Cha Yu-Jung, Lim Kyoung Soo, Park Min-Kyu, Schneider Stephen, Bray Brian, Kang Myung-Chol, Chung Jae-Yong, Yoon Seo Hyun, Cho Joo-Youn, Yu Kyung-Sang
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, South Korea.
Drug Des Devel Ther. 2014 Sep 26;8:1613-9. doi: 10.2147/DDDT.S65596. eCollection 2014.
KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type 1 infection.
This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects.
A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography-tandem mass spectrometry.
The average maximum concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC∞) values of KM-023 for the 75-600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng · h/mL to 33,705.6 ng · h/mL, respectively. Values of the mean Cmax at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng · h/mL to 10,232.6 ng · h/mL, respectively, following 75-600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600 mg dose group. The mean half-life values ranged between 20.7 and 31.2 hours. KM-023 was generally well tolerated without serious adverse events.
KM-023 demonstrated dose- and time-dependent nonlinear pharmacokinetic characteristics after single or multiple doses over a dose range (75-600 mg) in healthy subjects. KM-023 showed favorable tolerability in this study. This Phase I clinical trial information can be used to design further clinical studies appropriately to evaluate KM-023 in patients with HIV-1 infection.
KM-023是一种新型第二代非核苷类逆转录酶抑制剂，正在研发用于治疗1型人类免疫缺陷病毒（HIV）感染。
本研究确定了KM-023在健康受试者中的耐受性和药代动力学特征。
对80名健康韩国男性志愿者进行了一项随机、双盲、安慰剂对照、剂量递增研究。受试者被分配到单剂量或多剂量（每日一次，共7天）组，以4:1的比例接受75、150、300或600毫克药物或安慰剂。在研究期间进行安全性和药代动力学评估。使用液相色谱-串联质谱法定量血浆和尿液浓度。
在单剂量研究中，75-600毫克剂量的KM-023的平均最大浓度（Cmax）和从时间0到无穷大的浓度-时间曲线下面积（AUC∞）值分别为440.2纳克/毫升至1245.4纳克/毫升和11142.4纳克·小时/毫升至33705.6纳克·小时/毫升。在多剂量研究中，75-600毫克剂量后，稳态时的平均Cmax值和给药间隔内的AUC值分别为385.1纳克/毫升至1096.7纳克/毫升和3698.9纳克·小时/毫升至10232.6纳克·小时/毫升。未观察到KM-023的剂量比例关系。在600毫克剂量组中，多剂量后KM-023显示出0.6倍的蓄积。平均半衰期值在20.7至31.2小时之间。KM-023总体耐受性良好，无严重不良事件。
在健康受试者中，在剂量范围（75-600毫克）内单次或多次给药后，KM-023表现出剂量和时间依赖性的非线性药代动力学特征。在本研究中，KM-023显示出良好的耐受性。该I期临床试验信息可用于合理设计进一步的临床研究，以评估KM-023在HIV-1感染患者中的疗效。
