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at the highest dose levels [11]. In my own clinical practice, with a number of competing Phase I protocols, patients often elect to enter those studies that are at or are close to MTD and will be more reluctant to go for entry dose levels. We urgently require methods of dose selection that minimise patient numbers at low doses and accelerate escalation to the MTD. |
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The choice of schedule of drug administration may be crucial for a number of reasons. A drug may have different levels of activity with different administration, one example being Etoposide (VP-16) [12]. It is theoretically possible that a drug may be incorrectly abandoned as inactive when a more appropriate schedule would reveal anticancer action. Toxicity may be quantitatively or qualitatively different with alteration of schedule; such as with taxotere, where non-hematological toxicity (mucositis) was clearly schedule dependent [13]. This may also lead to erroneous decisions on the future development of the drug. Even when a drug is active and toxicity acceptable with one schedule in early clinical trials, this may not be the optimal schedule, and it may take many years to investigate this point in clinical practice [14] with grave consequences for individuals not exposed to the optimal schedule in the meantime. |
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The relevance of animal data to patients with respect to schedule is questionable. Occasionally data do exist on mechanism of action, cycle specificity, or pharmacokinetics that will argue for particular administration parameters. Pragmatic and financial constraints limit our ability to explore very prolonged infusions, 34 times daily chronic IV, and other inconvenient schedules. All too often the empirical approach will prevail with IV bolus dosing once every 3 weeks as the initial selected schedule. |
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It is possible that a more detailed preclinical investigation of pharmacokinetics and pharmacodynamics, or development of assay systems that measure the biological effect of the drug on its target, could help to guide our choice of schedule. However, there is an understandable reluctance on the part of pharmaceutical companies to initiate even more preclinical studies for an agent with a high risk of not becoming a product. In addition, clinicians are so desperate to try any new agent in this patient population that they will accept much more limited preclinical data than is customary for noncytotoxics and will push for the most convenient schedule for patients, sometimes to the exclusion of clear scientific data that an alternative schedule is likely to be more active. |
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D. Dose Escalation Scheme |
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Again, in the absence of good predictive animal model systems, dose escalation is often based on empirical formulae, the most widely used being a modified |
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