Calcium channel blockers are often co-administered with digoxin because of a high frequency of hypertension and cardiac arrhythmia in patients undergoing hemodialysis. There have been several reports about the interactions between calcium channel blockers and digoxin mediated by P-glycoprotein in subjects with normal renal function, but few reports in patients undergoing hemodialysis. In this report, the interactions between digoxin and calcium channel blockers in patients undergoing hemodialysis were investigated. The serum digoxin concentration/digoxin dosage per week per body weight ratio (C/D ratio) was calculated, and the C/D ratio before and after co-administration of Ca channel blockers (verapamil, nifedipine, amlodipine) was compared. The rate of change in C/D ratio of digoxin was calculated, and the relationship between the rate of change in the C/D ratio of digoxin and the dose of Ca channel blocker per body weight was investigated. The C/D ratio of digoxin was significantly higher after co-administration of verapamil than that without verapamil (P<0.05), but there was no significant difference between co-administration of nifedipine or amlodipine and without co-administration. There was a significant correlation between the rate of change in the C/D ratio of digoxin before and after co-administration of verapamil and the dose of verapamil per body weight (r=0.909, P<0.001). It was suggested that the magnitude of the drug interaction between digoxin and verapamil was dependent on the verapamil dose per body weight.
Based on these results, when a high dose of verapamil is co-administered, it appears that adequate precautions are needed regarding digoxin intoxication even in patients undergoing hemodialysis.

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On the basis of the notice of the ICH-E5 guideline, it has become evident that the similarity between the characteristics in the relationship (PK/PD) of pharmacokinetics (PK) and efficacy or safety (PD) is the important factor for bridging to be established. Due to this, attention has been recently paid to population pharmacokinetics (PPK) and PK/PD. Hence, we have investigated the current research status in PPK and PK/PD in actual drug development processes and in relation to bridging. The subject of the investigation was the 137 NDA review data disclosed on internet from September of 1999 to March of 2003 by the Ministry of Welfare and Labor. In addition, in order to make a comparison with the domestic cases, we investigated 67 cases among the NDA review data of 2001 by the FDA. As a result of the investigation, the rates of implementation of PPK and PK/PD research in Japan were low, both around 5%. In foreign countries, that of PPK was 14.9% and that of PK/PD 38.8%, which were both higher than those of Japan. Among the 9 drugs, which had been approved in Japan by utilizing bridging studies, there was only one drug approved by use of PPK research, 4 drugs by PK/PD research, and one drug by PK/PD study that was established as a bridging study. These results emphasize that PPK and PK/PD research have not effectively functioned in drug developmen to date.

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