Clinical pharmacokinetics of laninamivir, a novel long-acting neuraminidase inhibitor, after single and multiple inhaled doses of its prodrug, CS-8958, in healthy male volunteers.
Phase 1 studies of laninamivir, a novel long-acting neuraminidase inhibitor, were carried out to assess its safety, tolerability, and pharmacokinetics after inhaled administration of its prodrug, CS-8958. Healthy male volunteers (total N = 76) participated in double-blind, randomized, placebo-controlled trials and received 5, 10, 20, 40, 80, or 120 mg of a single dose or 20 or 40 mg of a twice-daily dose for 3 days. The clinical and laboratory parameters and plasma and urinary concentrations of CS-8958 and laninamivir for 144 hours post dosing were measured. There were no adverse events related to the test drug. CS-8958 disappeared from plasma with a half-life of about 2 hours, although laninamivir was slowly eliminated from the body, lasting for even up to 144 hours after administration with a half-life of about 3 days. Area under the curve and maximum concentration increased almost linearly with the dose administered. The cumulative urinary excretion amounts of CS-8958 and laninamivir were 2.3% to 3.6% and 10.7% to 14.6% of the dose, respectively. The half-life of the urinary excretion rates of laninamivir at higher single dose is comparable to plasma half-life. CS-8958, when inhaled by healthy volunteers, is well tolerated and exhibits a suitable pharmacokinetic profile, suggesting potential for long-lasting anti-influenza activity.
Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo Co, Ltd, 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan. ishizuka.hitoshi.h8@daiichisankyo.co.jp
Hitoshi
H
Ishizuka
Satoshi
S
Yoshiba
Hiromi
H
Okabe
Kazutaka
K
Yoshihara
D000280:Administration, Inhalation; D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D006146:Guanidines; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D011355:Prodrugs; D011714:Pyrans; D012794:Sialic Acids; D055815:Young Adult; D053243:Zanamivir / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
C546919:CS 8958; D004791:Enzyme Inhibitors; D006146:Guanidines; D011355:Prodrugs; D011714:Pyrans; D012794:Sialic Acids; C546918:laninamivir; D009439:Neuraminidase; D053243:Zanamivir