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

• Published in: Journal of clinical pharmacology Vol. 51; no. 2; p. 243
• Main Authors: Ishizuka, Hitoshi, Yoshiba, Satoshi, Yoshihara, Kazutaka, Okabe, Hiromi
• Format: Journal Article
• Language: English
• Published: England 01.02.2011
• Subjects: Administration, Inhalation; Aged; Aged, 80 and over; Area Under Curve; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Female; Half-Life; Humans; Male; Middle Aged; Neuraminidase - antagonists & inhibitors; Prodrugs; Renal Insufficiency - complications; Renal Insufficiency - physiopathology; Severity of Illness Index; Zanamivir - adverse effects; Zanamivir - analogs & derivatives; Zanamivir - pharmacokinetics
• ISSN: 1552-4604
• DOI: 10.1177/0091270010361914

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.