|
|
|
|
|
|
|
The introduction of the measurement of drug levels during pivotal safety studies undertaken to GLP standards means that much of the important and useful animal biodisposition data is now available to design the studies and interpret and extrapolate the data to humans. Indeed, when we examine the other preclinical studies that have been undertaken in the past, we must question their relevance (Table 2). Recently, Warrender [57,58] undertook a survey of more than 80 companies in Japan, Europe and North America asking when and what preclinical ADME were undertaken. The results make for interesting reading. Certain studies such as enterohepatic recirculation (particularly in Europe), milk uptake, biliary cannulation (in Europe and the USA), induction and inhibition studies, pregnancy kinetics in nonrodent teratology species, and kinetics in special animal populations, and multiple dose balance studies (mostly in Japan), are all undertaken after the drug has been given to man for the first time but prior to marketing approval (Figure 6). Clearly these studies can provide little information to help the decision to go into man for the first time. Unless there is a particular need, as suggested by some specific toxicity, the fact that they are often undertaken at the end of drug development suggests that they are only completed as part of the checklist of regulatory requirements and not necessarily for any justifiable scientific necessity. For example, biliary circulation in rodents occurs with drugs with relatively low molecular weights (~ 250 MW) but, in man, rarely occurs for compounds with an MW lower than 500 and direct gastric secretion is probably a more important elimination route. Rarely is this an important issue in clinical pharmacokinetics. Milk transfer studies undertaken in animals cannot be meaningfully extrapolated to human infants because of differences in the frequency in weaning and the fat and protein composition. Approximations of likely infant exposure can be obtained from simple in vitro equilibrium dialysis of milk and plasma and a knowledge of the Pka of the compound [2]. Similar considerations hold for the implicit requirement for information on the kinetics in pregnant animals. Unless there |
|
|
|
|
| Table 2 What Information Does Toxicokinetics Provide? | | 1. Design of safety studies | | 2. Interspecies differences in kinetics | | 3. Absorption | | 4. Linearity (dose, induction, inhibition) | | 5. Accumulation | | 6. Exposure and safety margins for humans | | 7. PK-PD relationships |
|
|
|