L M Cass1, C Efthymiopoulos, J Marsh, A Bye. 1. Clinical Pharmacology Division, Glaxo Wellcome Research and Development, Greenford, Middlesex, England.
Abstract
OBJECTIVE:Zanamivir is eliminated almost exclusively by renal excretion. This study evaluated the effect of renal impairment on the pharmacokinetics of intravenous zanamivir. DESIGN: This open-label study compared individuals with mild/moderate or severe renal impairment, as defined by creatinine clearance (CLCR), with healthy 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 impairment (CLCR 25 to 70 ml/min) and 5 had severe renal impairment (CLCR < 25 ml/min). INTERVENTIONS: Single 4 mg doses of zanamivir were administered intravenously to healthy participants and those with mild/moderate renal impairment; participants with severe renal impairment received 2 mg. Zanamivir concentrations 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 impairment and in healthy volunteers. There were no clinically significant changes attributable to zanamivir treatment. Renal dysfunction had marked effects on the pharmacokinetics of zanamivir. Although no statistically significant differences were detected between either renal impairment group and the normal renal function group for the maximum serum concentration (Cmax) or the time this occurred (tmax), 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, respectively. The area under the serum concentration-time curve from zero to infinity (AUC infinity) was on average increased 2-fold in individuals with mild/moderate renal impairment (4 mg dose) and 3.5-fold in those with severe impairment (2 mg dose) compared with healthy individuals (4 mg dose). CONCLUSIONS: The proposed total daily dosage of zanamivir by oral inhalation is 20 mg. Given the tolerability (observed in a separate study to be reported in this supplement) after daily intravenous dosages of 1200 mg, and the limited systemic absorption after oral inhalation, the increased drug exposure in patients with severe renal failure is not considered clinically significant. Furthermore, the local concentrations in the lung following oral inhaled delivery are essential for efficacy. Therefore, for orally inhaled zanamivir, no dosage adjustment is required in patients with renal impairment.
RCT Entities:
OBJECTIVE:Zanamivir is eliminated almost exclusively by renal excretion. This study evaluated the effect of renal impairment on the pharmacokinetics of intravenous zanamivir. DESIGN: This open-label study compared individuals with mild/moderate or severe renal impairment, as defined by creatinine clearance (CLCR), with healthy 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 impairment (CLCR 25 to 70 ml/min) and 5 had severe renal impairment (CLCR < 25 ml/min). INTERVENTIONS: Single 4 mg doses of zanamivir were administered intravenously to healthy participants and those with mild/moderate renal impairment; participants with severe renal impairment received 2 mg. Zanamivir concentrations 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 impairment and in healthy volunteers. There were no clinically significant changes attributable to zanamivir treatment. Renal dysfunction had marked effects on the pharmacokinetics of zanamivir. Although no statistically significant differences were detected between either renal impairment group and the normal renal function group for the maximum serum concentration (Cmax) or the time this occurred (tmax), 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, respectively. The area under the serum concentration-time curve from zero to infinity (AUC infinity) was on average increased 2-fold in individuals with mild/moderate renal impairment (4 mg dose) and 3.5-fold in those with severe impairment (2 mg dose) compared with healthy individuals (4 mg dose). CONCLUSIONS: The proposed total daily dosage of zanamivir by oral inhalation is 20 mg. Given the tolerability (observed in a separate study to be reported in this supplement) after daily intravenous dosages of 1200 mg, and the limited systemic absorption after oral inhalation, the increased drug exposure in patients with severe renal failure is not considered clinically significant. Furthermore, the local concentrations in the lung following oral inhaled delivery are essential for efficacy. Therefore, for orally inhaled zanamivir, no dosage adjustment is required in patients with renal impairment.
Authors: M von Itzstein; W Y Wu; G B Kok; M S Pegg; J C Dyason; B Jin; T Van Phan; M L Smythe; H F White; S W Oliver Journal: Nature Date: 1993-06-03 Impact factor: 49.962
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