Herbig, W. J. Curatolo, and H. L. Freidman for their scientific leadership, and the reviewers for their helpful suggestions.

Author information

Authors and Affiliations

  1. BioPharmaceutics Group, Pharmaceutical R&D Department, Pfizer Global R&D, Groton, Connecticut, 06357, USA

    Steven C. Sutton, Loreen A. Evans, Jennifer M. McCarthy & Kathy Sweeney

  2. Comparative Medicine, Pfizer Global R&D, Groton Campus, Groton, Connecticut, 06357, USA

    Jay H. Fortner

  3. PPD, 3900 Paramount Parkway, Morrisville, North Carolina, 27560, USA

    Jennifer M. McCarthy

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  1. Steven C. Sutton
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  2. Loreen A. Evans
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  3. Jay H. Fortner
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  4. Jennifer M. McCarthy
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  5. Kathy Sweeney
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Corresponding author

Correspondence to Steven C. Sutton.

Additional information

Retired

Electronic Supplementary Material

Glossary

AC

ascending colon

AM

arithmetic mean

AMT

asymmetric membrane technology tablet

\({\text{AUC}}_{{{\text{0 - }}\infty }} \)

area under the plasma concentration–time curve from 0 h and extrapolated to infinity

BCS

Biopharmaceutical Classification Scheme

BLQ

below LLOQ

C max

first occurrence of the maximum plasma concentration

C min

the minimum plasma concentration during a dosing interval

CR

controlled release formulation

CV

coefficient of variation (percentage), given by: 100 * (SD/AM)

FIH

first-in-human studies

GI

gastrointestinal

GIT

gastrointestinal tract

GM

geometric mean

HP

high permeability

HS

high solubility

ICJ

ileal–cecal junction

IR

immediate release formulation

IS

internal standard

k a

absorption rate constant

k el

elimination rate constant—used to extrapolate AUC from the last time point (C LTP) to infinity with the following Eqn: \({\text{AUC}}_{{{\text{LTP - }}\infty }} = {C_{{{\text{LTP}}}} } \mathord{\left/ {\vphantom {{C_{{{\text{LTP}}}} } {k_{{{\text{el}}}} }}} \right. \kern-\nulldelimiterspace} {k_{{{\text{el}}}} }\)

K m

the concentration that gives 50% of the maximum activity

LLOQ

lower limit of quantification

LP

low permeability

LS

low solubility

P app

apparent permeability

PGRD

Pfizer Global Research & Development

RBA

bioavailability \({\text{AUC}}_{{{\text{0 - }}\infty }} \) relative to an orally administered dose

SD

standard deviation

SE

standard error

SPIP

(rat) single pass intestinal perfusion

TC

transverse colon

T max

time of C max

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Sutton, S.C., Evans, L.A., Fortner, J.H. et al. Dog Colonoscopy Model for Predicting Human Colon Absorption. Pharm Res 23, 1554–1563 (2006). https://doi.org/10.1007/s11095-006-0252-3

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