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Current Aspects of Pediatric Pharmacokinetics and Pharmacodynamics of Antimicrobials in Japan

Importance of the Promotion of Population PK/PD Analysis

Shoji, Kensuke MD, PhD*; Saito, Jumpei PhD; Nakamura, Hidefumi MD, PhD; Matsumoto, Kazuaki PhD§; Oda, Kazutaka PhD; Takesue, Yoshio MD, PhD‖,**; Miyairi, Isao MD, PhD*,††

Author Information
The Pediatric Infectious Disease Journal: June 28, 2022 - Volume - Issue - 10.1097/INF.0000000000003622
doi: 10.1097/INF.0000000000003622
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Abstract

Pharmacological knowledge becomes important when conducting feasible and effective pharmacokinetic or pharmacodynamic (PK/PD) studies to maximize the results using limited resources, and it is also important when providing effective antimicrobial therapy to pediatric patients. We describe the current clinical and research perspectives of pediatric PK/PD studies of antimicrobials in Japan, specifically focusing on the importance of population PK/PD studies in children.

IMPORTANCE OF PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES IN CHILDREN

Pharmacokinetics (PK) is the dynamic movement of a given drug in the body. In other words, it represents the time course of blood (or tissue) concentration of a given drug. Pharmacodynamics (PD) is the relationship between blood (or tissue) concentration and its therapeutic effects or side effects (Fig. 1). The PK parameters, such as clearance (CL), volume of distribution (Vd) and bioavailability (F), are important for the prediction of drug concentration profiles. Time above minimum inhibitory concentration (MIC), Cmax or Cpeak/MIC and area under the concentration-time curve (AUC)/MIC are the major PD (or PK/PD) parameters that are important for predicting the effects of antimicrobials (Fig. 2).1 The factors that affect PK parameters are absorption, distribution, metabolism and elimination. As all of these are affected by body composition, growth, and developing organ functions,2 determining the PK parameters in children is more complex than doing so in adults, and identifying an appropriate dose regimen for different age groups, including neonates, is often difficult. Simply reducing the adult dose per body weight for children is often insufficient for antimicrobial therapy. Vancomycin, for example, one of the most common antibiotics that is used for methicillin-resistant Staphylococcus aureus (MRSA) infections in children, requires different doses per weight and frequency of administration depending on the age to achieve an adequate PD target. Rainkie et al investigated vancomycin AUC at a dose of 60 mg/kg/d in different age groups and revealed that only half of the patients in the 1 month to 6 years age group could achieve AUC ≥ 400 µg*h/mL. Therefore, they recommended a higher dose (70 mg/kg/d every 6 hours) in patients 1 month to 6 years compared with patients > 6 years of age (60 mg/kg/d every 8 hours).3 Such clinical pharmacological knowledge is essential to implement an effective dosage strategy to maximize the therapeutic effects of the drug and minimize side effects. However, it is not easy to conduct PK/PD studies in pediatric patients who are less receptive to providing blood samples than adults.

F1
FIGURE 1.:
Principles of pharmacokinetics and pharmacodynamics.
F2
FIGURE 2.:
Pharmacodynamic parameters of antimicrobial agents.

CURRENT STATUS AND FUTURE PROSPECTS FOR PEDIATRIC DRUG DEVELOPMENT AND DOSAGE INFORMATION

Historically, there were many drugs that did not include “dosage and administration” information for children in the package inserts because of the lack of pediatric data, and many drugs had been used off-label in children. In the European Union (EU) and the United States, laws and regulations mandate the development of pediatric drugs and provide incentives for pharmaceutical companies.4–7 As a result, pediatric drug development is advancing rapidly and off-label use in children is decreasing.8 On the other hand, in Japan, although there are certain measures to promote pediatric drug development, companies are not obliged to do so by the law, and it is still estimated that 75% of drugs do not include sufficient information necessary for pediatric use in their package inserts. In the “Proposal for the Promotion of Pediatric Drug Development in Japan,” Dr. Masao Nakagawa, who chaired the Committee on Pharmaceutical Affairs of the Japanese Pediatric Society, concluded that it has become essential to promote legislation similar to that in the EU and the United States to further promote the development of pediatric drugs in Japan.9 He also stated it is important to consider appropriate incentives for companies, improve the infrastructure for pediatric clinical trials and train personnel familiar with pediatric drug evaluation. As it is often difficult for companies to conduct sufficient clinical trials for all ages and medical conditions, post-marketing collaboration on PK/PD studies between academia and industry is essential. Without pharmacometrics knowledge and PK/PD study infrastructure, it is difficult to optimize dosages for the pediatric subpopulations.

