title: Assessment of the effects of renal impairment on the pharmacokinetic profile of laninamivir, a novel neuraminidase inhibitor, after a single inhaled dose of its Prodrug, CS-8958.
abstract: This open-label, single-dose study assessed the safety and pharmacokinetics of laninamivir, a new long-acting neuraminidase inhibitor, after an inhaled 20-mg dose of its prodrug, CS-8958, to a total of 20 subjects with normal, mild, moderate, or severe renal impairment. CS-8958 and laninamivir concentrations were measured in plasma and urine by validated liquid chromatography tandem mass spectrometry methods. The area under the concentration-time curve extrapolated to infinity (AUC(0-inf)), maximum concentration (C(max)), and time to C(max) of CS-8958 did not change with the degree of renal impairment, whereas the half-life (t(1/2)) of CS-8958 increased with increasing renal insufficiency. The AUC(0-inf) and C(max) of laninamivir tended to increase along with the decrease of creatinine clearance. The AUC(0-inf) of laninamivir compared with normal subjects increased 1.10-, 2.03-, and 4.92-fold in subjects with mild, moderate, and severe renal impairment, respectively, without changing t(1/2) among the subjects. Renal clearance of both CS-8958 and laninamivir was well correlated with creatinine clearance. These data indicate that the rate-limiting step for the elimination of laninamivir would not be the renal excretion rate but rather the drug release rate to plasma from the retained tissues. CS-8958 was well tolerated by all the subjects, although increasing renal dysfunction leads to increasing systemic exposure to laninamivir, particularly in severe renal insufficiency.
authors.affiliation: 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
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishizuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshiba
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yoshihara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Okabe
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006146:Guanidines; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D011355:Prodrugs; D011714:Pyrans; D051437:Renal Insufficiency / Q000150:complications* / Q000503:physiopathology; D012720:Severity of Illness Index; D012794:Sialic Acids; D053243:Zanamivir / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C546919:CS 8958; D004791:Enzyme Inhibitors; D006146:Guanidines; D011355:Prodrugs; D011714:Pyrans; D012794:Sialic Acids; C546918:laninamivir; D009439:Neuraminidase; D053243:Zanamivir