Page 75 - JCTR-11-1

Journal of Clinical and
Translational Research Pediatric dosing of antituberculosis medicines

of the observations were predicted within a 30% prediction Dose/area under the curve (AUC)). It is widely believed
error. that the pediatric doses should be selected based on the
exposure or CL of a medicine rather than per kg body
4. Discussion weight basis extrapolated from adults. 12-14

Generally, pediatric dose is extrapolated from adults A general tendency for PK-based pediatric dose
(especially, in neonates) based on the body weight basis selection is by matching the adult exposure of a medicine
(per kg), mainly due to the difficulties in conducting to pediatrics. 6,13,14 This concept may and may not be
pediatric clinical trials. Although, this approach is simple always applicable. There are different manifestations of
but not satisfactory. Besides, some other simple methods tuberculosis, for example, severity of tuberculosis by age
as described previously in the introduction section were or nutritional status, ethnicity, the region (South East Asia
not found reliable. 12,28,29 or Africa), and co-infection with other diseases such as
Lack and Stuart-Taylor developed a simple method HIV. These are important factors that should be considered
30
known as the “Salisbury Rule” to predict pediatric doses. 30 before pediatric doses are selected for antituberculosis
The method is based on body weight but is not linearly medicines. Therefore, from a clinical perspective, the
related with body weight (per kg). Despite its simplicity and predicted pediatric dose of antituberculosis medicines
fairly accurate prediction of pediatric doses, 26,31,32 Salisbury should be based on pediatric PK studies not on body
Rule has not been widely used for pediatric dose prediction. weight. However, the results of this study indicate that body
Mahmood used Salisbury Rule to predict pediatric dose weight can provide reasonable dose of antituberculosis
for small molecules as well as macromolecules26, 31, 32. medicines provided the body weight is used as described
Mahmood applied the Salisbury Rule to predict pediatric in this manuscript (not on a per kg body weight basis). It
doses for both small and large molecules. 26,31,32 For small should be noted that titration of dose is an integral part
molecules, the Salisbury Rule was comparable to the of clinical practice due to a patient’s response to the dose.
whole-body PBPK model for pediatric dose selection. The Therefore, a dose can vary from one patient to another.
26
predictive performance of the Salisbury Rule for pediatric From a dosing perspective, isoniazid offers a complex
dosing reconciled very well with the recommended human problem. There are slow, intermediate, and fast acetylators,
clinical dose. In a recent study, Salisbury Rule was used and the clearance of isoniazid in these three groups
32
to predict pediatric doses of antimalarial medicines with considerably vary. Population PK studies indicated that
33
excellent results (n = 88; 100% observations within 50% the clearance of isoniazid not only differs among the three
prediction error, 97.7% within 30% prediction error, and groups of acetylators but within the group there is a high
93.2% within 20% prediction error). variability.
Both the Salisbury Rule and allometric methods provide In adults, the FDA and WHO recommend 5 mg/kg
a basis to initiate a pediatric clinical trial or to be used in up to 300 mg daily dose of isoniazid as a single dose or
a clinical setting with a very simple but robust approach 15 mg/kg up to 900 mg/day, two or three times/week. In
to predict pediatric doses not only for antituberculosis children, the recommended dose is 10 mg/kg to 15 mg/kg
medicines but for other classes of medicines. 26,31,32 up to 300 mg daily as a single dose, or 20 mg/kg to 40 mg/
Although, the WHO emphasizes that the doses of kg up to 900 mg/day, two or three times/week. In both
antituberculosis medicines both in adults and children cases, there is no mention about dose adjustment across
be based on PK studies, the methodology used by the the three groups of acetylators.
6
WHO for the recommendation of pediatric doses for Based on various population PK studies, the opinion of
34
antituberculosis medicines is not clear. It is unknown this author is that one can use a median clearance value of
whether these recommended doses are based on clinical 13 L/hr, 20 L/hr, and 30 L/hr for slow, intermediate, and fast
trials, pediatric PK studies, or extrapolated from adult acetylators, respectively. In this study, where pediatric data
doses on a per kg body weight basis. In addition, the were available, in order to predict pediatric dose, an adult
pediatric recommended doses by the WHO may also be dose of 300 mg/day, 450 mg/day, and 600 mg/day was used
influenced by the unavailability of appropriate pediatric for slow, intermediate, and fast acetylators (Table S1). Based
formulations, which limits the ability to administer more on a population PK study, Jing et al. suggested an isoniazid
33
precise doses in children. dose of 300 mg/day, 500-600 mg/day and 700-900 mg/day,
Through PK, one can estimate optimal or near optimal for slow, intermediate, and fast acetylators, respectively.
dose of a drug in adults and pediatrics. The most important Both the allometric and Salisbury Rule approaches are
PK parameter is CL which is inverse of exposure (CL = not based on a linear system per kg body weight basis. In

Volume 11 Issue 1 (2025) 69 doi: 10.36922/jctr.24.00070