Pediatric fluoroquinolone prescription in South Korea before and after a regulatory intervention: A nationwide study, 2007-2015.

OBJECTIVE: To investigate the impact of national implementation of age restriction on fluoroquinolone prescription in children and adolescents. METHODS: Data collected from the database of Health Insurance Review and Assessment Service in South Korea, a national health insurance system to analyze fluoroquinolone prescribing practice in children and adolescents younger than 18 years, between 2007 and 2015. The age restriction was implemented in December 2009. The annual prescription rate of FQ per 100,000 person-years was calculated and an autoregressive model was used to predict the prescription pattern if an intervention had not occurred. RESULTS: A total of 505,859 children received systemic fluoroquinolone during the study period-297,054 ciprofloxacin, and 208,805 levofloxacin. After implementation of the drug utilization review program, the annual prescription rate for ciprofloxacin declined by 97.5% (from 840 to 21 per 100,000 person-years, P < 0.001), and for levofloxacin by 96.4% (from 598 to 11 per 100,000 person-years, P < 0.001). The decline was more dramatic in the outpatient setting than in the inpatient setting for both drugs. CONCLUSION: The dramatic and sustained decline in prescription number and change in prescription pattern after the regulatory action suggests that the implementation under drug utilization review program was successful in controlling excessive and inappropriate use of fluoroquinolones in children, possibly guiding towards more judicious and selective prescription behavior.

Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects.

AIMS: The aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in healthy Caucasian and Korean subjects to investigate interethnic differences in susceptibility to drug-induced arrhythmia. METHODS: A randomized, double-blind crossover study was conducted in 24 (12 male and 12 female) Korean and 13 (seven male and six female) Caucasian subjects. After a 20 min infusion of quinidine (4 mg kg(-1)) or saline, the serum concentration of quinidine and the QT interval corrected by Bazett's formula (QTc) were monitored. The dynamic data were analyzed by means of a population modelling approach using NONMEM. RESULTS: There were no statistical differences in the pharmacokinetic profiles of quinidine between ethnic groups. The QTc values in Caucasians were higher than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations and in female subjects. According to an E(max) model [equation: see text], the population modelling approach revealed that E0 (ms) was related to gender (408 + [34*(1 - Sex)]; 1 for male and 0 for female), DeltaE(max) (ms) was related to ethnicity ((136*f(ETHN)) + C(female): f(ETHN) = 1 for Koreans and 1.26 for Caucasians; C(female) was 106 only for Caucasian females), and EC50 was estimated to be 3.13 microm. CONCLUSIONS: These results suggest that Korean subjects were less sensitive to quinidine-induced QT prolongation than Caucasian subjects, and that this trend was particularly true for females. Further population-based studies are merited to characterize more completely the ethnic differences in drug-induced QT prolongation between Asians and other ethnic groups.

Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans.

OBJECTIVE: Cilostazol is an antiplatelet agent with vasodilating properties. It has been used to treat patients with peripheral ischemia, such as intermittent claudication. We used a pharmacokinetic-pharmacodynamic model to analyze the relation between the plasma concentration of cilostazol, the inhibitory effect of the drug on platelet aggregation, and the cardiovascular effects of the drug on healthy humans. METHODS: A single oral dose of 100 mg cilostazol was administered to 20 healthy volunteers. Serial blood sampling and pharmacodynamic measurements were performed up to 48 hours thereafter. The effects of cilostazol on platelet aggregation, blood pressure, and heart rate were measured during the same period. The plasma concentration of cilostazol was measured with a validated HPLC method that entailed ultraviolet detection. The time courses of plasma cilostazol concentration, platelet aggregation, and cardiovascular effects were analyzed by means of pharmacokinetic-pharmacodynamic modeling with the program ADAPT II. RESULTS: The plasma concentration-time course followed a 2-compartment model. Mean peak concentration was 775 ng/ml approximately 3.65 hours after administration of cilostazol. The maximal effect on platelet aggregation was a 31.14% reduction 6.05 hours after administration. No significant difference in systolic blood pressure was found. The maximal increase in heart rate was 13.49%, whereas the maximal decrease in diastolic blood pressure was 29.51%. Both peak effects were detected approximately 6 hours after administration of the drug. Platelet aggregation and cardiovascular effects (change in diastolic blood pressure and heart rate) were analyzed with the effect-link sigmoid maximal effect model. CONCLUSION: This pharmacokinetic-pharmacodynamic model successfully described the relation between plasma concentration of cilostazol and the antiplatelet and cardiovascular effects of the drug.