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1. Clin Ther. 2012 Jan 25. [Epub ahead of print]

Tolerability and Pharmacokinetics of a New P-Glycoprotein Inhibitor, HM30181, in
Healthy Korean Male Volunteers: Single- and Multiple-Dose Randomized,
Placebo-Controlled Studies.

Kim TE, Gu N, Yoon SH, Cho JY, Park KM, Shin SG, Jang IJ, Yu KS.

Department of Clinical Pharmacology and Therapeutics, Seoul National University
College of Medicine and Hospital, Seoul, Republic of Korea.

Background: HM30181 is an oral P-glycoprotein (P-gp) inhibitor developed to
enhance the oral bioavailability of P-gp substrate drugs. OBJECTIVE: The
objective of this study was to investigate the tolerability and pharmacokinetic
properties of HM30181 after single and multiple oral administrations to healthy
Korean male volunteers. The study was performed to meet regulatory criteria for
marketing the test product in South Korea. METHODS: A dose-block-randomized,
double-blind, placebo-controlled, dose-escalation study was performed in 180-,
360-, 600-, and 900-mg single-dose groups and 60-, 180-, and 360-mg multiple-dose
groups with 10 subjects (8 active; 2 placebo) per group. In the single-dose
study, blood and urine samples were collected for up to 120 hours after drug
administration. In the multiple-dose study, subjects received the study drug or
placebo orally once daily for 5 days. Blood samples were collected up to 624
hours after the last dose, and up to 24 hours after the first dose to evaluate
the accumulation index. Urine samples were collected up to 120 hours after the
last dose. Pharmacokinetic analysis was performed using noncompartmental methods.
Adverse events were collected by the spontaneous reporting of the subjects or
when subjects were asked general health-related questions. RESULTS: Thirty and 70
healthy male volunteers completed the single- and multiple-dose studies,
respectively. Mean (SD) age and body weight of subjects in the single
administration group were 24.0 (1.8) years and 68.8 (7.4) kg, respectively, and
those of the multiple administration group were 24.5 (2.6) years and 67.6 (7.7)
kg, respectively. The plasma concentrations peaked at 14 to 42 hours and declined
with t(½) of 75.7 to 169.3 hours after single administration, and peaked at 5.5
to 8.0 hours and declined with t(½) of 153.5 to 215.2 hours after multiple
administrations. C(max) and area under the concentration curve within dosing
intervals (AUC(τ)) increased dose dependently after single administration;
however, dose-dependent increases in C(max) and AUC(τ) were not observed after
multiple administrations. The fraction of drug excreted unchanged in urine was
minimal, with values <0.01% in all dose groups. HM30181 accumulated after
multiple administrations with an accumulation index of 4.0 to 7.4. All adverse
events reported were mild in intensity; there were no serious adverse events
reported. The most frequently reported adverse event was gastrointestinal
disorder. CONCLUSIONS: HM30181 was well tolerated after oral administration
within the dose range evaluated, with the exception of the repeated
administration of 360 mg, for which gastrointestinal disorders were frequently
reported. The systemic exposure of HM30181 was relatively low, and dose
proportional properties of HM30181 were not observed.

Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

PMID: 22284902 [PubMed - as supplied by publisher]