Pharmacokinetic, pharmacodynamic, and safety evaluation of an accelerated dose titration regimen of sotalol in healthy middle-aged subjects.

BACKGROUND: Current labeling recommends that therapy with sotalol be initiated in a monitored setting at 80 mg every 12 hours for 2 to 3 days, followed by 120 to 160 mg every 12 hours for at least 2 days before safety and efficacy can be ascertained and patients discharged. An accelerated titration regimen that shortens hospital stay without compromising patient safety would improve the usefulness of the drug. Although such regimens have been used by clinicians, they have not been formally evaluated. METHODS: Healthy, middle-aged sedentary men and women received sotalol in a double-blind, two-way crossover study with a 2-week washout phase to evaluate an accelerated titration regimen--placebo every 6 hours for four doses, followed by 80 mg sotalol every 6 hours for four doses, then 160 mg sotalol every 12 hours for nine doses--and compare it with the standard titration--placebo alternating with 80 mg sotalol every 6 hours for eight doses, followed by 160 mg sotalol every 12 hours for nine doses. QT intervals, RR intervals, and sotalol concentrations in plasma were measured at specific times throughout the study and during washout in a similar fashion for both regimens. RESULTS: Thirty-four subjects completed both regimens. The target prolongation of QTc (90% of the value achieved at steady state) was achieved 22 1/2 hours sooner with the accelerated titration regimen (P = .0003). There were no cardiovascular adverse events during either loading phase. At no time during the accelerated titration regimen did the sotalol concentrations in plasma or the QTc or RR interval prolongation exceed the values eventually achieved at steady state. The relationship between sotalol concentration and QTc was linear and independent of the regimen. CONCLUSION: The accelerated titration regimen for sotalol can shorten the time to attain the dosage usually required to effectively control arrhythmias, without excessive QT prolongation and the associated increased risk of torsades de pointes. The hospital stay of patients in whom antiarrhythmic therapy with sotalol is initiated can be shortened by 1 day if this accelerated titration regimen is used.

Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: a population approach.

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2 or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50 of 9.22 micrograms/ml. This IC50 is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 micrograms/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.

The electrocardiographic effects of cetirizine in normal subjects.

OBJECTIVE: To establish whether the antihistamine cetirizine has the potential to prolong the QTc interval in normal volunteers at up to six times the usual recommended dose. METHODS: Twenty-five healthy volunteers were studied in a prospective, double-blind crossover design conducted on inpatients in a Clinical Research Center. The primary end point of the study was QTc prolongation on the surface electrocardiogram (ECG). Plasma concentrations of cetirizine were also measured for pharmacokinetic analysis. The end point for the pharmacokinetic analysis was the dose/area under the concentration-time curve (apparent clearance of an oral dose). The subjects received the following three treatments in random sequence: placebo, 20 mg/day cetirizine, and 60 mg/day cetirizine for 7 consecutive days. A series of baseline ECGs was recorded over 2 days before each treatment, while the subject receiving placebo. ECG effects of the treatments were then compared with the baseline ECGs. RESULTS: Analysis of variance showed no difference between the treatment groups (placebo, 20 mg cetirizine, and 60 mg cetirizine every day) in effect on QTc compared with baseline. A paired Student t test showed no difference in dose/area under the concentration-time curve between the 20 mg/day and 60 mg/day dosing groups at steady state. CONCLUSION: In healthy volunteers, cetirizine does not prolong the QTc interval at doses of up to six times the usual recommended dose.