Pharmacokinetics (animals/man)

Figure 1 Typical drug development scheme (simplified).

be tested in these followup measurements: the racemic mixture or each of the component enantiomers? Depending on the chemistry of what is now a drug candidate, the synthesis/resolution of the individual enantiomers may be somewhat difficult and thus time-consuming, thereby delaying further testing. Since time is a critical resource in drug development and, at this stage, sufficient data are required for a decision on whether or not toxicity studies should be initiated, delays in synthesis of sufficient amounts of the pure enantiomers may be contra indicated. After all, should the racemate not be sufficiently active in the subsequent biological tests, the candidate drug would not be further evaluated. The earlier such information is available, the more efficient the overall process. However, should the drug product still demonstrate desirable activity, the next step would be initiation of the safety evaluation studies. Again, a critical decision is required. What should be tested? It would certainly be desirable to know whether the desired pharmacological activity resides in a single enantiomer (which is more common), or whether both enantiomers are required (rare). Such information may indeed be available as a result of synthesis of sufficient amounts of enantiomers on a laboratory scale. However, should activity be due to a single enantiomer, such small-scale synthesis may not be adequate for the large amounts required to initiate toxicological evaluations. Numerous techniques are emerging for the large-scale preparation of single enantiomers (2) and the fact that such entities need to be rapidly available for appropriate testing has provided the stimulus for the explosive development of efficient synthetic techniques over the past few years. Ideally, only the pharmacologically active moiety should be tested in the toxicity studies, so that subsequent evaluation of the data is not subject to potentially complex interpretations.

The IND (investigational new drug) application is submitted to regulatory agencies upon completion of sufficient animal safety and efficacy studies to support initiation of clinical trials. Should the sponsor decide to perform the early clinical studies with the racemic mixture, such a decision would have to be appropriately justified to the respective regulatory authority. The justification could include life-threatening indication, novel therapeutic approach, or difficulty in large-scale synthesis of the single enantiomer. Occasionally, the drug company may wish to obtain early positive clinical efficacy data before committing resources to follow up with the active enantiomer. It is appreciated that the later the decision is delayed as to whether to develop the racemate or a single enantiomer, the greater the "gamble" the sponsor is making insofar that tests made with the racemate may have to be repeated with the single stereoisomer.


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