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.

Materials and 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 (C_max) 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 C_max 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.

Conclusion

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.

Keywords:

• KM-023
• HIV-1
• nonnucleoside reverse-transcriptase inhibitor
• pharmacokinetics
• tolerability
• healthy subjects

Acknowledgments

Kainos Medicine, Inc. sponsored and funded the research described in this report. We thank Ms Hyewon Kim for assisting with the clinical trials. YJC received a training program grant from the Korea Healthcare Technology R&D Project at the Ministry for Health and Welfare (A070001).

Disclosure

SS, BB, and MCK were employees of Kainos Medicine USA Inc. The other authors have no conflicts of interest to disclose.