Cefclidin

Prediction of human clearance plays a critical role in early drug discovery and development. However, there is no consensus on the most appropriate method to gather such data. A variety of in vivo and in vitro methods exist and a comparison of in vitro data from a standard set of compounds has been called for. This paper compares the predictive capacity of human liver microsomes and single-species scaling (SSS) from rat and non-human primate for a standard set of compounds representing marketed drugs. The results enable a framework to be proposed wherein compounds are selected using in vitro methods alone or in vitro methods combined with SSS in the rat. Further investigation of this framework has the potential to increase the efficiency of drug discovery and reduce animal use.

Identifying any extrahepatic excretion phenomenon in preclinical species is crucial for an accurate prediction of the pharmacokinetics in man. This understanding is particularly key for drugs with a small volume of distribution, because they require an especially low total clearance to be suitable for a once-a-day dosing regimen in man. In this study, three animal scaling techniques were applied for the prediction of the human renal clearance of 36 diverse drugs that show active secretion or net reabsorption: 1) direct correlations between renal clearance in man and each of the two main preclinical species (rat and dog); 2) simple allometry; and 3) Mahmood's renal clearance scaling method. The results show clearly that the predictions to man for the methods are improved significantly when corrections are made for species differences in plasma protein binding. Overall, the most accurate predictions were obtained by using a direct correlation with the dog renal clearance after correcting for differences in plasma protein binding and kidney blood flow (r² = 0.84), where predictions, on average, were within 2-fold of the observed renal clearance values in human.