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Use of population pharmacokinetic-pharmacodynamic modelling to inform antimalarial dose optimization in infants
Clifford G Banda1,2,3, Joel Tarning4,5, Karen I Barnes2,6
1Malawi-Liverpool-Wellcome Programme, Blantyre, Malawi.
Insights
Population pharmacokinetic-pharmacodynamic (PK-PD) modeling can optimize antimalarial drug doses for infants, who are often excluded from trials. This approach addresses under- or overdosing in this vulnerable group.
Area of Science:
- Pharmacology
- Pediatrics
- Infectious Diseases
Background:
- Infants face a high malaria burden but are typically excluded from early dose-finding studies for antimalarial drugs.
- This exclusion leads to limited evidence for accurate dosing, often relying on extrapolated data from older populations, risking under- or overdosing.
- Accurate dosing is crucial for both treating uncomplicated malaria and providing preventive treatment in infants.
Purpose of the Study:
- To review the utility of population pharmacokinetic-pharmacodynamic (PK-PD) modeling for optimizing antimalarial dosing in infants.
- To highlight how PK-PD modeling can inform dosing strategies in programmatic settings within malaria-endemic regions.
- To discuss the challenges and potential of PK-PD modeling for antimalarial dose optimization in this understudied population.
Main Methods:
- Review of existing literature and methodologies.
- Discussion of population pharmacokinetic-pharmacodynamic (PK-PD) modeling principles and applications.
- Analysis of developmental physiological factors influencing drug exposure in infants.
Main Results:
- PK-PD modeling can aid in designing infant clinical studies and analyzing sparse pharmacokinetic data.
- The approach can support the derivation of optimized antimalarial dosing regimens for infants.
- Examples of PK-PD modeling informing antimalarial dose optimization in infants were considered.
Conclusions:
- PK-PD modeling offers a valuable tool for antimalarial dose optimization in infants, addressing critical knowledge gaps.
- Generating robust, albeit sparse, PK and PD data in infants is essential for effective model utilization.
- Optimized dosing informed by PK-PD modeling is crucial for improving malaria control in infants.
Abstract:
Infants bear a significant malaria burden but are usually excluded from participating in early dose optimization studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants' exclusion from early-phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria-preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under- or overdosing. Population pharmacokinetic-pharmacodynamic (PK-PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimized antimalarial dosing in this complex and at-risk yet understudied subpopulation. In this review, we reflect on what PK-PD modelling can do in programmatic settings of most malaria-endemic areas and how it can be used to inform antimalarial dose optimization for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimization studies in infants, and examples of how PK-PD modelling has previously informed antimalarial dose optimization in this subgroup. Additionally, we discuss the limitations and gaps of PK-PD modelling when used for dose optimization in infants. To utilize modelling well, there is a need to generate useful, sparse, PK and PD data in this subpopulation to inform antimalarial optimal dosing in infancy.
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