Therapeutic drug monitoring-guided dosing for pediatric cystic fibrosis patients: recent advances and future outlooks

ABSTRACT

Introduction

Medicine use in children with cystic fibrosis (CF) is complicated by inconsistent pharmacokinetics at variance with the general population, a lack of research into this and its effects on clinical outcomes. In the absence of established dose regimens, therapeutic drug monitoring (TDM) is a clinically relevant tool to optimize drug exposure and maximize therapeutic effect by the bedside. In clinical practice though, use of this is variable and limited by a lack of expert recommendations.

Areas covered

We aimed to review the use of TDM in children with CF to summarize recent developments, current recommendations, and opportunities for future directions. We searched PubMed for relevant publications using the broad search terms “cystic fibrosis” in combination with the specific terms ”therapeutic drug monitoring (TDM)” and ”children.” Further searches were undertaken using the name of identified drugs combined with the term ”TDM.”

Expert opinion

Further research into the use of Bayesian forecasting and the relationship between exposure and response is required to personalize dosing, with the opportunity for the development of expert recommendations in children with CF. Use of noninvasive methods of TDM has the potential to improve accessibility to TDM in this cohort.

KEYWORDS:

• Antimicrobials
• children
• cystic fibrosis
• cystic fibrosis transmembrane regulator (CFTR)
• pharmacokinetics
• therapeutic drug monitoring

Article highlights

• Therapeutic drug monitoring (TDM) is a clinically relevant tool to optimize drug exposure and maximize therapeutic effect by the bedside. It is of particular relevance to children with CF where dosing of medicines is complicated by inconsistent pharmacokinetics at variance with the general population, and where there is limited research into optimal dosage regimens, and their clinical outcomes.

• The minimum inhibitory concentration of an organism taking into account the PK/PD profiles of antimicrobials to maximize effectiveness and minimize toxicity, is increasingly incorporated into TDM in children with CF.

• Use of Bayesian forecasting methods, combining a priori population-based data with a posteriori individual patient data to inform a patient’s dosing regimen, has been used for vancomycin and aminoglycosides in children with CF, and represents an opportunity to personalize dosing. Further research into the relationship between exposure and response in children with CF is required, with the opportunity for the development of expert recommendations.

• Although the use of TDM in clinical practice for CFTR modulators is not routine, there is case emerging for TDM to minimize adverse effects and maximize their clinical and cost effectiveness.

• Barriers to TDM include a lack of expert recommendations and availability of timely assays. Use of more sophisticated methods of TDM for antimicrobials include the need for additional information e.g. MIC of targeted organism, and may be limited by the availability of technology and clinical expertise to implement it.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

Funding was received from the UK MRC (MR/M008665), awarded to JF Standing.