Time-varying brentuximab vedotin pharmacokinetics and weight-based dosing in paediatric patients despite lower exposure in those aged 2 to <6 and 6-11 years.

AIMS: We studied the pharmacokinetics and exposure-response relationships of the brentuximab vedotin (BV) antibody-drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies. METHODS: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia. RESULTS: BV ADC exhibited linear pharmacokinetics, well-described by a three-compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time-varying formation rate. Simulated steady-state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%-38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence. CONCLUSIONS: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight-based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted.

A model-based approach for a practical dosing strategy for the short, intensive treatment regimen for paediatric tuberculous meningitis.

Following infection with Mycobacterium tuberculosis, young children are at high risk of developing severe forms of tuberculosis (TB) disease, including TB meningitis (TBM), which is associated with significant morbidity and mortality. In 2022, the World Health Organization (WHO) conditionally recommended that a 6-month treatment regimen composed of higher doses of isoniazid (H) and rifampicin (R), with pyrazinamide (Z) and ethionamide (Eto) (6HRZEto), be used as an alternative to the standard 12-month regimen (2HRZ-Ethambutol/10HR) in children and adolescents with bacteriologically confirmed or clinically diagnosed TBM. This regimen has been used in South Africa since 1985, in a complex dosing scheme across weight bands using fixed-dose combinations (FDC) available locally at the time. This paper describes the methodology used to develop a new dosing strategy to facilitate implementation of the short TBM regimen based on newer globally available drug formulations. Several dosing options were simulated in a virtual representative population of children using population PK modelling. The exposure target was in line with the TBM regimen implemented in South Africa. The results were presented to a WHO convened expert meeting. Given the difficulty to achieve simple dosing using the globally available RH 75/50 mg FDC, the panel expressed the preference to target a slightly higher rifampicin exposure while keeping isoniazid exposures in line with those used in South Africa. This work informed the WHO operational handbook on the management of TB in children and adolescents, in which dosing strategies for children with TBM using the short TBM treatment regimen are provided.

A Model-Based Tool for Guiding Infliximab Induction Dosing to Maximize Long-term Deep Remission in Children with Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: Adequate infliximab concentrations during induction treatment are predictive for deep remission [corticosteroid-free clinical and endoscopic remission] at 6 months in children with inflammatory bowel diseases [IBD]. Under standard infliximab induction dosing, children often have low infliximab trough concentrations. Model-informed precision dosing [MIPD; i.e. model-based therapeutic drug monitoring] is advocated as a promising infliximab dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric infliximab induction treatment. METHODS: Data from 31 children with IBD [4-18 years] receiving standard infliximab induction dosing (5 mg/kg at week [w]0, w2 and w6) were repurposed. Eight paediatric population pharmacokinetic models were evaluated. Modelling and simulation were used to identify exposure targets, identify an optimal sampling strategy, and develop a multi-model prediction algorithm for implementation into an MIPD software tool. A role for infliximab clearance monitoring was evaluated. RESULTS: A 7.5 mg/L infliximab concentration target at w12 was associated with 64% probability of deep remission at 6 months. With standard dosing, less than 80% of simulated children <40 kg attained this target. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 infliximab concentration [rapid assay required]. The multi-model algorithm outperformed single models when optimizing the w6 dose based on both w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. Infliximab clearances at w6 and w12 were predictive for deep remission. CONCLUSIONS: A freely available, multi-model MIPD tool facilitates infliximab induction dosing and improves deep remission rates in children with IBD.

Description of a clinical decision support tool with integrated dose calculator for paediatrics.

