Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study

Willmann, Stefan; Thelen, Kirstin; Kubitza, Dagmar; Lensing, Anthonie W. A.; Frede, Matthias; Coboeken, Katrin; Stampfuss, Jan; Burghaus, Rolf; Mück, Wolfgang; Lippert, Jörg

doi:10.1186/s12959-018-0185-1

Cited by 45 publications

(70 citation statements)

References 21 publications

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“…Figure shows a recent example of PBPK predictions for children that was later confirmed in a clinical trial from a pediatric development program. Figure shows the single‐dose exposure (expressed as area under the concentration‐time curve [AUC]) predicted for children with a PBPK model in comparison to the data observed in the first clinical trial with rivaroxaban in children . Another example is the fluoroquinolone antibiotic moxifloxacin the clearance of which was predicted in children by PBPK modeling before the conduction of pediatric trials and compared with individual data observed in 2 pediatric trials .…”

Section: Application Of Pbpk In Pediatric Researchmentioning

confidence: 99%

“…Figure 3 shows the single-dose exposure (expressed as area under the concentration-time curve [AUC]) predicted for children with a PBPK model 24 in comparison to the data observed in the first clinical trial with rivaroxaban in children. 25 Another example is the fluoroquinolone antibiotic moxifloxacin the clearance of which was predicted in children by PBPK modeling before the conduction of pediatric trials and compared with individual data observed in 2 pediatric trials. [26][27][28] In both case examples, PBPK modeling in children using previous ontogeny information has been proven to be very helpful to guide the development of suitable dosing regimens in pediatric development programs.…”

Section: Established Ontogeny Functionsmentioning

confidence: 99%

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Predictive Pediatric Modeling and Simulation Using Ontogeny Information

Ince

Solodenko

Frechen

et al. 2019

The Journal of Clinical Pharma

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Food and Drug Administration submissions of physiologically based pharmacokinetic (PBPK) modeling and simulation of small‐molecule drugs document the relevance of pediatric drug development and, in particular, information on dosing strategies in children. The most relevant prerequisite for reliable PBPK‐based translation of adult pharmacokinetics of a small molecule to children is knowledge of the drug‐specific absorption, distribution, metabolism, and elimination (ADME) processes in adults together with existing information about ontogeny of ADME processes relevant for the drug. All mechanisms driving a drug's clearance are of specific importance. For other drug modalities, our knowledge of ADME processes and ontogeny is still limited. More research is required, for example, to understand why some therapeutic proteins show complex differences in pharmacokinetics between adults and children, whereas other proteins seem to follow simple allometric scaling rules. Ontogeny information originates from various sources, such as (semi)quantitative mRNA expression, in vitro activity data, and deconvolution of in vivo pharmacokinetic data. The workflow for pediatric predictions is well described in several articles documenting successful translation from adults to children. The technical hurdles for PBPK modeling are low. State‐of‐the‐art PBPK modeling software tools provide integrated pediatric translation workflows. For example, PK‐Sim and MoBi are freely available as fully transparent open‐source software via Open Systems Pharmacology (OSP). With the latest 2019 software release, version 8.0, OSP even provides a fully integrated technical framework for the qualification (and requalification) of any specific intended PBPK use in line with Food and Drug Administration and European Medicines Agency PBPK guidance. Qualification packages for pediatric translation are available on the OSP platform.

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Section: Application Of Pbpk In Pediatric Researchmentioning

confidence: 99%

Section: Established Ontogeny Functionsmentioning

confidence: 99%

Predictive Pediatric Modeling and Simulation Using Ontogeny Information

Ince

Solodenko

Frechen

et al. 2019

The Journal of Clinical Pharma

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“…The PK of a single rivaroxaban dose in children using population PK modeling was assessed in a phase I study. 39,40 In this study, two rivaroxaban dose levels equivalent to adult doses of rivaroxaban 10 and 20 mg, and two different formulations (tablet and oral suspension), were tested in 59 children aged 0.5 to 18 years who had completed treatment for VTE. 39,40 The observed plasma concentration-time profiles in all subjects receiving body-weight-adjusted doses were mostly within the 90% prediction interval, irrespective of dose or formulation.…”

Section: Clinical Pediatric Studiesmentioning

confidence: 99%

“…39,40 In this study, two rivaroxaban dose levels equivalent to adult doses of rivaroxaban 10 and 20 mg, and two different formulations (tablet and oral suspension), were tested in 59 children aged 0.5 to 18 years who had completed treatment for VTE. 39,40 The observed plasma concentration-time profiles in all subjects receiving body-weight-adjusted doses were mostly within the 90% prediction interval, irrespective of dose or formulation. 39 The PD assessment based on PT and aPTT demonstrated that the anticoagulant effect of rivaroxaban was not affected by development hemostasis (►Table 3).…”

Section: Clinical Pediatric Studiesmentioning

confidence: 99%

Use of Direct Oral Anticoagulants in Children and Adolescents

Albisetti

2020

Hamostaseologie

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While the need for anticoagulation in children has increased over the last decades, dose regimens of currently used anticoagulants, including low-molecular-weight heparin (LMWH) and vitamin K antagonist (VKA), are still extrapolated from adult guidelines because well-designed clinical trials were never performed in children. This approach is not optimal due to specific pediatric features of the hemostatic system and pathophysiology of thrombosis. These anticoagulants also present several disadvantages that further hamper optimal anticoagulation of pediatric patients, especially newborns and infants. The new direct oral anticoagulants (DOACs), which have the potential to overcome these disadvantages, were extensively investigated in adults and have become a valid alternative to LMWH and VKA for anticoagulation in the adult population. Several pediatric trials on all approved DOACs are currently ongoing, providing specific pediatric formulations and age- and weight-adjusted dose guidelines. First results of phase III trials indicate that DOACs are at least as efficient and safe as LMWH and VKA for the treatment and prevention of thrombotic events in children with different clinical conditions. This review article summarizes available data from terminated and ongoing controlled trials on DOACs in children and adolescents.

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“…Presently, several direct oral anticoagulants (DOACs) are undergoing evaluation in paediatric development programs [ 68 , 69 , 70 , 71 , 72 , 73 ]. Randomized clinical trials for DOACs in paediatric VTE are ongoing.…”

Section: Treatmentmentioning

confidence: 99%

Venous Thromboembolism in Children: From Diagnosis to Management

Lassandro

Palmieri

Palladino

et al. 2020

IJERPH

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Venous thromboembolism (VTE) in children is a rare occurrence, although in recent decades we have seen an increase due to several factors, such as the rise in survival of subjects with chronic conditions, the use of catheters, and the increased sensitivity of diagnostic tools. Besides inherited thrombophilia, acquired conditions such as cardiovascular diseases, infections, chronic disorders, obesity and malignancy are also common risk factors for paediatric VTE. The treatment of paediatric VTE consists of the use of heparins and/or vitamin K antagonists to prevent dissemination, embolization, and secondary VTE. Randomized clinical trials of direct oral anticoagulants in paediatric VTE are ongoing, with the aim to improve the compliance and the care of patients. We reviewed the physiological and pathological mechanisms underlying paediatric thrombosis and updated the current diagnosis and treatment options.

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Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study

Cited by 45 publications

References 21 publications

Predictive Pediatric Modeling and Simulation Using Ontogeny Information

Predictive Pediatric Modeling and Simulation Using Ontogeny Information

Use of Direct Oral Anticoagulants in Children and Adolescents

Venous Thromboembolism in Children: From Diagnosis to Management

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