Is there evidence to support single dose of oseltamivir 75 mg for treatment prior to 30 mg BID for renally impaired patients?

Comment by InpharmD Researcher

Despite prescribing information of oseltamivir recommending a treatment dose of 30 mg BID for 5 days for patients with a creatinine clearance >30 to 60 mL/minute, expert opinion suggests that current dosing advice for oseltamivir is likely to reduce its efficacy and delay the attainment of effective therapeutic concentrations in patients with mild to moderate renal impairment. Thus, an initial dose of 75 mg followed by subsequent doses reduced in proportion to the degree of renal impairment is suggested. Clinical trials evaluating the efficacy and safety of an initial oseltamivir dose of 75 mg in patients with moderate renal impairment were not identified.

Background

A 2015 pharmacokinetic (PK) study utilized simulated renal impairment models to explore exposure metrics of oseltamivir (AUC 48h, Cmax, Cmin) at steady-state after administration of various dosing regimens. Results were then compared to patients with normal renal function receiving approved regimens. Specifically for influenza treatment, 30 mg once daily and twice daily regimens provided oseltamivir carboxylate (OC) exposures similar to or above those of the approved 75 mg twice daily treatment regimen in subjects with normal renal function. Thus, these regimens were selected for patients with severe (creatinine clearance [CrCl 10-30 mL/min]) and moderate (CrCl 30-60 mL/min) renal impairment (see Table 1). [1]

A 2021 review explored if dose reductions of oseltamivir based on renal function can still lead to early attainment of therapeutic levels by comparing concentrations of the active metabolite, OC, achieved in the first 24 hours in those with renal impairment to patients with normal renal function. Different from the previously published PK study (Kamal et al.) focusing on steady-state concentrations, the authors stressed the importance of concentrations achieved after the first dose and early attainment of effective OC concentrations. After taking recommended adult doses of oseltamivir (75 mg BID for CrCl 100-120 mL/min; 30 mg BID for 30 and 60 mL/min), patients with normal function mostly likely achieve a Cmax of 250 mcg/L and a Cmin of 125-165 mcg/L over the first dosing interval. In contrast, Cmax and Cmin are expected to be lower in those with renal impairment, 100 mcg/L and 66-77 mcg/L, respectively, for CrCl of 60 mL/min, and 100 mcg/L and 81-88 mcg/L, respectively, for CrCl of 30 mL/min. Although the Cmax after the initial 30 mg dose exceeds the IC50 for most strains of influenza, the Cmin (66–88 mcg/L) may not, leading to a delay in reaching therapeutic concentration. Given the concern of attenuated efficacy from a reduced dosing regimen (30 mg BID) in those with CrCl of 30-60 mL/min, the authors suggested an initial dose of 75 mg for all patients except those with severe renal impairment and those requiring dialysis. Subsequent doses can be reduced in proportion to the degree of renal impairment, either by increasing the interval or reducing the dose size, to ensure renally impaired patients have similar oseltamivir exposure as healthy individuals with normal renal function receiving 75 mg BID. [2]

References:

[1] Kamal MA, Brennan BJ, Subramoney V, et al. Identification of new oral dosing regimens for the neuraminidase inhibitor oseltamivir in patients with moderate and severe renal impairment. Clin Pharmacol Drug Dev. 2015;4(5):326-336. doi:10.1002/cpdd.203
[2] Jones TE. Oseltamivir-Current Dosing Recommendations Reduce the Therapeutic Benefit in Patients With Mild to Moderate Renal Function and/or Large Body Mass: A Review of the Literature With Recommendations to Optimize Dosing, Including the Use of Therapeutic Drug Monitoring. Ther Drug Monit. 2021;43(1):103-107. doi:10.1097/FTD.0000000000000797
Relevant Prescribing Information

DOSAGE AND ADMINISTRATION [3]
Treatment of influenza
- Adults and adolescents (13 years and older): 75 mg twice daily for 5 days
- Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg twice daily for 5 days
- Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once daily for 5 days

References:

[3] Tamiflu (oseltamivir phosphate). Prescribing information. Genetech, Inc.; 2021.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is there evidence to support a single dose of oseltamivir 75 mg for treatment prior to 30 mg BID for renally impaired patients?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Table 1 for your response.

 

Simulated Mean (SD) Pharmacokinetic Exposure Metrics of Oseltamivir Carboxylate for Treatment of Influenza After Administration of Several Different Oral Oseltamivir Dosing Regimens in Subjects With Normal Renal Function and Subjects With Mild, Moderate, or Severe Impaired Renal Function (n ¼ 100 Subjects by Dosing Regimen)
Renal Function Normal (ClCr >
90 mL/min)		 Mild (ClCr
60–90 mL/min)		 Moderate (ClCr
30–60 mL/min)		 Severe (ClCr
10–30 mL/min)
Regimen/PK exposure
parameter		 75 mg BIDa 150 mg BIDb 450 mg BIDb 75 mg BIDa 75 mg BIDa 30 mg BIDc 75 mg QDa 30 mg QDc
Cmin, ng/mL 141 (57) 284 (132) 927 (469) 255 (126) 417 (160) 175 (96) 668 (418) 221 (139)
Cmax, ng/mL 377 (165) 793 (364) 2,410 (989) 595 (258) 986 (390) 413 (198) 2,192 (1,359) 774 (495)
AUC48 h, ng·h/mL 12,200 (4,880) 25,300 (10,700) 78,700 (32,000) 20,500 (9,200) 33,700 (12,200) 14,300 (7,070) 63,700 (40,200) 21,800 (15,400)

AUC, area under the curve; BID, twice daily; ClCr, creatinine clearance; PK, pharmacokinetic
aPreviously recommended dosing regimens.
bThe 150-mg BID dose is a well-tolerated dose from phase 3 studies. The 450-mg BID regimen was also well tolerated and represents an upper ceiling of safe OC exposure.
cCurrently recommended dosing regimens.

 

 
References:

Adopted from:
Kamal MA, Brennan BJ, Subramoney V, et al. Identification of new oral dosing regimens for the neuraminidase inhibitor oseltamivir in patients with moderate and severe renal impairment. Clin Pharmacol Drug Dev. 2015;4(5):326-336. doi:10.1002/cpdd.203