In the present study, the effects of coadministration of fexofenadine hydrochloride and erythromycin on the pharmacokinetics and electrocardiographic findings, focussed on QTc, were investigated. A double-blind, randomized, placebo-controlled, repeated-dose, orthogonal Latin square crossover study was conducted in 18 male healthy volunteers. Trial medication was given for three periods of 7 days separated by washout periods of 14 days. Fexofenadine hydrochloride (120 mg) was given twice a day for 7 days. Erythromycin (300 mg) was concomitantly given four times a day for 7 days.
During the administration of fexofenadine hydrochloride alone as well as during that of concomitant administration of fexofenadine hydrochloride and erythromycin, no problematic abnormality was observed in subjective/objective symptoms, blood pressure, pulse rate, body temperature or clinical laboratory findings.
The effect of concomitant administration on maximum plasma concentration at steady state (C_max, ss), the steady-state area under the plasma concentration-time curve from 0 h to 12 h [AUCss (0-12)] and the apparent oral clearance from 0 h to 12 h at steady state [CLpo, ss (0-12)] was assessed comparing 90% confidence intervals with the range of 0.80-1.25 in accordance with EU and US FDA operating guidelines. When fexofenadine hydrochloride was coadministered with erythromycin, both mean C_max, ss and mean AUCss (0-12) of fexofenadine were significantly higher than those for the administration of fexofenadine alone (p <0.05, respectively), while the mean CLpo, ss (0-12) of fexofenadine was significantly decreased (p <0.05). The change in plasma concentrations of erythromycin by the coadministration of fexofenadine hydrochloride, however, did not differ from that of the administration of erythromycin alone.
The QTc interval prolongation was evaluated as the difference between the mean values over 2 days before drug administration and the mean values over the 6th and 7th day after the administration. The QTc interval was not affected by the coadministration of fexofenadine and erythromycin. No significant periodical change in ECG parameters was noted.
These results indicate that neither the administration of fexofenadine hydrochloride alone nor the concomitant use of fexofenadine hydrochloride and erythromycin affects the ECG findings. It is also unlikely that concomitant use of fexofenadine hydrochloride and erythromycin results in clinical adverse events related to the cardiovascular system.

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Objective: To confirm the hypothesis that fexofenadine hydrochloride (in the therapeutic dose range) does not impair the quality of life, we assessed the effects of fexofenadinehydrochloride (120 mg-higher than Japanese dose) by using an English word processor.
Methods: A double-blind, randomized, placebo-controlled, single dose, Latin square crossover study was conducted in 18 healthy volunteers, including 9 males and 9 females, who used word processors in their daily lives. The ratio of the total number of characters input after drug administration to the number input before drug administration was assessed for the following 4 parameters: number of total keyed-in characters, number of correctly keyed-in characters, number of wrongly keyed-in characters and number of revised characters. Subjective self-ratings (visual analogue scale) were also measured. d-Chlorpheniramine maleate (6 mg) was used as a positive control drug.
Results: For the total number of keyed-in characters and the total number of correctly keyed-in characters, the ratios were significantly lower for subjects with d-chlorpheniramine maleate than those for subjects with placebo (p<0.05, respectively). For the total number of wrongly keyed-in characters and the total number of revised characters, the ratios with d-chlorpheniramine maleate were significantly higher than those with placebo (p < 0.05, respectively). These results indicate that dchlorpheniramine maleate can be used as the active control drug. The ratios for both the total number of correctly keyed-in characters and the total number of keyed-in charac ters were significantly higher for subjects with fexofenadine hydrochloride than for subjects with d-chlorpheniramine maleate (p <0.05, respectively). The ratio for the total number of revised characters was significantly lower for subjects with fexofenadine hydrochloride than for subjects with d-chlorpheniramine maleate (p < 0.05). The ratio for the total number of wrongly keyed-in characters, however, did not differ significantly between subjects with fexofenadine hydrochloride and d-chlorpheniramine maleate (p=0.051). There were no significant differences between fexofenadine hydrochloride and placebo in all parameters.
One subject on fexofenadine experienced mild headache and drowsiness, which were considered likely to be drug related. Another subject experienced dizziness, which was probably an adverse event in the placebo treatment. There was no report of adverse events related to blood pressure, pulse rate, body temperature, electrocardiographic findings or clinical laboratory results.
Conclusion: The impairment of word processor performance caused by fexo fenadine hydrochloride was considerably less than that caused by d-chlorpheniramine maleate, and similar to placebo. These results suggest that fexofenadine does not impair quality of life domains related to activities of daily living. In contrast, dchlorpheniramine maleate significantly impaired performance, which may reflect impairment in the quality of life.

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Nonlinear mixed effects models are often used for the analysis of repeated measure ments in clinical trials. A typical example is population pharmacokinetic analysis. Due to the statistical complexity, careful attention must be paid to some statistical issues in order to obtain reliable and robust results. This paper provides a description of the notes on the use of nonlinear mixed effects models for the analysis of repeated measurements in clinical trials. Three main issues are discussed in this paper: 1) a first-order lineariza tion, 2) a missing data, and 3) a measurement error.

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