Page 73 - JCTR-11-1

Journal of Clinical and
Translational Research Pediatric dosing of antituberculosis medicines

also be infected by TB bacteria. TB disease can be divided available in the literature. 12,28,29 These rules are: Clark’s
into two types: latent TB infection and active TB disease. If rule (2-17 years), Clark’s surface area rule, Young’s rule,
not treated, latent TB infection can progress to TB disease. Webster’s rule, Fried’s rule, and Shirkey’s body surface
Although, TB is treatable but without proper treatment TB area (BSA) recommendation. 12,28 However, the predictive
patients can die. TB bacteria spread through the air from power of these rules are not robust and lack precision. In
1
one person to another. Drug-resistant TB occurs when the a study, Munzenberger and McKercher evaluated the
29
bacteria become resistant to TB medicines. 1 performance of several pediatric dosing rules (Clark’s
Like adults, children are also susceptible to TB. In 2020, it weight rule, Clark’s surface area rule, Young’s age rule,
was found that 11% children aged <15 years of the estimated and Shirkey’s dosing recommendations) by comparing the
10 million cases of TB were affected and 16% children died predicted doses with the actual doses given to pediatric
of TB disease (230,000 of 1.4 million). Children <5 years patients. The authors concluded that these pediatric
2,3
of age, children with human immunodeficiency virus dosing rules although, simple but were not reliable.
(HIV), and malnourished children are at high risk for TB. 4 A simple method known as ‘Salisbury Rule’ to predict
30
Over the years, WHO has revised the pediatric dosing pediatric dose was developed by Lack and Stuart. This
for TB and in 2014 pediatric dosing was adjusted based method is based on body weight and is very useful for
30
on the pharmacokinetic (PK) studies as well as safety. pediatric dosing for small molecules. Salisbury Rule,
5,6
The FDA and the European Medicines Agency (EMA) along with allometric scaling, has been successfully used
recommended that pediatric optimal dose should be to predict pediatric doses for small molecules as well as
26,31
based on the child-adult exposure matching. The notion therapeutic proteins. The predicted doses of these
7,8
behind child-exposure matching is that if the exposures medicines by Salisbury Rule or allometry reconciled very
26
are comparable between children and adults then a similar well with the recommended pediatric dose. A study
treatment effect is expected in children as of adults. PK involving small molecules compared the Salisbury Rule and
7,8
studies for first-line antituberculosis medicines such as allometry with whole-body PBPK modeling. The results
isoniazid, rifampicin, pyrazinamide, and ethambutol have indicated that the predicted pediatric doses predicted by
indicated that the exposures in children are lower than the Salisbury Rule and allometry with whole-body PBPK
adults 9-11 at the recommended doses by WHO and as such modeling. The results indicated that the predicted pediatric
may be suboptimum. doses by Salisbury Rule or allometry were comparable with
whole body PBPK. In a recent study, Mahmood used
32
There are physiological and biochemical differences Salisbury Rule and allometry to predict pediatric dose for
between children and adults hence, dosing of medicines in antimalarial medicines and the predicted doses reconciled
children require proper understanding of these processes. vary well with the administered doses.
Besides, pediatric diseases may differ from adults in terms
of mechanisms, etiology, and the course of disease. All Since the Salisbury Rule and allometric scaling for
these factors impact the PK and pharmacodynamics the prediction of pediatric dose is simple and robust,
(PD) of medicines and can be different in children than the objective of this study was to evaluate the predictive
adults. 12-14 performance of the Salisbury Rule and the allometric
scaling to predict pediatric doses of antituberculosis
In pediatric drug development, the first-in-children medicines and compare the predicted doses with the
dose is of practical significance. Before conducting a recommended clinical doses of antituberculosis medicines.
pediatric clinical trials, generally, the PK information and
a safe and efficacious dose of a medicine in adults are well 2. Methods
known. Such information plays an important role and There were 7 antituberculosis medicines in this study. These
provide insight for the selection of first-in-pediatric dose. medicines were approved by the FDA and EMA for adult
Over the years, several methods in terms of modeling and pediatric use. At least four (Isoniazid, pyrazinamide,
have been proposed to predict first-in-pediatric dose. ethambutol, rifampicin) out of seven medicines are
12
Models such as allometric scaling, modeling and considered first-line antituberculosis medicines. Three
simulation using adult data, population pharmacokinetics, other medicines used in this study are levofloxacine,
and physiologically-based pharmacokinetic (PBPK) rifapentene, and streptomycin.
models (whole body or minimal) have been suggested to The recommended therapeutic doses of the
predict the first-in-children dose. 15-27 aforementioned antituberculosis medicines in pediatrics
Over the years, many investigators have attempted were obtained from WHO guidelines for the treatment
to device simple mathematical rules and these rules are of TB and the FDA package inserts. The recommended

Volume 11 Issue 1 (2025) 67 doi: 10.36922/jctr.24.00070