BOSENTAN, A NEW ENDOTHELIN RECEPTOR ANTAGONIST - PREDICTION OF THE SYSTEMIC PLASMA-CLEARANCE IN MAN FROM COMBINED IN-VIVO AND IN-VITRO DATA

1. Accurately predicting the kinetics in man greatly improves the desi gn of the phase I clinical studies. This was particularly crucial in t he case of bosentan, a new endothelin receptor antagonist, as very lar ge interspecies differences in systemic clearance were observed in the animal species investigated, namely from 1.5 ml/min/kg in the dog up to 70 ml/min/kg for the rabbit. 2. Bosentan was shown to be metabolize d by the hepatic cytochrome P450, therefore the rate of metabolism was investigated in vitro in liver microsomes and hepatocytes, across the species which had been tested in vivo. The same rank-order of metabol ism was found for the laboratory animals both in vitro and in vivo, an d hepatocytes appeared to be more representative of the in vivo situat ion than liver microsomes. The in vitro clearance in human hepatocytes was very close to that observed in dog hepatocytes. 3. A plasma clear ance for bosentan in man of 1-2 ml/min/kg was predicted by combining t he in vivo and in vitro data from a few animal species with the in vit ro data in man. This expectation was subsequently found to agree reaso nably well with the plasma clearance observed in healthy volunteers: c a 2 ml/min/kg. Integrating this prediction into the design of the firs t clinical protocols substantially improved the quality of the human p harmacokinetic data obtained.