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Figure 3 shows the fit of the relationships between the day-4 GG211 lactone area under the blood curve and the nadir in both the absolute neutrophil and platelet counts using a sigmoidal Emax model [8]. From this type of information the development team was able to anticipate the maximally tolerated dose before it was achieved and adjust doses along with the clinical investigators. Other analyses of the data found that there was not a relationship between the pharmacodynamic effect and either prior treatment with other bone-marrow suppressing drugs or the clinical site. During the trial there was reason to believe that both factors were influencing response. |
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To achieve this benefit the company oncologist, pharmacokineticist, study monitor, and bioanalyst functioned as a coordinated team to plan the data flow and analysis. The partnership with the clinical sites included an open sharing of the information collected and analyzed centrally. Benefits gained from this style of Phase I study include sparing patients from unwanted toxicity, more efficiently selecting doses based upon information gained from prior doses, and possibly decreasing the time needed to conduct the study. The experience gained pointed to the need for electronic remote data-entry systems for clinical pharmacology studies. Collecting the information from the clinical sites was performed manually by the clinical research scientist. If the patient information in the case record form is accumulated and graphed electronically as it is collected from the patient, efficiency, productivity, and quality would increase. |
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Problem 3: When a target subpopulation (e.g., children, elderly, hepatic failure) is likely to need a different dose from the primary population due to either altered drug pharmacokinetics or dynamics, how should the dosing recommendation be developed? |
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Traditionally, dosage recommendations for special populations result from either a pharmacokinetic study when dynamic differences are considered unlikely or perhaps a clinical trial when the population is large, the drug's therapeutic index is low, and/or dynamic differences are suspected. When pharmacodynamic differences are considered more likely, dosage recommendations for these special populations may be delayed at the time a drug comes to the market due to the expense and time needed to conduct clinical trials. Performing a high intensity PK/PD study may allow dose recommendations to emerge earlier by indexing PK/PD findings to the dosing recommendation in the primary population. |
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Remifentanil is an esterase metabolized opioid drug with a very high clearance and short elimination half-life of about 510 minutes that is being developed for clinical anesthesia. The drug was designed to allow the anesthesiologist to dial in the desired anesthetic effect by changing the intravenous infusion rate. The objective was to minimize delays in achieving the desired pharmacodynamic effect by changing the infusion rate during surgery and to shorten the postoperative recovery period awaiting the anesthetic effect to dissipate. |
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