Evaluation of exposure of regorafenib (REG) and its metabolites in pediatric patients by modeling, simulation, and clinical study

Ploeger, Bart; Grevel, Joachim; Frede, Matthias; Block, Michael S.; Schnizler, Katrin; Gerisch, Michael; Hafner, Frank-Thorsten; Trnková, Zuzana; Agostinho, A. Chassot; Sturm, Isrid; Cleton, Adriaan

doi:10.1093/annonc/mdw392.40

Cited by 2 publications

(8 citation statements)

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“…Although numerous pediatric PBPK model for orally administered drugs can be found in the literature, 10 important knowledge gaps remain 10,59 . For the orally aministered compounds in this analysis (eg, rivaroxaban and ciprofloxacin), dissolution was described by an empirical Weibull function with relevant parameters in this function being fitted in the adult PBPK model 13,15 . Typically, new (suspension) formulations need to be developed for children who cannot swallow the tablet given to adults (eg, for rivaroxaban and riociguat).…”

Section: Discussionmentioning

confidence: 99%

“…The PBPK models for amikacin, gadovist, and magnevist were updated to PK‐Sim version 9, 20,21 as additional simulations needed to be performed for this analysis, which is described in more detail below. As the developed PBPK models that were applied for clinical decision making have been filed for regulatory request, most of these models are also already published, whereas some of them are still part of the ongoing drug development program 3,12–17 …”

Section: Methodsmentioning

confidence: 99%

“…For amikacin, 3 ciprofloxacin, 15 copanlisib, 14 levonorgestrel, 12 moxifloxacin, 17 regorafenib, 13 and rivaroxaban, 16 building and evaluation of the PBPK models have been presented or published previously. The other PBPK models have been used to inform clinical trials.…”

Section: Methodsmentioning

confidence: 99%

“…A PBPK model for regorafenib and its active metabolites was built using PK‐Sim version 4.2.5 to support dose selection for the pediatric dose‐finding study and to estimate exposure based on sparse PK sampling 13 . The PBPK model includes the different processes representing phase I (CYP3A4) and phase II metabolism (UGT1A9) for the parent drug and metabolites implemented in the liver, kidney, and gut lumen.…”

Section: Methodsmentioning

confidence: 99%

“…For evaluating the predictive performance in children, the PopPK model–based results were applied, by aggregation of the calculated geometric mean of the individual simulated exposure (AUC from time 0 to 24 hours after the last dose in steady state [AUC 24,ss ]) estimates 13 from the individual patients for each age group 47 . The PBPK predictions for each individual matched to the demographics of the individual patients were aggregated by calculating the geometric mean of the individual AUC 24,ss for each predefined age group.…”

Section: Methodsmentioning

confidence: 99%

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Predictive Performance of Physiology‐Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small‐Molecule Compounds in Children

Ince

Dallmann

Frechen

et al. 2021

The Journal of Clinical Pharma

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Development and guidance of dosing schemes in children have been supported by physiology‐based pharmacokinetic (PBPK) modeling for many years. PBPK models are built on a generic basis, where compound‐ and system‐specific parameters are separated and can be exchanged, allowing the translation of these models from adults to children by accounting for physiological differences. Owing to these features, PBPK modeling is a valuable approach to support clinical decision making for dosing in children. In this analysis, we evaluate pediatric PBPK models for 10 small‐molecule compounds that were applied to support clinical decision processes at Bayer for their predictive power in different age groups. Ratios of PBPK‐predicted to observed PK parameters for the evaluated drugs in different pediatric age groups were estimated. Predictive performance was analyzed on the basis of a 2‐fold error range and the bioequivalence range (ie, 0.8 ≤ predicted/observed ≤ 1.25). For all 10 compounds, all predicted‐to‐observed PK ratios were within a 2‐fold error range (n = 27), with two‐thirds of the ratios within the bioequivalence range (n = 18). The findings demonstrate that the pharmacokinetics of these compounds was successfully and adequately predicted in different pediatric age groups. This illustrates the applicability of PBPK for guiding dosing schemes in the pediatric population.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Predictive Performance of Physiology‐Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small‐Molecule Compounds in Children

Ince

Dallmann

Frechen

et al. 2021

The Journal of Clinical Pharma

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Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies

Geoerger

Morland²,

Jiménez

et al. 2021

European Journal of Cancer

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Background: This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. Patients and methods: Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m 2 ) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort. Treatment-emergent adverse events (TEAEs) were evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Regorafenib PK was evaluated using a population PK model. Results: Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60 e93 mg/m 2 ). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n Z 1]). The MTD was defined as 82 mg/m 2 . The most common Grade !3 drugrelated TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and handefoot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks. Conclusions: The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m 2 . Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients. Clinical trial number: NCT02085148.

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Evaluation of exposure of regorafenib (REG) and its metabolites in pediatric patients by modeling, simulation, and clinical study

Cited by 2 publications

References 0 publications

Predictive Performance of Physiology‐Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small‐Molecule Compounds in Children

Predictive Performance of Physiology‐Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small‐Molecule Compounds in Children

Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies

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