Medication errors, especially dosing errors are a leading cause of preventable harm in paediatric patients. The paediatric patient population is particularly vulnerable to dosing errors due to immaturity of metabolising organs and developmental changes. Moreover, the lack of clinical trial data or suitable drug forms, and the need for weight-based dosing, does not simplify drug dosing in paediatric or neonatal patients. Consequently, paediatric pharmacotherapy often requires unlicensed and off-label use including manipulation of adult dosage forms. In practice, this results in the need to calculate individual dosages which in turn increases the likelihood of dosing errors. In the age of digitalisation, clinical decision support (CDS) tools can support healthcare professionals in their daily work. CDS tools are currently amongst the gold standards in reducing preventable errors. In this publication, we describe the development and core functionalities of the CDS tool PEDeDose, a Class IIa medical device software certified according to the European Medical Device Regulation. The CDS tool provides a drug dosing formulary with an integrated calculator to determine individual dosages for paediatric, neonatal, and preterm patients. Even a technical interface is part of the CDS tool to facilitate integration into primary systems. This enables the support of the paediatrician directly during the prescribing process without changing the user interface.Conclusion: PEDeDose is a state-of-the-art CDS tool for individualised paediatric drug dosing that includes a certified calculator. What is Known: • Dosing errors are the most common type of medication errors in paediatric patients. • Clinical decision support tools can reduce medication errors effectively. Integration into the practitioner's workflow improves usability and user acceptance. What is New: • A clinical decision support tool with a certified integrated dosing calculator for paediatric drug dosing. • The tool was designed to facilitate integration into clinical information systems to directly support the prescribing process. Any clinical information system available can interoperate with the PEDeDose web service.

Evaluation of the practice of dose-rounding in paediatrics.

OBJECTIVES: To investigate the rounding of prescribed drug doses for paediatric administration. METHODS: A cross-sectional medication chart review was conducted at a UK paediatric hospital. Proposed administration dose volumes were calculated for prescribed doses using available manufactured liquids measured with oral and intravenous syringes. Resulting percentage deviations in doses administered were calculated. RESULTS: Of 2031 doses observed, 524 (25.8%) required rounding. The majority of which were for children aged 1-12 months. Twenty-seven rounded doses deviated from the prescribed dose by more than 10%. CONCLUSION: This study highlights the impact of dose-rounding in paediatrics and the need for standardisation.

Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re-evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function.

AIMS: Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. METHODS: Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml-1 ·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight-based dosing. RESULTS: Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min-1 1.73 m-2 but not for those with a GFR ≥100 ml min-1 1.73 m-2 . A weight-based dosing regimen of 50 mg kg-1 achieved the target AUC more consistently than the other formulas, regardless of renal function. CONCLUSIONS: GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

AIMS: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability. RESULTS: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell. CONCLUSIONS: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

Discontinuities and disruptions in drug dosage guidelines for the paediatric population.

AIMS: This study investigates paediatric drug dosage guidelines with the aim of investigating their agreement with body surface area (BSA) scaling principles. METHODS: A total of 454 drug dosage guidelines listed in the AMH-CDC 2015 were examined. Data extracted included the administration, frequency and dose per age bracket from 0 to 18 years. Drug treatments were categorized as follows: (1) The same dose recommendation in milligrams per kilogram (mg kg-1 ) for all age/weights; (2) Change in the mg kg-1 dosing according to age/weight; (3) Change in dose in mg according to age/weight; (4) Change from mg kg-1 dosing to a dose in mg according to age/weight; (5) The same recommendation for all age/weight groups in mg; or (6) BSA dosing. Example drugs were selected to illustrate dose progression across ages. RESULTS: Most drug treatments (63%) have the same mg kg-1 dose for all age/weight groups, 14% are dosed in mg kg-1 across all ages with dose changes according to age/weight, 13% were dosed in mg across all ages with dose changes, 10% switched from mg kg-1 to a set dose in mg, 4.2% have the same dose in mg for all age and weight groups and 2.2% are dosed according to BSA. CONCLUSIONS: Paediatric dosage guidelines are based on weight-based formulas, available dosing formulations and prior patterns of use. Substantial variation from doses predicted by BSA scaling are common, as are large shifts in recommended doses at age thresholds. Further research is required to determine if better outcomes could be achieved by adopting biologically based scaling of paediatric doses.

Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa-2a dosing regimen for children with hepatitis C.

AIM: The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C. METHODS: A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen. RESULTS: The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged ≥5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged ≥5 years in combination with ribavirin. CONCLUSION: Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients.