Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women

Figures

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  Fig. 1. Mean plasma concentrations of DEX and BET in study subjects following administration of a single dose 6 mg intramuscularly (upper panel) and orally (lower panel). Bars indicate standard deviations. The inset shows plasma concentrations during the first 6 h

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  Fig. 2. Visual predictive check plots for cortisol plasma concentrations following administration of a single IM and PO dose of dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), and phosphate/acetate mixture (BET-PA). Symbols represent observed plasma concentrations, continuous line is the median, and dashed lines are 5th and 95th percentiles of observed values. The shaded regions are model-predicted confidence intervals for these percentiles. The baselines are shown in both semi-log (left) and linear (right) scales. Other panels show results from Period I on the left and Period II on the right

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  Fig. 3. Model for plasma cortisol (Cort) produced by the adrenal gland that is subject to the circadian rhythm (kin(t)) and by another source at a constant rate kin0. Cortisol is eliminated from plasma at a first- order rate. Adrenal gland production is inhibited by corticosteroid plasma concentrations (C(t)). The inhibition follows the Imax model. Both Imax and IC50 are drug specific (DEX, BET). Symbols are further defined in Table 1

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  Fig. 4. Simulated expected cortisol plasma concentrations in linear (upper panel) and logarithmic (lower panel) scales versus time following administration of 6 mg of indicated corticosteroid. Continuous lines depict IM and dashed lines PO routes

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  Fig. 5. Visual predictive check plots for basophils following administration of a single IM and PO dose of DEX-P, BET-P, and BET-PA. Graphical features are the same as in Fig. 2

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  Fig. 6. Basophil model where cells are released to the circulation from a precursor pool at the first-order rate kp and exit the circulation at the first-order rate koutBASO. The precursor pool for basophils is replenished at the zero-order rate kinP. Corticosteroids inhibit the transfer of basophils from the precursor to the circulation. The inhibition (ImaxBASO, IC50BASO) will result in a temporal decrease of BASO followed by a rebound. Symbols are further defined in Table 2

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  Fig. 7. Simulated expected basophil absolute counts following administration of 6 mg of indicated corticosteroid. Continuous lines depict IM and dashed lines PO routes

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  Fig. 8. Visual predictive check plots for neutrophils following administration of single IM and PO doses of DEX-P, BET-P, and BET-PA. Graphical features are the same as in Fig. 2

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  Fig. 9. Neutrophil model where cells (ANC) are released from the bone marrow to the circulation at a rate that is subject to the circadian rhythm (kinANC(t)). The neutrophil production is stimulated by corticosteroids (C(t)). The stimulation obeys the Smax model. Both SmaxANC and SC50ANC are drug-specific (DEX, BET). Neutrophils are removed from the blood at a first-order rate koutC. Symbols are further defined in Table 3

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  Fig. 10. Simulated expected neutrophil absolute counts following administration of 6 mg of indicated corticosteroids. Continuous lines depict IM and dashed lines PO routes

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  Fig. 11. Visual predictive check plots for T-helper cells following administration of single IM and PO doses of DEX-P, BET-P, and BET-PA. Graphical features are the same as in Fig. 2

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  Fig. 12. T-helper cell model where cells (TH) are released from extravascular tissues to the blood at the zero-order rate (kinTH) that is subjected to the circadian rhythm due to the cortisol (CORT(t)) inhibition (IC50C). The TH production is inhibited by corticosteroids (C(t), IC50TH). TH are removed from blood at the first-order rate kbe. Symbols are further defined in Table 4