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Background: Increasing oral doses of mibefradil (10 to 320 mg) decrease its apparent oral clearance; however, intravenous doses up to 80 mg do not reduce its systemic clearance. This study aimed to understand the mechanisms underlying the zero-order kinetics of mibefradil., Methods: A group of 10 normotensive volunteers received 50 mg/day oral mibefradil for 8 days and, on days 1 and 8, 5 mg deuterated mibefradil by infusion. Ten additional volunteers observed the same protocol with a daily oral dose of 100 mg mibefradil. Serial blood samples were withdrawn, and mibefradil plasma concentrations were assayed by liquid chromatography-mass spectrometry. Blood pressure and heart rate were measured for 4 hours, and an ECG was performed 2 hours after drug administration., Results: Repeated oral administration of 50 mg mibefradil generated zero-order kinetics secondary to a decrease in mibefradil systemic clearance. Compared with the 50-mg dose, single and repeated oral doses of 100 mg further decreased mibefradil clearance. Mibefradil bioavailability was not affected by increasing mibefradil doses. Mean diastolic blood pressure was decreased by single and repeated doses of 100 mg to the same extent. Repeated doses of 100 mg reduced heart rate and prolonged the PR and QTc, changes that were associated with mibefradil plasma concentrations., Conclusions: Repeated doses of 50 mg or doses of 100 mg mibefradil generated zero-order kinetics secondary to a decrease in hepatic extraction of the drug. Zero-order kinetics did not affect the response-concentration relationship of mibefradil.

Although transdermal nicotine patches have been studied extensively under recommended conditions, the present studies were designed to assess the nicotine plasma levels and the safety of transdermal nicotine patches in smokers undergoing situations suspected to result in increased nicotine plasma levels. The first study examined the effects of increasing nicotine intake through sequential administration of a nicotine patch (day 2), a patch followed by consumption of nicotine gum (day 3), and a patch followed by gum consumption and cigarette smoking (day 4). In this study, nicotine plasma levels increased transiently after the addition of each nicotine source. Mean areas under the concentration-time curves from 0 to 24 hours (AUC0-24) for nicotine were 453 +/- 120 ng.hr/mL (day 2), 489 +/- 143 ng.hr/mL (day 3), and 485 +/- 143 ng.hr/mL (day 4). The second study evaluated the effects of physical exercise on the kinetics and the safety of two different types of nicotine transdermal devices: Nicoderm and Habitrol. The mean delivered dose of nicotine was higher with Nicoderm compared with Habitrol, and the two products were not considered to be bioequivalent. During a 20-minute exercise period, nicotine plasma levels increased by 13 +/- 9% for Nicoderm and 30 +/- 20% for Habitrol. This increase in nicotine plasma levels was probably related to the exercise-induced increase in peripheral circulation at the patch site. Results from both studies indicate a clinically nonsignificant increase in blood pressure and heart rate after the administration of nicotine. After exercise, subjects taking Habitrol tended to have a higher incidence of adverse events compared with baseline values. Safety profiles remained acceptable in both studies despite the increases in nicotine plasma levels. It was concluded that both superimposed nicotine sources and physical exertion result in short-lived plasma nicotine elevations and temporarily increase nicotine pharmacodynamic parameters without increased risk to the volunteers.

The authors compared, in a double-blind, randomized, crossover study in 13 healthy adult volunteers, the single- and multiple-dose pharmacokinetics, relative bioavailability, and side effects of a new oral sustained-release formulation of codeine (SRC) containing 150 mg codeine base, with oral immediate-release codeine phosphate (IRC). Sustained-release codeine was given at a dose of 150 mg every 12 hours for 5 doses; IRC was given at a dose of 60 mg (2 x 30 mg) every 4 hours for the first 3 doses, and 30 mg every 4 hours thereafter for 12 doses. Plasma codeine levels were determined using a sensitive and specific high-performance liquid chromatography method and corrected for dose administered and codeine base equivalent. Mean values for single-dose pharmacokinetic parameters for SRC and IRC, respectively, were: Cmax of 217.8 and 138.8 ng/mL; Tmax of 2.3 and 1.1 hours; AUC0-inf of 1202.3 and 1262.4 ng.mL-1.hour-1; and t1/2el of 2.6 hours for both formulations. Their respective mean steady-state pharmacokinetic parameters were: Cmax of 263.8 and 222.9 ng/mL; Tmax of 3.2 and 1.1 hours; AUC0-12h of 1576.4 and 1379.1 ng.mL-1.hour-1; and t1/2el of 2.8 and 2.3 hours. These results indicate comparable bioavailability between both formulations with SRC providing delayed peak plasma levels. The sustained-release character of SRC can be explained by a delayed absorption, which is not limiting to drug elimination. Sustained-release codeine provides higher plasma codeine levels over a broader time interval and is expected to improve pain management.

