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The remifentanil dose-finding strategy was driven by predicting doses in healthy volunteers from animal PK/PD studies and predicting doses in clinical efficacy studies for patients undergoing anesthesia from healthy-volunteer PK/PD studies. Dynamic measurements in animals and human included rod-induced pain, minute ventilation, EEG spectral edge, visual analog, and psychomotor tests. Dynamic measures used in patient-efficacy studies included loss of consciousness time, incision response, major surgical response, and post-surgical spontaneous ventilation time and analgesia. Links between these responses and with other drugs of the same pharmacologic class (i.e., fentanyl, sufentanil, alfentanil) showed that remifentanil acted in a predictable fashion and met the initial design criteria. |
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The relationship between remifentanil blood concentration and EEG spectral edge in a healthy volunteer is shown in Figure 4 [9]. Dosing recommendations in patients are generally based on the results of the clinical efficacy studies. By confirming predictability in studies linking animals to humans and volunteers to patients, the development team was able to improve the dose recommendations by conducting several high-intensity PK/PD studies in various special populations using EEG spectral edge and minute ventilation as dynamic measures. Dosage considerations based upon patient age, gender, and the presence of hepatic disease are partially derived from a comparison of PK/PD outcome measures in these populations to those in healthy volunteers and recognizing the established link to the clinical outcome measures. This development program required close collaboration amongst the bioanalyst, preclinical pharmacologist, clinical pharmacologist, monitors, Phase II/III clinical staff, and academic anesthesiologists. |
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Problem 4: Pharmacokinetic drug interactions are often reported once a drug is marketed. This often stimulates a clinical and regulatory interest to consider dose label changes. When the interaction is thought to be potentially clinically insignificant, how should this be studied to determine the need for additional dosing recommendations? |
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The lead article in a major medical journal reported ranitidine increased blood ethanol levels by from 30.5 mg/dL to 40.9 mg/dL after an oral ethanol dose of 0.3 g/kg (about 1.5 12-oz beers). The authors concluded patients treated with the combination should be warned of possible functional impairment [10]. The legal limit for driving while intoxicated is either 80 or 100 mg/dL depending on the state. However, measurable physiologic or psychological changes can be detected at alcohol levels below these limits. Media and regulatory interest was heightened both in that the article was published on New Year's Day and that ranitidine is frequently taken to counteract the gastrointestinal upset associated with a hangover. |
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To address concern over this interaction, two studies were conducted. Having noted that the published study used only 7 subjects given one dose and that |
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