Pharmacokinetics and tolerability of KM-023 in healthy subjects

다국어 초록 (Multilingual Abstract)

Introduction: KM-023 is a new second-generation non-nucleoside reverse transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type-1 infection. This study determined KM-023 pharmacokinetic characteristics and tolerability in healthy subjects.
Methods: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) study that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. The plasma and urine concentrations were quantified using liquid chromatography-tandem mass spectrometry. Plasma concentration-time data of KM-023 was analyzed by using non-compartmental methods. Adverse events were reported and tolerability monitoring was conducted.
Results: The average maximum concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUCinf) values of KM-023 for the 75-600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1245.4 ng/mL and 11142.4 ng·h/mL to 33705.6 ng·h/mL, respectively. The mean Cmax at steady-state (Cmax,ss) and area under the concentration-time curve within a dosing interval (AUCτ,ss) values ranged from 385.1 ng/mL to 1096.7 ng/mL and 3698.9 ng·h/mL to 10232.6 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. KM-023 was generally well tolerated.
Conclusions: 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.

목차 (Table of Contents)

• 1. Introduction 1
• 2. Material and Methods 4
• 2.1 Subjects 4
• 2.2 Study design 5
• 2.3 Determining KM-023 concentration 6
• 2.4 Pharmacokinetic analysis 8
• 2.5 Tolerability assessments 9
• 2.6 Statistical analysis 9
• 3. Results 10
• 3.1 Study population 10
• 3.2 Pharmacokinetics 12
• 3.3 Tolerability 18
• 4. Discussion 22
• References 25
• Abstract in Korean 27