CLINICAL ASPECTS OF THE APPLICATION OF PEDIATRIC PK/PD INFORMATION IN JAPAN

Availability of Therapeutic Drug Monitoring of Antimicrobials

Therapeutic drug monitoring (TDM) is a standard clinical practice where dosages of certain drugs with a narrow therapeutic range need to be adjusted based on the measured blood concentration to maximize the therapeutic effects and minimize the adverse effects. The antimicrobial agents for which TDM is commonly performed in Japan are glycopeptides (vancomycin and teicoplanin), aminoglycosides (gentamicin, tobramycin, amikacin and albekacin; a derivative of kanamycin developed in Japan which has anti-MRSA activity) and voriconazole. TDM for other drugs is not covered by national health insurance, and occasionally performed for research purposes at tertiary care institutions, such as university hospitals. For example, the importance of TDM for β-lactams in critically ill adult patients is increasingly being recognized,10 although it is not commonly performed in Japan. Accumulation of PK/PD data in Japanese patients may allow for more appropriate utilization of TDM in Japan.

Antimicrobials TDM Guidelines in Japan

There are clinical practice guidelines for TDM of antimicrobials that were created by the Japanese Society for Chemotherapy and the Japanese Society for TDM, which have been widely used in Japan. This information was initially published in 2012 and was revised in 2016 and 2022.11 Before the last revision, the guidelines committee members conducted thorough systematic reviews and meta-analyses, or single/multiple center PK studies, to establish evidence to cite in the guidelines.12–26 These guidelines included the antimicrobials which TDM is commonly performed in Japan, described previously.

Here, we briefly introduce the current vancomycin TDM recommendations in the guidelines because this issue is an important topic in current PK/PD clinical practice. Historically, the trough-guided vancomycin TDM had been implemented in Japan. However, the latest guidelines in Japan recommend AUC-guided TDM in the adult population.27 To promote the AUC-guided vancomycin TDM, the committee created a web application which incorporated the Japanese population PK model to estimate vancomycin AUC.14 This application allows us to estimate vancomycin AUC with at least one blood concentration, although 2 concentrations at different time points are recommended for its accuracy. The target vancomycin AUC/MIC is 400–600. The MIC of vancomycin for MRSA is generally reported as discontinuous values of 0.5, 1 or 2 µg/mL, which indicates that vancomycin dosages may need to be doubled accordingly to achieve appropriate AUC/MIC. However, given that the accuracy of automated MIC analyzers is limited, and the knowledge that the MIC of most MRSA isolates in Japan28–30 is 1 µg/mL, these guidelines state that a uniform AUC ≥ 400 µg•h/mL should be used as a practical target.11 Unfortunately, the utility of AUC-guided vancomycin TDM has not been well assessed in children, and therefore, the guidelines in Japan still recommend trough-guided TDM in children. The guidelines committee members, Moriyama et al, conducted a systematic review and meta-analysis to investigate optimal trough-guided monitoring of vancomycin in children. They found that the treatment failure for MRSA infection in pediatric patients was significantly lower with vancomycin trough ≥10 µg/mL, but that nephrotoxicity was higher in patients with vancomycin trough ≥15 µg/mL13; therefore, the guidelines in Japan recommend vancomycin trough within 10–15 µg/mL for pediatric patients with MRSA infection. For initial vancomycin dosing in children, the guidelines suggest age-based dosing (Table 1). Loading dose for children was not recommended because there was a lack of sufficient evidence in children.31

TABLE 1. - Recommended Initial Dosage of Vancomycin According to the Age Group
Age Dosage (mg/kg/dose) Interval (hours) Daily Dose (mg/kg/d)
Neonate PMA a < 35 weeks 15 12 30
Neonate PMA ≥ 35 weeks 15 8 45
1 b to <3 months 15 6-8 45–60
3 months to <1 year 15 6 60
1 to 6 years 20 6 80
7 to 12 years 15 6 60
13 to 17 years 15–20 8 45–60
aPMA, postmenstrual age (gestational weeks + postnatal weeks).
bIf the patient was born at full term (37 weeks 0 days to 41 weeks 6 days). For PMA, > 44 weeks.
Created by the guidelines committee of the Japanese Society for Chemotherapy and the Japanese Society for TDM; further clinical investigation is necessary.

