Objective To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available. Methods This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT. Results All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns–Visual Analog Scale, and Clinical Global Impression Scale–Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure. Conclusion These results, together with those from a previous adolescent/adult trial, indicate trofinetide9s potential for treating core RTT symptoms and support further trials. Classification of evidence This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.

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The mechanism by which COX inhibitors exert their analgesic effect is well established. However, data show no direct correlation between drug concentrations in plasma and the analgesic or adverse effects in chronic inflammatory conditions. This represents a major problem in the development of COX inhibitors, since it is difficult to predict the appropriate dosing regimen for the treatment of chronic inflammatory pain, based upon information from pre-clinical studies and eventually early clinical studies. The factors that determine response in inflammatory pain must be understood in order to make predictions about the time course of the analgesic effect. In this review the determinants of drug response and their variability will be discussed: physicochemical properties, pharmacokinetics (PK), pathophysiology and disease progression. From a mechanistic point of view, endogenous mediators of inflammation might be used as a biomarker for the analgesic effect and safety assessment. Such a biomarker can be an intermediate step between drug exposure and response. In addition, its concentration–effect relationship could be characterized by pharmacokinetic–pharmacodynamic (PK/PD) modelling. Indeed, recent investigations have shown that COX-2 inhibition, as determined by modelling of prostaglandin E2 (PGE₂) levels in the whole blood assay in vitro can be used as a marker to predict drug effects (analgesia) in humans. A model-derived parameter, IC₈₀, (total and unbound) was found to correlate directly with the analgesic plasma concentration of different COX inhibitors varying in enzyme selectivity. These findings indicate that PGE₂ and thromboxane B2 inhibition can be used to predict and select efficacious doses in humans.

Purpose Although practical and ethical constraints impose special requirements for the evaluation of treatment safety and efficacy in children, the main issue remains the empirical basis for patient stratification and dose selection at the early stage of the development of new chemical and biological entities. The aim of this review is to highlight the advantages and limitations of modelling and simulation (M&S) in supporting decision making during paediatric drug development. Methods A literature search on Pubmed’s database Medical Subject Headings (MeSH) has been performed to retrieve relevant publications on the use of model-based approaches in paediatric drug development and therapeutics. Results M&S enable the assessment of the impact of different regimens as well as of different populations on a drug’s safety and efficacy profile. It has been widely used in the last two decades to support pre-clinical and early clinical drug development. In fact, M&S have been applied to drug development as decision tools, as study optimization tools and as data analysis tools. In particular, this approach can be used to support dose adjustment in specific subgroups of a population. M&S may therefore allow the individualisation of drug therapy in children, improving the risk–benefit ratio in this population. Conclusions The lack of consensus on how to assess the impact of developmental factors on pharmacokinetics, pharmacodynamics, efficacy and safety has so far prevented a broader use of M&S. This problem is compounded by the limited collaboration between stakeholders, which prevents data sharing in this field. In this article, we emphasise the need for a concerted effort to promote the effective use of this technology in paediatric drug development and avoid unnecessary exposure of children to clinical trials.

Although the number of countries participating in pivotal trials submitted to enable drug registration has nearly doubled over the past 25 years, there has not been a substantial increase in the diversity of clinical trial populations. In parallel, our understanding of factors that influence medicine response and variability has continued to evolve. The notion of intrinsic and extrinsic sources of variability has been embedded into different regulatory guidelines, including the recent guideline on the importance of enhancing the diversity of clinical trial populations.In addition to presenting the clinical and scientific reasons for ensuring that clinical trial populations represent the demographics of patient populations, this overview outlines the efforts of regulatory agencies, patient advocacy groups and clinical researchers to attain this goal through strategies to meet representation in recruitment targets and broaden eligibility criteria. Despite these efforts, challenges to participation in clinical trials remain, and certain groups continue to be underrepresented in development programmes. These challenges are amplified when the representativeness of specific groups may vary across countries and regions in a global clinical programme.Whilst enhanced trial diversity is a critical step towards ensuring that results will be representative of patient populations, a concerted effort is required to characterise further the factors influencing interindividual and regional differences in response for global populations. Quantitative clinical pharmacology principles should be applied to allow extrapolation of data across groups or regions as well as provide insight into the effect of patient‐specific characteristics on a medicine's dose rationale and efficacy and safety profiles.