GAPPS (Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies) a critical appraisal system for antimicrobial PKPD studies – development and application in pediatric antibiotic studies

ABSTRACT

Introduction: There are limited data on optimal dosing of antibiotics in different age groups for neonates and children. Clinicians usually consult pediatric formularies or online databases for dose selection, but these have variable recommendations, are usually based on expert opinion and are not graded based on the existing pharmacokinetic-pharmacodynamic (PKPD) studies. We describe here a potential new tool that could be used to grade the strength of evidence emanating from PKPD studies.

Areas covered: A scoring system was developed (GAPPS tool) to quantify the strength of each PK assessment and rate the studies quality in already published articles. GAPPS was evaluated by applying it to pediatric PKPD studies of antibiotics from the 2019 Essential Medicines List for children (EML_C), identified through a search of PubMed.

Expert opinion: Evidence for most antibiotic dose selection decisions was generally weak, coming from individual PK studies and lacked PKPD modeling and simulations. However, the quality of evidence appears to have improved over the last two decades.

Incorporating a formal grading system, such as GAPPS, into formulary development will provide a transparent tool to support decision-making in clinical practice and guideline development, and guide PKPD authors on study designs most likely to influence guidelines.

KEYWORDS:

• Antibiotic dosing
• grading evidence
• pediatric dosing
• PKPD
• WHO EMLc

Article highlights

• Literature search across all Pubmed listed articles for WHO EMLc Antibiotics revealed heterogeneity in reporting PKPD results

• Need for a common grading system to rate evidence in pediatric PKPD studies

• Importance to assess the underlying study quality when grading PKPD evidence

• Most evidence in PKPD for WHO EMLc Antibiotics still comes from individual PK studies

• Evidence from PKPD studies improved during recent years

• A grading evidence tool such as GAPPS should be developed further by expanding it to other populations including validation

Declaration of interest

AN Rashed was funded by the WHO during this study and JF Standing was supported by a United Kingdom Medical Research Council Fellowship (MRC grant MR/M008665/1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

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Additional information

Funding

This paper was funded by the World Health Organization (WHO).