CURRENT STATUS OF PEDIATRIC PK/PD RESEARCH IN JAPAN

The Need for Clinical PK/PD Studies in Pediatric Patients

Conducting PK/PD studies in children is not easy. Unlike for adult patients, it is generally difficult to draw blood multiple times for PK studies in children because of procedural difficulty and the limited blood amount that is allowed to be collected. In addition, it is relatively difficult to obtain parental consent for invasive blood sampling in children for research purposes. For these reasons, there is often limited evidence on PK/PD of antimicrobial agents in pediatric patients, and it is not easy to provide optimal dosing design for them (particularly in situations such as sepsis, posttransplantation and extracorporeal circulation), which may affect PK/PD in children. There is no guarantee that sufficient blood concentration is achieved in these situations if blood concentrations are not measured. For example, we reported that vancomycin trough concentration in pediatric liver transplant recipients could be lower with standard dosing.32 It is also reported that meropenem time above MIC in patients with extracorporeal membrane oxygenation33 or after liver transplantation with massive ascites was not high enough with standard dosing and that a higher dose or prolonged infusion might be warranted.33,34 Therefore, it is imperative to perform antimicrobial PK/PD studies in pediatric patients with special conditions.

The Role of Population PK Studies in Pediatrics

The use of population PK analysis is expected to be one of the methodologies to overcome the problems mentioned above. Population PK is a well-established PK analysis methodology that can describe the PK data quantitively at the population level.35,36 It allows the identification of measurable pathophysiological factors that cause changes in the dose-concentration relationship. In conventional PK analysis, large numbers of blood samples (intensive sampling) from an individual patient are required to estimate PK parameters. However, in population PK analysis, sparse sampling (at least one point) from an individual patient can be allowed, and therefore, it is considered suitable for pediatric PK study because it can minimize invasive procedures in children. The difference between conventional PK study and population PK study is depicted in Fig. 3. The optimal sampling method often allows us to utilize residual blood or additional blood from other blood draws. It is also possible to explore the factors that affect PK (such as age, body size and renal function) quantitively, thus helping our understanding of physiological parameters affecting pediatric PK. Furthermore, population PK allows us to explore the optimal dosing to achieve identical PD or PK/PD targets by Monte Carlo simulation. Shoji et al conducted a study to integrate datasets from 2 previously performed PK studies of cefepime in children to explore the dosing design to achieve the target PD parameters for susceptible-dose-dependent (SDD) Enterobacteriaceae.37 This study reported that conventional dosing (50 mg/kg/dose, every 8–12 hours, with 30 minutes infusion) is insufficient for SDD organisms and that 50 mg/kg/dose, every 8 hours, with 3 hours infusion improves the possibility of achieving the PD target.

F3
FIGURE 3.:
Graphical representations of conventional method and population pharmacokinetic analysis. Each symbol represents an individual patient.

These features of population PK are utilized to determine the optimal dosing design for pediatric clinical trials. In fact, the Food and Drug Administration,35 European Medicines Agency,38 and the Japanese regulatory agency, Pharmaceuticals and Medical Devices Agency,39 have established guidelines for population PK analysis for drug evaluation, and strongly recommend their implementation. Population PK analysis is also used in clinical practice for simulation analysis incorporated with Bayesian estimation to determine appropriate dosing in each patient with various conditions.40 Dosage arrangement by utilizing the results from population PK analysis can offer the individually optimized dosing strategy depending on the patients’ conditions.

Application of Population Pharmacokinetics in Research for Children

The population PK method allows drug concentrations in a large number of individual patients to be analyzed as a population, even if the timing of blood collection differs in each patient. PK analysis of antimicrobial agents using population PK has been progressing in the Japanese pediatric field (Table 2).32,41–49 Shoji et al reported on the population PK analysis of meropenem in critically ill patients in the pediatric intensive care unit.45 In this study, the authors reported that a longer time above MIC might result in a shorter time to resolution of fever and higher efficacy, and that patients with more severe inflammation (patients presenting with one or more systemic inflammatory response syndrome criteria) are more likely to have higher clearance of meropenem and may not achieve adequate time above MIC with standard doses. Furthermore, we conducted population PK analysis of fosfluconazole in extremely low birth weight infants and explored the optimal dosing in this population.41 Recently, the information obtained by physiologically based pharmacokinetic modeling and population PK analysis information from real-world data are being utilized and some of them are reflected in the package inserts globally.50–53 We have started collaboration with a pharmaceutical company for PK analysis utilizing academic clinical trial data and are currently discussing with Japanese regulators and industry representatives how we can utilize the real-world PK/PD information for regulatory purposes in Japan.

