Use of prior knowledge and extrapolation in paediatric drug development: A case study with deferasirox

Borella, Elisa; Oosterholt, Sean; Magni, Paolo; Pasqua, Oscar Della

doi:10.1016/j.ejps.2019.05.009

Cited by 5 publications

(5 citation statements)

References 39 publications

(40 reference statements)

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“…In fact, our group has previously shown the contribution of historical data for the analysis of pediatric data and optimization of study design when an increase in the number of subjects is not feasible. 35 In this context, a recent meta-analysis involving 124 drugs revealed different treatment effects for one drug and a difference in the magnitude of treatment effect in 13. 36 The The third aspect is the possibility of exploring the effect of interindividual variability and heterogeneity on PKs, pharmacodynamics, efficacy, and safety through simulation scenarios, which allow for the inclusion of significantly larger groups or cohorts of patients than an actual trial.…”

Section: Discussionmentioning

confidence: 99%

“…The first one regards the value of available data from adults and other indications when evaluating the efficacy and safety of medicines in children. In fact, our group has previously shown the contribution of historical data for the analysis of pediatric data and optimization of study design when an increase in the number of subjects is not feasible 35 . In this context, a recent meta‐analysis involving 124 drugs revealed different treatment effects for one drug and a difference in the magnitude of treatment effect in 13 36 .…”

Section: Discussionmentioning

confidence: 99%

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Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain

Healy,

Verrest,

Felisi

et al. 2023

Pharmacology Res & Perspec

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Despite off‐label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure‐response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0–8) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2–5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7–63 and 5–45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain

Healy,

Verrest,

Felisi

et al. 2023

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

show abstract

“…One major difference between systematic review and MBMA is that the latter explicitly incorporates the effect of dose and duration using standard pharmacology models and assumptions, allowing dose–response relationships to be characterized as well as the impact of covariates on the dose–response relationships ( 42 ). The incorporation of adult information as well as the use of optimization techniques in MBMA could increase parameter precision in pediatric rheumatology ( 43 ). As such, literature review and meta-analyses can support development of new treatments in pediatric rheumatology, by providing quantitative tools to bridge adult and pediatric clinical outcomes data and better characterize and compare the efficacy-safety balance of existing and new bDMARDs and JAK inhibitors in vulnerable children with a PiRD such as JIA.…”

Section: Discussionmentioning

confidence: 99%

Value of Literature Review to Inform Development and Use of Biologics in Juvenile Idiopathic Arthritis

et al. 2022

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BackgroundJuvenile idiopathic arthritis (JIA) is one of the most common pediatric inflammatory rheumatic diseases (PiRDs). Uncontrolled disease activity is associated with decreased quality of life and chronic morbidity. Biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi) have considerably improved clinical outcomes. For optimized patient care, understanding the efficacy-safety profile of biologics in subgroups of JIA is crucial. This systematic review based on published randomized controlled trials (RCTs) aims to assess efficacy and safety data for bDMARDs and JAKi with various JIA subgroups after 3 months of treatment.MethodsData for American College of Rheumatology (ACR) pediatric (Pedi) 30, 50, and/or 70 responses after 3 months of treatment were selected from RCTs investigating bDMARDs or JAKi in JIA according to predefined inclusion/exclusion criteria. Treatment and control arms were compared by calculating risk ratios (RRs) with 95% confidence intervals (CIs), and proportions of overall, serious adverse events (AEs) and infections were analyzed. Forest plots were generated to summarize efficacy and safety endpoints across studies, JIA subgroups, and type of biologics.ResultsTwenty-eight out of 41 PiRD RCTs investigated bDMARD or JAKi treatments in JIA. 9 parallel RCTs reported ACR Pedi 30, 50, and/or 70 responses 3 months after treatment initiation. All treatment arms showed improved ACR Pedi responses over controls. RRs ranged from 1.05 to 3.73 in ACR Pedi 30, from 1.20 to 7.90 in ACR Pedi 50, and from 1.19 to 8.73 in ACR Pedi 70. An enhanced effect for ACR Pedi 70 was observed with infliximab combined with methotrexate in PJIA vs. methotrexate monotherapy. A slightly higher risk of gastrointestinal AEs and infections was observed with treatment arms compared to placebo or methotrexate monotherapy.ConclusionInvestigated bDMARDs and JAKi showed superior treatment responses compared to controls after 3 months of treatment, which were more pronounced in ACR Pedi 50 and 70 than in ACR Pedi 30. Higher susceptibility to infections associated with bDMARDs or JAKi vs. control arms must be weighed against efficacious treatment of the underlying disease and prevention of disease-related damage. Additional RCTs are warranted to further inform development and utilization of biologics in JIA.

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“…A 2‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the concentration vs time profiles of deferasirox in plasma. Full details about the model development and evaluation have been previously reported by Borella et al 33 . Similarly, the pharmacokinetics of deferiprone was characterised by a 1‐compartment model with first‐order absorption, as described by Bellanti et al 34 .…”

Section: Methodsmentioning

confidence: 99%

“…A 2-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the concentration vs time profiles of deferasirox in plasma. Full details about the model development and evaluation have been previously reported by Borella et al 33 Similarly, the pharmacokinetics of deferiprone was characterised by a 1-compartment model with first-order absorption, as described by Bellanti et al 34 Given the lack of individual pharmacokinetic data, these models were used to simulate average steady-state drug concentrations (Css AV ) based on the reported dose (s) in each study. The rationale for using (Css AV ) as a measure of exposure is based on the mechanism of action of the two chelating agents.…”

Section: Pharmacokinetic Modelsmentioning

confidence: 99%

Characterisation of individual ferritin response in patients receiving chelation therapy

Borella

Oosterholt

Magni

et al. 2022

Brit J Clinical Pharma

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Aims To develop a drug–disease model describing iron overload and its effect on ferritin response in patients affected by transfusion‐dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox. Methods Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations. Results An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079–0.0131] vs. 0.0013 [90% CI: 0.0008–0.0018] L/mg mo). In addition to drug‐specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline. Conclusion Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug‐induced changes in iron elimination rate and ferritin production. The use of a semi‐mechanistic parameterisation allowed us to disentangle disease‐specific factors from drug‐specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.

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Use of prior knowledge and extrapolation in paediatric drug development: A case study with deferasirox

Cited by 5 publications

References 39 publications

Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain

Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain

Value of Literature Review to Inform Development and Use of Biologics in Juvenile Idiopathic Arthritis

Characterisation of individual ferritin response in patients receiving chelation therapy

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