title: Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  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. 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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Cha
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, South Korea.
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
authors.forename: Min-Kyu
authors.initials: MK
authors.lastname: Park
authors.affiliation: Kainos Medicine USA Inc., Morrisville, NC, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Kainos Medicine USA Inc., Morrisville, NC, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bray
authors.affiliation: Kainos Medicine USA Inc., Morrisville, NC, USA.
authors.forename: Myung-Chol
authors.initials: MC
authors.lastname: Kang
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Chung
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Yoon
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000328:Adult; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D007094:Imides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: C000599300:3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile; D007094:Imides; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors
keywords: HIV-1; KM-023; healthy subjects; nonnucleoside reverse-transcriptase inhibitor; pharmacokinetics; tolerability