Pharmacokinetics of the Soluble Guanylate Cyclase Stimulator Riociguat in Healthy Young Chinese Male Non-Smokers and Smokers: Results of a Randomized, Double-Blind, Placebo-Controlled Study.
OBJECTIVE
The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of riociguat after single and multiple oral doses of 1 or 2 mg three times daily (tid), and to determine the effect of smoking on riociguat pharmacokinetics in Chinese men.


METHODS
In a randomized, double-blind, placebo-controlled, single-center study stratified for smokers and non-smokers, healthy Chinese men aged 18-45 years received two riociguat doses: Dose Step 1 (1 mg) then Dose Step 2 (2 mg) conducted after the safety and tolerability at Dose Step 1 was confirmed. For each step, 12 subjects received riociguat and six received placebo. A single dose was given on Day 1, followed by a 48-h pharmacokinetic profile. Multiple-dose treatment tid was then given for 6 days (Days 3-8), with a last single dose on Day 9, followed by a 72-h pharmacokinetic profile. Primary outcomes were pharmacokinetic parameters for riociguat after single and multiple dosing.


RESULTS
Thirty-six subjects (18 smokers; 18 non-smokers) were randomized and provided valid pharmacokinetic data. Riociguat and its pharmacologically active metabolite M1 (BAY 60-4552) showed nearly dose-proportional pharmacokinetics. Accumulation was minimal in smokers and approximately two-fold in non-smokers. Exposure for riociguat was decreased by ≥60% in smokers. No serious or significant adverse events occurred during the study.


CONCLUSIONS
Riociguat pharmacokinetics showed dose proportionality in healthy Chinese men, as previously demonstrated in healthy white male individuals. Exposure to riociguat was substantially decreased in smokers compared with non-smokers. Riociguat was well tolerated in Chinese men.
Peking University First Hospital, No. 6 Da Hong Luo Chang Street, Beijing, 100034, China. zxyjk@126.com.
Xia
X
Zhao
Peking University First Hospital, No. 6 Da Hong Luo Chang Street, Beijing, 100034, China.
Zining
Z
Wang
Clinical Pharmacology Asia, Bayer HealthCare Co. Ltd., Beijing, China.
Yukun
Y
Wang
Clinical Pharmacology Asia, Bayer HealthCare Co. Ltd., Beijing, China.
Hong
H
Zhang
Clinical Pharmacology Asia, Bayer HealthCare Co. Ltd., Beijing, China.
Hartmut
H
Blode
Clinical Pharmacology Asia, Bayer Yakuhin, Ltd., Osaka, Japan.
Kenichi
K
Yoshikawa
Clinical Pharmacology, Bayer Pharma AG, Pharma Research Center, 42113, Wuppertal, Germany.
Corina
C
Becker
Global Biostatistics, Bayer Pharma AG, Pharma Research Center, Wuppertal, Germany.
Sigrun
S
Unger
Clinical Pharmacology, Bayer Pharma AG, Pharma Research Center, 42113, Wuppertal, Germany.
Reiner
R
Frey
Peking University First Hospital, No. 6 Da Hong Luo Chang Street, Beijing, 100034, China.
Yimin
Y
Cui
D000328:Adult; D044466:Asian People; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D011720:Pyrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012907:Smoking / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000071756:Soluble Guanylyl Cyclase; D055815:Young Adult
C569640:BAY 60-4552; D011720:Pyrazoles; D011743:Pyrimidines; D000071756:Soluble Guanylyl Cyclase; C542595:riociguat