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 (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.

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: HIV-1; KM-023; healthy subjects; nonnucleoside reverse-transcriptase inhibitor; pharmacokinetics; tolerability.

Figure 1

(A and B) Mean plasma KM-023 concentration–time profiles after oral administration. (A) single dose; (B) multiple doses.

Figure 2

Comparisons of C_max/dose (A), AUC_∞/dose (B), C_max,ss/dose (C), and AUC_τ,ss/dose (D) with respect to KM-023 doses. (A and B) single dose; (C and D) multiple doses. Abbreviations: C_max, maximum plasma concentration; AUC_∞, area under the plasma concentration–time curve extrapolated to infinity; C_max,ss, C_max at a steady state; AUC_τ,ss, AUC within a dosing interval at a steady state.