NDT Advance Access originally published online on June 24, 2006
Nephrology Dialysis Transplantation 2006 21(12):3606-3608; doi:10.1093/ndt/gfl345
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Pharmacokinetics and dosage adjustment of oseltamivir and zanamivir in patients with renal failure
Email: svetlana.karie{at}psl.aphp.frSir,
In the last few months, more and more countries in Asia, Europe and Africa have reported cases of avian influenza in migrating birds as well as in cats and humans. The virus has expanded its geographical area, being propagated to new countries, and increasing, as a result, the size of the population at risk. As of 21 April 2006, the World Health Organization (WHO) has reported 204 confirmed human cases of influenza A (H5N1) across nine countries, with 113 deaths (a 55% mortality rate for identified cases) [1].
Chronic renal insufficiency is frequently encountered in the general population. In the US adult population, the prevalence of chronic kidney disease is 11%. In this study, 3.0% had a glomerular filtration rate [estimated with Modification of Diet in Renal Disease (MDRD) prediction equation] <80 ml/min/1.73 m2, 4.3% had <60 ml/min/1.73 m2, 0.2% had <30 ml/min/1.73 m2 and 0.2% had <15 ml/min/1.73 m2 [2].
The neuraminidase inhibitors oseltamivir and zanamivir are active against H5N1. In the context of epidemia or pandemia of avian influenza, these two drugs will be prescribed to patients presenting a reduction in renal function. Clinicians should thus be aware of the pharmacokinetics and potential dosage adjustments of those drugs in such patients. According to available data in the literature, we provide guidelines for dosage adjustment of oseltamivir and zanamivir in patients with altered renal function.
Oseltamivir
H5N1 virus is susceptible to oseltamivir in vitro. Moreover, oral oseltamivir is active in animal models of influenza A (H5N1) [3]. However, there is no clear evidence showing that oseltamivir may be effective in human H5N1 disease. Despite the absence of clinical trial, oseltamivir is recommended by the WHO for use in both treatment and prophylaxis of H5N1 infection [3]. The evidence of the effectiveness of oseltamivir for prophylaxis of H5N1 infection is based on the results of trials on the prevention of ordinary influenza. The recommended dose in adults with normal renal function is 75 mg twice a day for 5 days for curative treatment and 75 mg once a day for preventive treatment.
Oseltamivir is extensively converted by hepatic esterases to its active metabolite, oseltamivir carboxylate. Neither oseltamivir nor oseltamivir carboxylate are substrates for, or inhibitors of, cytochrome P450 isoforms. Renal elimination of oseltamivir carboxylate accounts for more than 99% of the administered dose. Renal clearance (313.3 ml/min) occurs through both glomerular filtration and tubular secretion [4]. It is therefore suggested that it is necessary to adjust oseltamivir dosage in patients with renal impairment. Indeed, the pharmacokinetics of oseltamivir are modified in patients with renal failure. The clearance of the parent compound and its metabolite decrease proportionally with the reduction of creatinine clearance (CrCl). The area under the serum concentration–time curve (AUC) of the active metabolite was on average increased 10-fold in patients with severe renal impairment (CrCl <30 ml/min) as compared with individuals without renal impairment [4].
Although increased drug exposure is not associated with poor tolerance, dosage adjustment is recommended for patients with CrCl <30 ml/min. For patients with CrCl between 15 and 30 ml/min (stage 4), a dosage reduction of 50% (75 mg once daily in curative treatment and 75 mg every other day in prophylactic treatment) is recommended [5]. There are no data on the pharmacokinetics and/or the tolerance of oseltamivir in patients with CrCl <15 ml/min and in patients on dialysis. It is therefore impossible to provide recommendations for dosage adjustment in those patients (Table 1). In severe infection, higher doses (150 mg twice a day for adults) and treatment for 7–10 days are recommended [3]. If the administration of such doses is necessary, it is recommended to apply the same dosage reductions (Table 1). Oseltamivir is generally well-tolerated, but gastrointestinal side effects and dizziness may appear with increasing doses, particularly in patients with renal failure.
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Zanamivir
Zanamivir is another neuraminidase inhibitor which may be recommended for the treatment of H5N1 influenza. Topical zanamivir is active in animal models of influenza A (H5N1) but has not been studied in humans with influenza A (H5N1) [3]. Nevertheless, treatment with nebulized zanamivir has been recommended in patients with H5N1 infection and with resistance to oseltamivir [6]. The recommended dosage of zanamivir by oral inhalation is 10 mg twice a day for 5 days.
Zanamivir is formulated as a dry powder for oral inhalation. Less than 20% of the dose is absorbed systemically, and 90% of the absorbed drug is excreted unchanged in urine [7]. In a pharmacokinetic study, the AUC was on average increased 2-fold in patients with CrCl between 25 and 70 ml/min and 3.5-fold in those with CrCl <25 ml/min as compared with healthy individuals after single doses administered intravenously: 4 mg for patients with CrCl between 25 and 70 ml/min and healthy participants, 2 mg for patients with CrCl< 25 ml/min [8]. There are no data on the pharmacokinetics of zanamivir after oral inhalation in patients with renal failure. However, given the good tolerance after daily intravenous dosages as high as 1200 mg [8], and the limited systemic absorption after oral inhalation, the increased drug exposure for patients with renal failure is not considered clinically significant. Therefore, for orally inhaled zanamivir, no dosage adjustment is required in patients with renal impairment [5,8] (Table 1). Because the drug is almost not absorbed, it is unlikely to be removed by haemodialysis to a significant extent. It may thus be administered before or after the session on haemodialysis days without significant influence on its pharmacokinetics. Adverse effects with zanamivir comprise nasal and throat discomfort, headache and cough.
Conclusion
Chronic renal disease is frequent in the general population. In the case of epidemia or pandemia of avian influenza A (H5N1), the two neuraminidase inhibitors, oseltamivir and zanamivir will therefore be used in patients with renal impairment. Although zanamivir does not necessitate any adjustment of its dosage in patients with renal failure, because it is not absorbed after oral inhalation, oseltamivir dosage must be reduced by half in patients with CrCl between 15 and 30 ml/min and may be used at the usual dose when CrCl is higher.
Conflict of interest statement. None declared.
ICAR, Department of Nephrology
Pitié-Salpêtrière Hospital
Paris
France
References
- http://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_04_21/en/index.html Accessed on the 21 April 2006.
- Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. (2003) Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41:1–12.[ISI][Medline]
- The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med (2005) 353:1374–1385.
[Free Full Text] - He G, Massarella J, Ward P. (1999) Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 37:47–84.
- Izzedine H, Launay-Vacher V, Deray G. (2003) GPR Antiviraux. Guide de prescription des medicaments chez le patient insuffisant renal. (Méditions International, Paris).
- de Jong MD, Thanh TT, Khanh TH, et al. (2005) Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 353:2667–2672.
[Abstract/Free Full Text] - Cass LM, Efthymiopoulos C, Bye A. (1999) Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 36:[Suppl 1], 1–11.[ISI][Medline]
- Cass LM, Efthymiopoulos C, Marsh J, Bye A. (1999) Effect of renal impairment on the pharmacokinetics of intravenous zanamivir. Clin Pharmacokinet 36:[Suppl 1], 13–9.[ISI][Medline]
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