Bioequivalence studies of drugs which are not systematically available must rely on the measure of the pharmacological response. Detection of a difference between two such preparations is often hampered by the need to include an elevated number of subjects. The number of subjects can be reduced whenever: (a) the characteristics of the subjects are well defined, (b) the selection of the baseline target effect is done rigorously, (c) the target effect can be quantified reliably, (d) the effect is measured when less variability is expected, e.g. at steady state, (e) the effect is measured repeatedly, and (f) when possible, the predicted maximal effect (Emax) and the concentration to elicit 50% of Emax are estimated. A simple equation has been derived to estimate the number of subjects needed in these bioequivalence studies.

The pharmacokinetics and pharmacodynamics of atracurium, a nondepolarizing neuromuscular blocking agent, were compared between morbidly obese patients and nonobese patients. Atracurium besylate (0.2 mg/kg) was administered intravenously as a bolus to patients who had received anesthesia. The force of contraction of the adductor pollicis was measured and plasma samples were collected for a 2-hour period. The concentrations of atracurium and its major end product, laudanosine, were determined by use of a chromatographic method. The pharmacokinetic-pharmacodynamic relationship was characterized by use of several models. No difference was observed between obese patients and nonobese patients in atracurium elimination half-life (19.8 +/- 0.7 versus 19.7 +/- 0.7 minutes), volume of distribution at steady state (8.6 +/- 0.7 versus 8.5 +/- 0.7 L), and total clearance (444 +/- 29 versus 404 +/- 25 ml/min). However, if values were expressed on a total body weight basis, there was a difference between obese and nonobese patients in the volume of distribution at steady state (0.067 versus 0.141 L/kg) and total clearance (3.5 +/- 0.2 versus 6.6 +/- 0.5 ml/min/kg). Although atracurium concentrations were consistently higher in obese patients than in nonobese patients, there was no difference in the time of recovery from neuromuscular blockade between the two groups. Consequently, the median effective concentration was higher in obese than in nonobese patients (470 +/- 46 versus 312 +/- 33 ng/ml).

Twenty-three adult patients with chronic pain due to cancer completed a double-blind, randomized, two-phase crossover trial comparing plasma morphine concentrations and analgesic efficacy of oral morphine sulfate solution (MSS) and controlled-release morphine sulfate tablets (MS Contin [MSC], Purdue Frederick, Inc., Toronto, Ontario, Canada). MS Contin was given every 12 hours to all patients except those whose daily morphine dose could not be equally divided into two 12-hour doses with the tablet strengths available. MSS was given every 4 hours. Patients received both of the test drugs for at least 5 days, and, on the final day of each phase, peripheral venous blood samples for morphine analysis were obtained. Eighteen patients received MSC every 12 hours, and five received it every 8 hours. The same total daily morphine dose was given in both phases. In the 18 patients who received MSC every 12 hours, the daily morphine dose was 183.9 +/- 140.0 mg (mean +/- SD). In this group, the mean area under the curve (AUC) with MSC was 443.6 +/- 348.4 ng/ml/hour, compared with 406.8 +/- 259.7 ng/ml/hour for MSS (P greater than 0.20). Mean maximum morphine concentrations (Cmax) for MSC and MSS were 67.9 +/- 42.1 and 58.8 +/- 30.3 ng/ml, respectively (P greater than 0.05). Mean minimum morphine concentrations (Cmin) were 17.0 +/- 17.7 and 18.3 +/- 15.0, respectively (P greater than 0.30). There was a significant difference (P less than 0.001) between the two drugs in time required to reach maximum morphine concentration (Tmax). Mean Tmax after MSC occurred at 3.6 +/- 2.3 hours. After MSS, it occurred at 1.3 +/- 0.4 hours. In the five patients who received MSC every 8 hours, the findings paralleled those in the principal group, with no significant differences between MSC and MSS in Cmax or Cmin and a highly significant difference between the two in Tmax. However, in this small group of patients, the AUC with MSC was significantly (P = 0.04) greater than that with MSS. All patients had very good pain control throughout the study and both formulations were well tolerated. There were no significant differences between MSC and MSS in pain scores or side effects. Under the conditions of this study there was no clinically significant difference in bioavailability between MSC and oral MSS. When given on a 12-hourly basis in individually titrated doses, the MSC provided therapeutic plasma morphine concentrations throughout the dosing interval.

A sensitive and specific gas chromatographic method using a nitrogen detector for the measurement of trimipramine plasma concentrations is described. This method was used to determine the relative bioavailability and some pharmacokinetic parameters of two formulations, tablets and capsules, in healthy volunteers. It was concluded the tablet and capsule formulations were pharmacokinetically equivalent.