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
| Autor: | Hitoshi Ishizuka, Kazutaka Yoshihara, Hiromi Okabe, Satoshi Yoshiba |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.drug_class Neuraminidase Renal function Urine Pharmacology Guanidines Severity of Illness Index Pharmacokinetics Administration Inhalation medicine Humans Prodrugs Zanamivir Pharmacology (medical) Renal Insufficiency Enzyme Inhibitors Aged Pyrans Aged 80 and over Neuraminidase inhibitor Chemistry Drug release rate Middle Aged Prodrug Laninamivir Area Under Curve Renal physiology Sialic Acids Female Half-Life |
| Zdroj: | The Journal of Clinical Pharmacology. 51:243-251 |
| ISSN: | 0091-2700 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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