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| Table 4 Areas of Toxicokinetic and Drug Metabolism Support That Warrant Greater or Less Emphasis in Nonclinical Discovery and Development | | Greater emphasis | | | Discovery | | Metabolism | Pharmacokinetics | | Transport | Bioavailability screens | | Pharmacologic activity screens | | | Development | | Metabolism | Single- and oral-dose pharmacokinetics | | In vitro interaction studies | Dose proportionality | | Toxicokinetics | Bioavailability | | Toxicokinetics/toxicodynamics | Food effects | | Autoradiography |
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proportion of which has considerable pharmacokinetic and metabolism involvement. As described previously, this is a difficult period involving intensive collaboration between clinical, pharmacokinetics, and statistical scientists. The focus of these initial studies is almost exclusively on safety, but they also have an extensive pharmacokinetic component. |
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Phase 1 studies provide preliminary safety and pharmacokinetic data essential for further development of a compound into Phase 2 and Phase 3. This segment of the clinical development program is unlikely to change, as is the pharmacokinetic component, due to the critical nature of the studies conducted. The only major change that has already occurred is that dose escalation, whether during single-dose or multiple-dose studies, is becoming increasingly drug concentration dependent. This places considerable demands on pharmacokinetics departments in that it requires rapid analytical turnaround to support concentration guided dose escalation. These early studies provide the first opportunity to initiate a clinical pharmacokinetic-pharmacodynamic database, which can be expanded as additional Phase 2 and 3 studies are conducted. |
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Metabolism work-up in humans is generally not done during Phase 1, but is usually started during Phase 2, continuing into Phase 3. With rapidly evolving metabolism technology, this delay in conducting human metabolic studies is no longer justified. While it may be appropriate to delay human mass-balance studies until clinical Phase 2, there is no reason why an initial metabolism profile should not be obtained, both in urine and plasma during Phase 1 studies. This will provide a critical comparison between metabolism profiles in toxicology animal species and man and will thus give an early indication of the relevance of the toxicity data to humans that could lead to possible changes in toxicology or clinical programs. It will streamline the system. |
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