Assessment of Bioavailability using Pharmacological Responses.

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  • MIYAZAKI Makoto
    Department of Pharmaceutics, Osaka University of Pharmaceutical Sciences

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  • 薬理効果を指標としたＢｉｏａｖａｉｌａｂｉｌｉｔｙの評価

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Abstract

A novel method of assessing the extent of bioavailability (EBA) of drugs from pharmacological data was presented. Disopyramide, a class Ia antiarrhythmic agent, arginine-vasopressin (AVP), a nona-peptide hormone, and human insulin were used as the model drugs. The prolongation of QT interval, the anti-diuretic response and the hypoglycemic response were used as the pharmacological indexes of disopyramide, AVP and human insulin, respectively. After intra-vascular administration (I.V. bolus, short-term infusion or long-term infusion) of drugs to the rats, the relationship between blood (plasma or serum) concentrations and their pharmacological responses were described on the basis of an integrated pharmacokinetic-pharmacodynamic (PK-PD) model. A sigmoid Emax model or a linear model was applied to describe the drugreceptor interaction. Pharmacological responses after intra-vascular administration of these 3 drugs were reasonably described by the PK-PD model. Since PK-PD relationship after oral administration was assumed to be identical with that after intra-vascular administration, the PK-PD model obtained under I.V. bolus study was used to assess the extent of oral bioavailability (EBAp.o.). The EBAp.o. values, estimated from pharmacological effects after oral administration of disopyramide (25 mg/kg to 100 mg/kg) was 96.6% and this value were almost identical with the actual EBAp.o. values (57.6 to 99.4%). However, the EBAp.o. values, estimated from pharmacological effects after oral administration of AVP were significantly underestimated the actual EBAp.o. values. While, the EBA values, estimated from pharmacological effects after subcutaneous administration of human insulin using an osmotic mini-pump were significantly overestimated the actual EBA values. These results indicated that PK-PD relationship was significantly influenced by intra-vascular input rate of drugs, especially the peptide drugs. Then we re-estimated the EBA values using the PK-PD model constructed under the long-term infusion study, and obtained reasonable results. From these results, we concluded that the EBA was reasonably predicted by a PK-PD model, provided that appropriate pharmacological effects and appropriate intra-vascular dosing rate as a reference formulation are available. The method may be the alternative to methods based on plasma concentrations, when drug concentration cannot be measured and when appropriate pharmacological data are available.

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