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Dosing regimen optimisation for oseltamivir in immunocompromised paediatric patients with influenza: Extrapolation of

Eric Burroughs Jordie¹, Leonid Gibiansky², Timothy Knab¹

¹Translational & Systems Pharmacology, Metrum Research Group LLC, Tariffville, CT, USA.

British Journal of Clinical Pharmacology

|August 27, 2021

Insights

Oseltamivir dosing for immunocompromised children with influenza is optimized using extrapolation and modeling. A 10-day course at the conventional dose is recommended to improve efficacy and limit viral rebound.

Area of Science:

Pharmacology
Infectious Diseases
Pediatrics

Background:

Influenza treatment in immunocompromised (IC) pediatric patients requires optimized dosing.
Oseltamivir is a key antiviral, but its dosing in this vulnerable population needs refinement.

Purpose of the Study:

To determine the optimal oseltamivir dosing regimen for immunocompromised pediatric patients (<18 years) with influenza.
To leverage extrapolation and modeling approaches for dose optimization.

Main Methods:

Extrapolated efficacy from adult IC patients to pediatric IC patients using existing models.
Utilized population pharmacokinetic (PK), PK/pharmacodynamic (PD), and disease progression models.
Included data from two pediatric IC patient studies (NV25719 and NV20234).

Main Results:

Oseltamivir and oseltamivir carboxylate clearance were similar in IC and otherwise-healthy (OwH) patients <10 years.
Clearance decreased significantly in IC patients aged 10-17 years compared to OwH patients.
No additional benefit was observed with exposures higher than the conventional dose; a 10-day treatment duration was favored.

Conclusions:

Established an oseltamivir dosage recommendation for IC pediatric patients with influenza.
The recommended regimen is the conventional dose, twice daily for 10 days.
This recommendation is based on extrapolated adult efficacy, PK/PD, disease modeling, and safety data.

Read full analysis

Abstract

Aims:

To optimise the dosing regimen of oseltamivir for immunocompromised (IC) paediatric patients (<18 years) with influenza, we used an extrapolation approach alongside clinical data.

Methods:

Efficacy was extrapolated from adult IC patients to paediatric IC patients by leveraging existing efficacy, safety, pharmacokinetic (PK)/pharmacodynamic (PD), and disease-progression models of oseltamivir and oseltamivir carboxylate (OC). Data of IC paediatric patients from two studies (NV25719 and NV20234) were included in the population PK (n = 30), PK/PD analysis (n = 22) and disease modelling approach (n = 36). Simulations were performed to identify the optimal dosing regimen.

Results:

Clearance of oseltamivir (CL) and OC (CL_M ) were similar in IC and otherwise-healthy (OwH) patients <10 years, but decreased by 44.4% (95% CI: 26.8-62.0) and 49.1% (95% CI: 34.5-63.8), respectively, in IC patients aged 10-17 years versus OwH patients. There were no notable exposure-response relationships for any of the virologic PD analyses. Thus, no additional benefit was seen with oseltamivir carboxylate exposures higher than achieved with the conventional dose (75 mg twice daily, age- and weight-adjusted for children <13 years). The disease model illustrated that doses above the conventional oseltamivir dose had limited impact on viral kinetics in IC paediatric patients and a prolonged treatment duration of 10 days was favoured to limit potential viral rebound.

Conclusion:

An oseltamivir dosage recommendation (conventional dose, twice daily for 10 days) was established in IC paediatric patients with influenza, based on extrapolation of efficacy from IC adults, leveraging population PK, PK/PD, and disease modelling, whilst taking resistance and safety data into account.

Keywords:

clinical trials immunosuppression modelling and simulation pharmacokinetic-pharmacodynamic population analysis

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