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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
Author(s) -
Ishizuka Hitoshi,
Yoshiba Satoshi,
Yoshihara Kazutaka,
Okabe Hiromi
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010361914
Subject(s) - pharmacokinetics , renal function , medicine , creatinine , area under the curve , pharmacology , neuraminidase inhibitor , chemistry , urology , disease , covid-19 , infectious disease (medical specialty)
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.