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

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.