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: Hitoshi Ishizuka, Satoshi Yoshiba, Kazutaka Yoshihara, Hiromi Okabe
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 51 Issue 2 Pg. 243-51 (Feb 2011) ISSN: 1552-4604 [Electronic] England
• PMID: 20197485 (Publication Type: Controlled Clinical Trial, Journal Article)

Chemical References

• CS 8958
• Enzyme Inhibitors
• Guanidines
• Prodrugs
• Pyrans
• Sialic Acids
• laninamivir
• Neuraminidase
• Zanamivir

Topics

• Administration, Inhalation
• Aged
• Aged, 80 and over
• Area Under Curve
• Enzyme Inhibitors (adverse effects, pharmacokinetics)
• Female
• Guanidines
• Half-Life
• Humans
• Male
• Middle Aged
• Neuraminidase (antagonists & inhibitors)
• Prodrugs
• Pyrans
• Renal Insufficiency (complications, physiopathology)
• Severity of Illness Index
• Sialic Acids
• Zanamivir (adverse effects, analogs & derivatives, pharmacokinetics)