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higher doses, caution is certainly needed. I was involved in one study where we used doses of an oral nitrate preparation of 30, 60, 120, and then up to 240 mg. The 240 mg was looked upon in horror by most investigators and they were correct if that was the starting dose. Giving the 240 mg without previous titration would result in a lot of adverse side effects. However, the lower doses were explored first, then to get to that higher dose, there was a two or three step titration. This enhanced the safety while still exploring the full dose-response range of the agent. |
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Perhaps the most dependable approach is a parallel design with escalating dose in each group. Group comparisons are best and a dose can be established without having carryover effect from the previous dose and missing the peak action of the previous dose in the patient. But these are just guidelines to the selection process and by the very nature are simplifications. Each situation presents unique problems to consider and there is no one dose-finding technique for all circumstances. |
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Let us consider two situations that indeed impact on drug development. If we are developing an antiarrhythmic agent, what endpoint do we use to establish dose? At times PVCs have been employed although even for the Ia or Ic agents, the dose of PVC suppression may not correlate with the dose for VT suppression at programmed electrical stimulation (PES) and neither may correlate with a dose that reduces mortality over a six-month to one-year follow-up after electrophysiologic testing. The type-III agent is even more problematic since a dose at EP testing and the results at EP testing, for that matter, may or may not correlate with outcome. VPC suppression with a type-III agent would be even less likely to correlate with outcome. Using prolongation of the Action Potential Duration (APD) employing a monophasic action potential catheter (FRANZ catheter) may be the most promising technique with the type-III Vaughan Williams' agents since action potential prolongation is inherent in the pharmacodynamic action of the drug. Thus, dose should be tied to the critical marker of the electrophysiologic mechanism of action of the drug, which in this case is action potential duration prolongation. |
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Another approach that might improve results to obtain serum concentrations and correlating these to drug action. Serum concentration varies less and this is a potential advantage (at least this is the claim of Pk/Pd proponents). However, the correlation of serum concentration to drug action is not well established in most areas in cardiovascular therapeutics and, in fact, one can generalize to most areas of therapeutics. In cardiology, PK/PD relationships are virtually nonexistent. Serum concentrations of beta blockers do not correlate with drug action. Levels of antiarrhythmic agents do not really correlate with outcome. Myerburg and Associates once reported that if one obtains a minimal defined concentration with an antiarrhythmic agent (mostly type Is), patients had a better outcome than if a lower concentration was obtained (2). |
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