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

Abstract

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC₅₀/SC₅₀ to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC₅₀), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

Keywords: Adrenal suppression; Betamethasone; Cell trafficking; Dexamethasone; Pharmacodynamics; Pharmacokinetics; Population modeling.

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

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 5^th 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

Fig. 3

Model for plasma cortisol (Cort) produced by the adrenal gland that is subject to the circadian rhythm (k_in(t)) and by another source at a constant rate k_in0. 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 I_max model. Both I_max and IC₅₀ are drug specific (DEX, BET). Symbols are further defined in Table 1

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

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

Fig. 6

Basophil model where cells are released to the circulation from a precursor pool at the first-order rate k_p and exit the circulation at the first-order rate k_outBASO. The precursor pool for basophils is replenished at the zero-order rate k_inP. Corticosteroids inhibit the transfer of basophils from the precursor to the circulation. The inhibition (I_maxBASO, IC_50BASO) will result in a temporal decrease of BASO followed by a rebound. Symbols are further defined in Table 2

Fig. 7

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

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

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 (k_inANC(t)). The neutrophil production is stimulated by corticosteroids (C(t)). The stimulation obeys the S_max model. Both S_maxANC and SC_50ANC are drug-specific (DEX, BET). Neutrophils are removed from the blood at a first-order rate k_outC. Symbols are further defined in Table 3

Fig. 10

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

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

Fig. 12

T-helper cell model where cells (TH) are released from extravascular tissues to the blood at the zero-order rate (k_inTH) that is subjected to the circadian rhythm due to the cortisol (CORT(t)) inhibition (IC_50C). The TH production is inhibited by corticosteroids (C(t), IC_50TH). TH are removed from blood at the first-order rate k_be. Symbols are further defined in Table 4

Fig. 13

Simulated expected T-helper cell absolute counts following administration of 6 mg of indicated corticosteroids. Continuous lines depict IM and dashed lines PO routes

Fig. 14

Visual predictive check plots for T-cytotoxic cells 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

Fig. 15

T-cytotoxic cell model where cells (TC) are released from the extravascular tissues to the blood at the zero-order rate (k_inTC) that is subjected to the circadian rhythm due to the cortisol (CORT(t)) inhibition (IC_50CTC). The TC production is inhibited by corticosteroids (C(t), IC_50TC) and removed from blood at the first-order rate k_beTC. Symbols are further defined in Table 5

Fig. 16

Simulated expected T-cytotoxic cell absolute counts following administration of 6 mg of indicated corticosteroids. Continuous lines indicate IM and dashed lines PO routes

Fig. 17

Visual predictive check plots for glucose plasma concentrations 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

Fig. 18

Glucose model where glucose in plasma (GLUC) is produced at the zero-order rate (k_inG) and removed at the first-order rate (k_outG). Corticosteroids stimulate k_inG according to the E_max (S_maxG, SC_50G). Food intake is modeled as a bolus dose of 75 g of glucose into the gut that is absorbed at the first-order rate k_aGL with bioavailability F_GL

Fig. 19

Simulated expected glucose plasma concentrations following administration of 6 mg of indicated corticosteroids. Continuous lines indicate IM and dashed lines PO routes

Fig. 20

Comparison of individual estimates of sensitivity parameters IC₅₀/SC₅₀ for indicated responses for 33 subjects who received both DEX and BET. The bold lines indicate the geometric means. Specific mean and SD values are listed in Table 7