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Published on: January 20, 2017
Oseltamivir drug-disease modelling in infants with influenza virus infection
Kun Wang1, David W Kimberlin2, Richard J Whitley2
1Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Insights
This study modeled oseltamivir pharmacokinetics and viral dynamics in infants to determine optimal dosing. The findings establish target drug exposures for effective influenza treatment in young children.
Area of Science:
- Pharmacology
- Virology
- Pediatric Infectious Diseases
Background:
- Oseltamivir is a key antiviral for influenza.
- Limited data exist on oseltamivir concentration-response relationships in infants.
- Understanding these relationships is crucial for optimizing pediatric treatment.
Purpose of the Study:
- To develop a pharmacokinetic (PK) and viral dynamic model for oseltamivir in infants.
- To determine the oseltamivir carboxylate exposure (EC95) needed for 95% viral suppression.
- To simulate dose-ranging studies for identifying target exposures.
Main Methods:
- Utilized PK and viral dynamic data from a pediatric influenza trial.
- Developed a linked PK and viral dynamic model.
- Performed dose-ranging simulations to identify EC95 for AUC12 and C12h.
Main Results:
- Included data from 78 infants (0-23 months).
- Modeled EC95 for AUC12 was 2710 ng*h/mL.
- Modeled EC95 for C12h was 179 ng/mL.
Conclusions:
- Population PK modeling linked to viral dynamics can guide dose selection.
- Simulations can identify target drug exposures when direct data are scarce.
- This approach serves as a valuable surrogate for establishing concentration-response data.
Aims:
Oseltamivir is a commonly used neuraminidase inhibitor for treatment of influenza infection, but little data exist regarding concentration-response relationships.
Methods:
Pharmacokinetic (PK) and viral dynamic data from an earlier NIAID Collaborative Antiviral Study Group trial in paediatric patients with influenza from 0-23 months of age were used to create a PK model linked to an influenza viral dynamic model. Population PK parameters were used to perform broad dose-ranging simulations to determine the oseltamivir carboxylate exposure required to achieve 95% of maximum viral suppression (EC95). PK parameters of interest included the oseltamivir carboxylate steady-state 12-h area-under-the-curve (AUC12) and 12-h trough concentration (C12h). AUC12 and C12h results were related to the time-averaged area under the log10 viral load-time curve from Day 0 to Day 5 minus the baseline viral load (AAUCMB) using a maximum effect model.
Results:
A total of 373 plasma samples for oseltamivir and 382 plasma samples for oseltamivir carboxylate from 78 infants were included. The median age and weight at the time of PK sampling were 8 months and 8 kg, respectively. Sixty-two babies with measured influenza viral loads over the course of treatment (12 days, n = 239) were included in the viral dynamic modelling. The modelled EC95 for AUC12 and C12h were 2710 ngxh/mL and 179 ng/mL, respectively.
Conclusions:
Population pharmacokinetic modelling can be directly linked to viral dynamic outcomes and through simulations, dose-ranging studies performed to identify target drug exposures. This approach could be used as a surrogate when concentration-response data do not exist.
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