Population analysis of PK/PD data for the dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg PO and IM dexamethasone phosphate (DEX-P), PO and IM betamethasone phosphate (BET-P), or an IM 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were given 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 bioavailability. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models. 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. This modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of the 5 commonly used dosage forms of DEX and BET in healthy women.
Upon completion, participants will appreciate that the betamethasone enantiomer has slower metabolism producing a longer half-life than dexamethasone. Betamethasone acetate exhibits very slow release persisting out to 14 days.
Upon, completion, participants will be amazed by the array of simple to complex indirect PD models needed to describe diverse corticosteroid effects onblood biomarkers. Capturing cortisol suppression is needed for several of these responses and models.
Upon completion, participants will appreciate that dexamethasone produces its effects at 'EC50' concentrations that are 1 to 3 times lower than for betamethasone.
Upon completion, participants will see that the faster kinetics of dexamethasone but greater pharmacodynamic sensitivity generally produces overall response time-courses that are similar to betamethasone.
Upon completion, participants will learn how these findings have implications for using these drugs to treat women at risk of preterm delivery and resultant respiratory distress syndrome in their neonates.