Phase I Single Dose Elevation and Food Interaction Study of Q-35, a New Oral Quinolone Antimicrobial Agent

새로운 Quinolone계 경구 항균제 Q-35의 제1상 임상시험-단회경구투여 및 Food-Interaction Study

Background : Phase I tolerance and pharmacokinetic studies of Q-35, a newly synthesized fluoroquinolone antibiotic. were performed in healthy male volunteers. Drug safety and pharmacokinetic profiles were evaluated after single oral administration. The effect of food on pharmacokinetics of Q-35 was also evaluated. Methods : Twenty seven young healthy male were randomly assigned to the dose,.escalation schedule after screening by physical and laboratoy examinations. After pilot evaluation of safety by 50mg single oral administration in three volunteers. the dosage was increased to 100, 200, 400mg for each group which was composed of 2 placebo and 6 Q-35 administered subjects. In addition to the pharmacokinetic evaluation. physical and laboratory examinaions including CBC, blood chemistry, urinalysis,. body sway test ECG, and slit lamp examination were performed to evaluate the safety of Q-35. Food interaction study was performed in 200mg administered group by crossover method. Results : No volunteers complained of any subjective symptoms related with Q-35 administration. Physical and labortory examinations did not show any significant changes after the drug administration except for some fluctuations in heart rate and blood pressure which were supposed to be due to the circardian variations in comparison with those of placebo administered volunteers. Q-35 was rapidly absorbed and its peak plasma concentration increased linearly in dose dependent fashion. Cmax and AUCs ranged $0.57-4.31{\mu}g/ml$ and $2.6-31.6{\mu}g/ml*hr$ in proportion to the administered dose. but half-lives of Q-35 were consistent in the range of 6.5-7 hours regardless of dose. Cumulative Q-35 excretion in 48 hour collected urine was as much as 45-68% of administered dose. Q-35 penetrated distributed to saliva after oral administration. The AUC ratio of saliva to plasma was 0.55. Time to peak drug concentration changed from $1.3{\pm}0.5$ hours of fasting state to $1.8{\pm}1.1$ hours after food intake. Tmax changed from $1.3{\pm}0.5$ hours of fasting state to $1.8{\pm}1.1$1 hours after food intake. Tmax changed from $1.3{\pm}0.5$ hours of fasting state to $1.8{\pm}1.1$ hours after food intake. Cmax changed form $2.0{\pm}0.6$ to $1.5{\pm}0.4{\mu}g/ml$. Food interaction resulted relative bioavailavility to be 84.3% compared to that of fasting state. In all dose groups Q-35 was rapidly distributed to saliva to the extent of 54-75% of AUC ratio(saliva/plasma) and half-lives of saliva concentration were similar to those of plasma. Conclusion : We concluded that Q-35 is tolerable in maximum 400mg single dose with desirable pharmacokinetic profile as a systemically administered antibiotic. The result of this study would be applicable for repetitive administration study and phase II study.

연구배경 : 새로운 fluoroquinolone계 항균제인 Q-35의 인체에서의 안전성과 약동학을 확인하기 위하여 건강인자원자 27명을 대상으로 제 1상 임상시험을 시행하였다. 연구방법 : 신체 검진과 혈액검사등으로 확인된 건강자원자 27명을 4개군으로 나누어 Q-35 50, 100, 200, 400mg을 순차적으로 낮은 용량군부터 단회 투여하였다. 약동학적 연구를 위해 혈액, 소변, 타액을 채취하였으며 안전성을 확인하기 위하여 실험시작 전, 중간 및 종료후에 활력징후를 포함한 신체검진, 혈액검사, ECG, 세극등 검사등을 시행하였다. 연구결과 : Q-35 단회투여와 연관된 부작용증상의 호소는 없었으며 각종 이학적 검진과 검사 등에서도 별다른 이상을 나타내는 경우는 없었다. Cmax는 $0.57{\sim}4.31{\mu}g/ml$, $AUC{\infty}$는 $2.6{\sim}31.6mcg/ml*hr$로서 용량의존적으로 증가하였으며 반감기는 용량과 무관하게 $6.5{\sim}7$시간이었다. Food interaction study 에서는 공복시 투여군에 비해 식후투여군에서 Tmax는 $1.3{\pm}0.5$에서 $1.8{\pm}1.1$시간으로, Cmax는 $2.0{\pm}0.6$에서 $1.5{\pm}0.4{\mu}g/ml$으로 각각 변화하였다. 모든 용량군에서 Q-35는 신속한 타액내 이행을 보였으며 AUC ratio(saliva/plasma)는 $54{\sim}75%$였고 48시간 소변으로의 누적배설량은 투여량의$45{\sim}68%$에 달하였다. 결 론: 이상의 연구결과에서 Q-35는 단회경구투여시 좋은 내약성을 보이며 전신적으로 투여되는 항균제로서의 우수한 약동학적 특성을 나타내었다고 볼 수 있었다. 또한 본 결과는 Q-35의 연속성경구투여 시험을 위한 기본적 정보로서 잠정적으로 일일 2회 경구투여가 적절할 것으로 결론내릴 수 있었다