TABLE 2. - Summary of Recent Publications from Japan Regarding Population Antimicrobial Pharmacokinetic and Pharmacodynamic Analyses in Children
Years Author Antimicrobials Target Population Major Findings Journal
2022 Tanzawa, et al Fosfluconazole Extremely low birth weight infants The proposed target trough concentration of fluconazole could be achieved in 43.3% and 72.2% of infants with a postmenstrual age (PMA) of ≥37 and 30 to 36 weeks, respectively, by administering 3 mg/kg every 72 hours. Target attainment might be improved by shortened dosing intervals at every 48 or 24 hours. Microbiol Spectr
2022 Onita et al Ampicillin-sulbactam Pediatric patients with community-acquired pneumonia Authors recommended 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage) for the empiric therapy of community-acquired pneumonia. Pediatr Infect Dis J
2021 Yamada et al Teicoplanin Neonates and children Authors recommended decreased dosing for premature infants (PMA ≤28 weeks) and children with renal failure and increased dosing for children (0.5-11 years) with normal renal function. Ther Drug Monit
2021 Shoji et al Vancomycin Pediatric liver transplant recipients Standard vancomycin dosing may be insufficient to achieve an AUC/MIC of ≥400 in pediatric liver transplant recipients with normal renal function and higher or more frequent dosing may be required. Microbiol Spectr
2021 Sasano et al Vancomycin Extremely low birth weight infants The optimal dosage regimen for infants with serum creatine level >0.6 mg/dL was 5.0 to 7.5 mg/kg every 12 hours. Antimicrob Agents Chemother
2021 Saito et al Meropenem Critically ill children The standard dosing regimen may provide insufficient pharmacodynamic (PD) exposures when targeting 100% free time above the MIC in critically ill pediatric patients. Higher doses with a prolonged 3-hour infusion may be required to achieve the appropriate PD target for patients with SIRS. Antimicrob Agents Chemother
2019 Koshimichi et al Baloxavir marboxil Pediatric influenza patients The body weight-based dose regimen for Japanese pediatric patients can provide comparable exposure to baloxavir acid to that for adults. J Pharm Sci
2019 Ohata et al Meropenem Pediatric patients with bacterial meningitis To achieve clinical efficacy in children with bacterial meningitis, a high dose of meropenem (40 mg/kg every 8 hours) is necessary. Int J Antimicrob Agents
2019 Matuo et al Doripenem Pediatric patients For Haemophilus influenzae and Streptococcus pneumoniae, 20 mg/kg, over a 1-hour infusion would achieve 90% probability of target attainment for 40% of time above MIC, and 40 mg/kg, the highest approved dose for children in Japan, administered over a 3-hour infusion achieved 98.6% for MIC=8 μg/mL. J Pharm Sci
2017 Tsuji et al Linezolid Pediatric patients The estimated mixture model fraction of patients with a platelet count decreased due to inhibition of the platelet production was 0.97 and stimulation of the elimination was only 0.03. Linezolid pharmacodynamics was not affected by the renal function. Br J Clin Pharmacol
MIC, minimum inhibitory concentration; SIRS, systemic inflammatory response syndrome.

CONCLUSIONS

Pediatric PK/PD data are still insufficient for antimicrobials, and it is important to perform more pediatric PK/PD studies and generate data to optimize antimicrobial treatment for children, particularly those with severe infections. Population PK/PD analysis has become an important part of pediatric PK/PD research and should be further utilized in the future.

ACKNOWLEDGMENTS

We thank the guidelines committee members of the Japanese Society for Chemotherapy and the Japanese Society for TDM for their contributions to establishing the TDM clinical practice guidelines in Japan. We also wish to express our gratitude to the senior medical English editor at the National Center for Child Health and Development for editing this article.

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Keywords:

pharmacokinetics; pharmacodynamics; population PK/PD

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