Prediction of Drug Terminal Half-Life and Terminal Volume of Distribution After Intravenous Dosing Based on Drug Clearance, Steady-State Volume of Distribution, and Physiological Parameters of the Body

The steady state, Vss, terminal volume of distribution, Vβ, and the terminal half-life, t1/2, are commonly obtained from the drug plasma concentration-time profile, Cp(t), following intravenous dosing. Unlike Vss that can be calculated based on the physicochemical properties of drugs considering the equilibrium partitioning between plasma and organ tissues, t1/2 and Vβ cannot be calculated that way because they depend on the rates of drug transfer between blood and tissues. Considering the physiological pharmacokinetic model pertinent to the terminal phase of drug elimination, a novel equation that calculates t1/2 (and consequently Vβ) was derived. It turns out that Vss, the total body clearance, Cl, equilibrium blood-plasma concentration ratio, r; and the physiological parameters of the body such as cardiac output, and blood and tissue volumes are sufficient for determination of terminal kinetics. Calculation of t1/2 by the obtained equation appears to be in good agreement with the experimentally observed vales of this parameter in pharmacokinetic studies in rat, monkey, dog, and human. The equation for the determination of the pre-exponent of the terminal phase of Cp(t) is also found. The obtained equation allows to predict t1/2 in human assuming that Vss and Cl were either obtained by allometric scaling or, respectively, calculated in silico or based on in vitro drug stability measurements. For compounds that have high clearance, the derived equation may be applied to calculate r just using the routine data on Cl, Vss, and t1/2, rather than doing the in vitro assay to measure this parameter.