Estimation of Bioavailability of Salmon Calcitonin from the Hypocalcemic Effect in Rats (I): Pharmacokinetic-Pharmacodynamic Modeling Based on the Endogenous Ca Regulatory System

Abstract

The hypocalcemic effect of salmon calcitonin (sCT) after intravenous administration was explained on the basis of an integrated pharmacokinetic-pharmacodynamic (PK-PD) model with the endogenous Ca regulatory system in the rat. The pharmacokinetics of sCT described by a conventional two-compartment model showed the extremely rapid elimination of sCT from plasma (MRT; 6.86 min). The hypocalcemic effect of sCT reached a peak from 0.5 to 1.5 hrs after administration, and the peak time tended to prolong with increasing doses. This delay in pharmacological effect of sCT against plasma concentration may be a result of a summation of multiple actions of the endogenous Ca regulatory system including feedback control. The plasma Ca regulation system in the rat was investigated by i.v. bolus administration of calcium gluconate and/or endogenous (rat) calcitonin (rCT). Since non-linearity in the relationship between Ca and rCT concentrations in plasma was observed, we assumed that rCT was secreted in accordance with the plasma Ca level via an exponential function. The pharmacokinetics of rCT was represented as a linear one-compartment model. To link the rCT level with plasma Ca level, an additional effect compartment was required to explain the delay in onset and decline of the pharmacological effect. This Ca regulation model explained the observed Ca and rCT profiles in plasma after administration of Ca and/or rCT. The plasma Ca levels after administration of sCT could be well described by the present integrated model. This suggested the potential for prediction of plasma sCT concentration only from the hypocalcemic effect after extravascular administration of sCT, using this PK-PD model.