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Research ArticleMetabolism, Transport, and Pharmacogenomics

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part II: Sex Differences in Methylprednisolone Pharmacokinetics and Corticosterone Suppression

Vivaswath S. Ayyar, Debra C. DuBois, Toshimichi Nakamura, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics August 2019, 370 (2) 327-336; DOI: https://doi.org/10.1124/jpet.119.257527
Vivaswath S. Ayyar
Departments of Pharmaceutical Sciences (V.S.A., D.C.D., T.N., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York; and DMPK Research Department, Teijin Institute for Biomedical Research, Teijin Pharma, Tokyo, Japan (T.N.)
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Debra C. DuBois
Departments of Pharmaceutical Sciences (V.S.A., D.C.D., T.N., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York; and DMPK Research Department, Teijin Institute for Biomedical Research, Teijin Pharma, Tokyo, Japan (T.N.)
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Toshimichi Nakamura
Departments of Pharmaceutical Sciences (V.S.A., D.C.D., T.N., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York; and DMPK Research Department, Teijin Institute for Biomedical Research, Teijin Pharma, Tokyo, Japan (T.N.)
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Richard R. Almon
Departments of Pharmaceutical Sciences (V.S.A., D.C.D., T.N., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York; and DMPK Research Department, Teijin Institute for Biomedical Research, Teijin Pharma, Tokyo, Japan (T.N.)
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William J. Jusko
Departments of Pharmaceutical Sciences (V.S.A., D.C.D., T.N., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York; and DMPK Research Department, Teijin Institute for Biomedical Research, Teijin Pharma, Tokyo, Japan (T.N.)
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    Fig. 1.

    Schematic of the mPBPK/PD model for PK and effects of MPL on adrenal suppression in male and female rats. Parameters are defined in the text and in Tables 2 and 3. The model is described by eqs. 2–11.

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    Fig. 2.

    PK profiles of MPL (50 mg/kg IM) in (A) plasma of 7-week-old (Cohort 4) and 11-week-old (Cohort 5) male rats; (B) plasma of estrus females (Cohort 1), proestrus females (Cohort 2), noncycling (NC) females (Cohort 3), and males (Cohorts 4 and 5); (C) plasma of females (Cohorts 1–3) and males (Cohorts 4 and 5); and (D) livers of females (Cohort 2) and males (Cohort 4). Symbols depict either replicate data from each animal (A) or mean observed data ± S.D. (B–D). Symbols are defined within the figure.

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    Fig. 3.

    Model fittings of the concentration–time profiles of total MPL in plasma (A) and liver (B) of male and female rats that received 50 mg/kg IM doses of MPL. Symbols depict mean observed data ± S.D. Solid lines represent model-fitting results for each sex. Symbols are defined within the figure.

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    Fig. 4.

    Model-based simulations of the PK profiles of MPL following 10 mg/kg (dashed line) and 50 mg/kg (solid line) IV doses in normal male rats. Triangles are low-dose data obtained from Jin and Jusko (2009), whereas open circles are high-dose data taken from Hazra et al. (2007b). Parameter values used in the simulations are listed in part in Table 2.

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    Fig. 5.

    Model fittings of plasma CST dynamics in estrus female rats (left), proestrus female rats (middle), and male rats (right) that received 50 mg/kg IM doses of MPL. Symbols depict mean observed data ± S.D. Solid lines represent model-fitting results for each group after MPL dosing, and broken line depicts simulated profile of CST rhythm in control animals. Dark (shaded) and light (unshaded) time periods are indicated.

Tables

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    TABLE 1

    PK parameters using NCA for plasma MPL in the study cohorts after intramuscular administration

    Experimental Group (n)λz (h−1)T1/2_λz (h)Cmax (ng/ml)AUC0-∞ (h × ng/ml)bCL/F (ml/h per kilogram)
    Cohort 1: estrus female (30)0.242.95348 ± 48810,489 ± 10544767 ± 479
    Cohort 2: proestrus female (39)0.272.63859 ± 7779142 ± 6465469 ± 386
    Cohort 3: noncycler female (20)0.203.43796 ± 1888735 ± 6015723 ± 394
    Cohort 4: male 7 wk (31)0.252.71470 ± 1092808 ± 16717,806 ± 1059
    Cohort 5: male 11 wk (23)0.262.61054 ± 942885 ± 31217,334 ± 1875
    All females0.242.94204 ± 3239751 ± 4825128 ± 252
    All males0.282.51174 ± 1942901 ± 18517,232 ± 1099
    • CL/F, clearance; T1/2, half-life.

    • a Values represent mean ± S.E.

    • ↵b AUC calculated using Bailer’s method for sparse (destructive) sampling.

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    TABLE 2

    PK parameter values for the mPBPK model of MPL

    ParameterDefinitionEstimate (% CV)
    FBioavailability0.214a
    FrFraction absorbed by ka10.725a
    ka1 (h−1)Absorption rate constant0.8 (8.8)b/4.1 (24.8)c
    ka2 (h−1)Absorption rate constant0.17 (17.3)
    CLEH (ml/h)Extrahepatic clearance347 (4.2)
    CLu,int,male (ml/h)Hepatic unbound intrinsic clearance (male)2987 (12.7)
    KP, hepPartition coefficient—liver12.6 (7.6)
    KP, PPT (muscle)Partition coefficient—poorly perfused tissue1.4d
    KP, RPT (lung)Partition coefficient—richly perfused tissue2.1d
    fu,pMPL fraction unbound in plasma0.4d
    • ↵a Parameter values fixed from Hazra et al. (2007b).

    • ↵b Male.

    • ↵c Female.

    • ↵d Fixed to in vitro estimates from Ayyar et al. (2019).

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    TABLE 3

    PD parameter estimates for plasma CST suppression by MPL

    ParameterDefinitionEstimate (% CV)
    Circadian Rhythm Parameters for CST
    T (h)Biorhythmic period24a,b,c
    a0Fourier coefficient115.7a,b/254.4b
    a1−120.9a,b/−168.7b
    a238.8a,b/56.9b
    b1−41.1a,b/−95.6b
    b21.6a,b/29.1b
    Pharmacodynamic Parameters
    kdeg,CST (h−1)Loss rate constant for CST1.38 (12.6)a,b,c
    τ (h)Time to CSTstress0.34 (12.8)a,b,c
    CSTstress (ng/ml)Maximal CST due to stress535 (18.0)a/1292 (13.3)b/1397 (12.9)c
    IC50,CST (ng/ml)Half-maximal inhibition concentration3.4 (47.6)a/41.6 (48.0)b/12.9 (45.6)c
    • ↵a Male.

    • ↵b Estrus female.

    • ↵c Proestrus female.

Additional Files

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      Supplemental model.

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Journal of Pharmacology and Experimental Therapeutics: 370 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 370, Issue 2
1 Aug 2019
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Minimal PBPK-PD Modeling of Sex Differences in Methylprednisolone

Vivaswath S. Ayyar, Debra C. DuBois, Toshimichi Nakamura, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics August 1, 2019, 370 (2) 327-336; DOI: https://doi.org/10.1124/jpet.119.257527

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Minimal PBPK-PD Modeling of Sex Differences in Methylprednisolone

Vivaswath S. Ayyar, Debra C. DuBois, Toshimichi Nakamura, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics August 1, 2019, 370 (2) 327-336; DOI: https://doi.org/10.1124/jpet.119.257527
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