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lations, to come up with a reasonable dose range. The other population can be studied at a later date. In fact, later studies to establish dose in special populations are very important. The FDA has mandated the inclusion of women in studies because they have been woefully underrepresented previously. A drug's effect in the black population or oriental population is also very important to discern and clearly there are racial differences in drug handling that can significantly affect the appropriate dose for a given population. As important, is the consideration of the disease state in the different racial groups. While hypertension is very prevalent in the black population, they usually manifest low renin hypertension and ACE inhibitors do not seem to be very useful in treating hypertension in blacks. This is not a major problem for the effective treatment of hypertension since alternative agents can be used in the black population. However, the problem is certainly an important consideration in terms of heart failure therapy. Heart failure is common in the black population, often as an end result of hypertensive cardiovascular disease. Whether ACE inhibitors have the same salutary effects, reducing mortality in the black population as it does in the general heart-failure group, has still not been clearly determined. Establishing dose and also utility of an agent in special populations is a matter that needs more attention. |
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What we are usually faced with early on is the need for a dose to initiate clinical studies. Even the most rudimentary of Phase I and II studies need a starting dose. For first-time studies in man, perhaps exploring the lower estimated dose range from preclinical studies is optimum. Further dose escalation following a logarthythmic approach may then be appropriate. All exposures in man should be based on milligram-per-kilogram exposures in prior animal models with some previous experience in that model's correspondence to the human condition. Incremental dose escalation is helpful to give some guidance, but time/action relationships and accumulation of drug combine to limit this technique. Establishing a dose in fixed combination is especially important and the FDA does require a synergistic effect to be established for the combined compound A and B as contrasted to either A or B alone at the peak of their dose response curve. |
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Dose escalation studies to toxicity are to be avoided. The IRBs and clinical common sense are not going to tolerate dangerous dose escalations. Careful exploration, even to what appears to be astronomical doses, is appropriate in controlled situations when the lower doses have been explored. A log exploration is to be recommended as the most appropriate choice when possible exploration of 0.1, 1, and 10 is better than the more usual 1-, 5-, and 10-dose titration approach. If no toxicity is observed in man or if it is mild and none observed in animals at higher doses, the effects of higher doses should then be explored in man. If 10 is tolerated, then perhaps 50 and 100 should be explored to further determine the concentration-effect curve. As one creeps up to the |
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