A number of drugs without pediatric indication are used off-label in infants and children who are described as “therapeutic orphans”. This practice is widespread and constitutes a global issue. We conducted a drug utilization study using a large-scale electronic medical record (EMR) database to explore off-label prescription of anticancer drugs in pediatric patients. The EMR database was provided by Medical Data Vision (MDV). The subjects of the present study were pediatric patients aged from 0 to 14 years who were prescribed anticancer drugs and enrolled in the database between January 2016 and December 2017. We surveyed the number of patients who were prescribed these drugs outside the approved age window. Of 700 pediatric patients included in this study, 277 patients (40％) were prescribed anticancer drugs off-label; especially, 182 patients were prescribed “cytotoxic antibiotics and related substances” according to the WHO ATC classification, predominantly pirarubicin (140 patients). Since pirarubicin has not been approved in overseas countries, it is difficult to apply for pediatric indication utilizing the development promotion schemes such as the “public knowledge-based application (kouchi-shinsei)”, and other drug development schemes have to be considered. Only a few subjects (0 to 3％) were prescribed anticancer drugs with pediatric indication but outside the approved age range. The prescribed doses［median (min-max) ］of methotrexate and cytarabine were 15 (2.8-21200) mg and 60 (3-9000) mg, respectively. The dose ranges of these drugs were wide compared to the other drugs in the study. It was speculated that these high doses were probably used as high-dose therapy according to clinical guidelines, within the framework of clinical research. Considering that anticancer drugs generally have narrow safety margins, drug development for approval of pediatric indication should be promoted to provide safe and effective treatments for pediatric patients.

Background: ST-QT200 is a newly developed over-the-counter (OTC) cold remedy. It contains an increased dose of ibuprofen as 600 mg compared to 450 mg per day in its immediate ancestor, S.TAC Ibu_®Fine EX.

Objective: A phase 3 study was conducted with open-label, single arm, multi-center design to evaluate efficacy and safety of ST-QT200.

Methods: Patients aged ≥15 years with mild or moderate common cold were enrolled to receive two-tablets of ST-QT200 after each meal (9 doses in total). Overall improvement, changes in symptomatic severity scores by symptom, improvement by symptom, changes in body temperature, and patients' impression were assessed. Adverse events (AEs) were collected to assess overall safety of the drug.

Results: Sixty-four (64) patients were enrolled and completed the study. Overall improvement was assessed as “marked” or “moderate” in 48 patients (75.0％; 95％ CI: 62.6％-85.0％). Symptomatic severity decreased significantly from baseline for any of defined, individual symptoms (Wilcoxon signed rank test, P＜0.001). The improvement in pain-related, febrile and inflammatory symptoms was notable. Mean body temperature significantly decreased in patients who were at ≥37℃ before start of dosing. Most (＞95％) patients had positive impression of the drug for symptomatic relief. Ten (15.6％) patients reported 14 AEs including somnolence, thirst, constipation, etc., which were already described in the package inserts for previous S.TAC formulations. While reported AEs were all treatment-related except for ear pain (1 patient), they were mild and resolved with no need of treatments. No novel safety concerns were observed based on the overall safety assessment.

Conclusion: ST-QT200 with an increased content of ibuprofen was highly effective in relieving various symptomatic aspects in patients with common cold. The anti-inflammatory effect of increased ibuprofen appeared especially in reduced pain, pyrexia, etc. No safety concerns were observed for the drug.

The utilization of a physiologically-based pharmacokinetic (PBPK) model has become prevalent, especially in drug development by pharmaceutical companies. The regulatory agencies in the US and Europe have already issued guidelines while the Japanese agency is preparing one to support the process. To some extent, applications of PBPK modeling to assess the risk of drug-drug interaction have mainly been discussed. It has been limited to discussing other utilizations such as: 1) conducting a virtual bioequivalence study for a new formulation; 2) assessing PK changes in a Japanese population; and 3) predicting PK profiles of drugs or drug candidates in pediatric subjects. The purpose of this paper is to discuss the current status and future challenges of potential utilizations of PBPK modeling through actual practices and to share regulatory experiences on PBPK modeling in Japan. We summarize the discussions on prospects from the perspective of industry, academia, regulatory agencies, and hospitals.