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Modeling Sex Differences in Anti-inflammatory Effects of Dexamethasone in Arthritic Rats

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Abstract

Purpose

Collagen-induced arthritic (CIA) rats are used commonly for preclinical pharmacologic research into rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid (CS), remains an important component in combination therapy for RA. Although sex differences in RA and CS pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, there has been no such comprehensive evaluation of sex differences in CIA rats.

Methods

Paw size measurements were obtained for males and females from four groups of animals: healthy controls, non-drug treated arthritic animals, and both 0.225 and 2.25 mg/kg DEX-treated arthritic animals. A turnover model for disease progression, minimal PBPK model for drug concentrations, and inhibitory indirect response model were applied using population PK/PD modeling.

Results

The clearances of DEX were 43% greater in males, but other PK parameters were similar. The temporal profiles of paw swelling exhibited earlier progression, peak edema times, and disease remission in females. DEX suppressed paw edema well in both males and females with similar capacity (Imax) values (=1.0), but DEX potency was less in females with higher IC50 values (0.101 versus 0.015 ng/mL).

Conclusions

The pharmacology of DEX was well characterized in CIA rats. This study addresses knowledge gaps about sex differences and can be a guide for more mechanistic assessment of sex, drug, and disease differences in RA.

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Abbreviations

AUC:

Area under the curve

CS:

Corticosteroids

CIA:

Collagen-induced arthritis

DEX:

Dexamethasone

DIS:

Disease

GR:

Glucocorticoid receptor

IIV:

Inter-individual variability

IL:

Interleukin

ISF:

Interstitial fluid

mPBPK:

Minimal physiologically-based pharmacokinetic

OFV:

Objective function value

PD:

Pharmacodynamics

PK:

Pharmacokinetics

RA:

Rheumatoid arthritis

SC:

Subcutaneous

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA

    Dawei Song, Debra C. DuBois, Richard R. Almon & William J. Jusko

  2. Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York, 14260, USA

    Debra C. DuBois & Richard R. Almon

Authors
  1. Dawei Song
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  2. Debra C. DuBois
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  3. Richard R. Almon
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  4. William J. Jusko
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Correspondence to William J. Jusko.

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Song, D., DuBois, D.C., Almon, R.R. et al. Modeling Sex Differences in Anti-inflammatory Effects of Dexamethasone in Arthritic Rats. Pharm Res 35, 203 (2018). https://doi.org/10.1007/s11095-018-2483-5

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  • DOI: https://doi.org/10.1007/s11095-018-2483-5

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