Effect of renal impairment on the pharmacokinetics of intravenous zanamivir

Objective: Zanamivir is eliminated almost exclusively by renal excretion. T his study evaluated the effect of renal impairment on the pharmacokinetics of intravenous zanamivir. Design: This open-label study compared individuals with mild/moderate or se vere renal impairment, as defined by creatinine clearance (CLCR), with heal thy participants. Study participants: There were 17 participants (9 men and 8 women), of whom 7 had normal renal function (CLCR >70 ml/min), 5 had mild/moderate renal i mpairment (CLCR 25 to 70 ml/min) and 5 had severe renal impairment (CLCR <2 5 ml/min). Interventions: Single 4mg doses of zanamivir were administered intravenousl y to healthy participants and those with mild/moderate renal impairment; pa rticipants with severe renal impairment received 2mg. Zanamivir concentrati ons were determined in blood and urine. Safety was evaluated by monitoring adverse events, vital signs and laboratory parameters. Results: Zanamivir was well tolerated both in participants with renal impai rment and in healthy volunteers. There were no clinically significant chang es attributable to zanamivir treatment. Renal dysfunction had marked effect s on the pharmacokinetics of zanamivir. Although no statistically significa nt differences were detected between either renal impairment group and the normal renal function group for the maximum serum concentration (C-max) or the time this occurred (t(max)), a strong relationship was detected between CLCR and total body clearance (CL), renal clearance (CLR) and the terminal phase elimination rate constant (lambda(z)). Each 2-fold increase in CLCR produced average increases of 100, 121 and 85% in CL, CLR and lambda(z), re spectively. The area under the serum concentration-time curve from zero to infinity (AUC(infinity)) was on average increased 2-fold in individuals wit h mild/moderate renal impairment (4mg dose) and 3.5-fold in those with seve re impairment (2mg dose) compared with healthy individuals (4mg dose). Conclusions: The proposed total daily dosage of zanamivir by oral inhalatio n is 20mg. Given the tolerability (observed in a separate study to be repor ted in this supplement) after daily intravenous dosages of 1200mg, and the limited systemic absorption after oral inhalation, the increased drug expos ure in patients with severe renal failure is not considered clinically sign ificant. Furthermore, the local concentrations in the lung following oral i nhaled delivery are essential for efficacy. Therefore, for orally inhaled z anamivir, no dosage adjustment is required in patients with renal impairmen t.