Dataset Information

Initial dose recommendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics.

ABSTRACT: OBJECTIVE:Sirolimus has been used to treat paediatric kaposiform haemangioendothelioma patients. However, there is considerable pharmacokinetic variability among individuals, and it is difficult to develop an initial dosing regimen. The goal of the present study is to recommend an initial sirolimus dose in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics. METHODS:This was a retrospective clinical study. A population pharmacokinetics model was established and population characteristics, laboratory test results, drug combinations, and pharmacogenomics were considered as potential covariates. The Monte Carlo method was used to simulate the optimal initial dosage. RESULTS:The final covariates that affect sirolimus clearance include weight and the CYP3A5 genotype. The initial dosage of sirolimus for individuals with CYP3A5*3/*3 was 0.20?mg/kg split into two doses for 5 to 60 kg body weight. For individuals with CYP3A5*1, the initial dose was 0.23?mg/kg split into two doses for 5 to 30 kg body weight and 0.20?mg/kg split into two doses for 30 to 60 kg body weight. CONCLUSION:The recommendation for the initial sirolimus dose in paediatric kaposiform haemangioendothelioma patients was based on population pharmacokinetics and pharmacogenomics. This study may provide practical value for sirolimus clinical use in paediatric kaposiform haemangioendothelioma patients.

SUBMITTER: Chen X

PROVIDER: S-EPMC7444137 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Initial dose recommendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics.

Chen Xiao X Wang Dong-Dong DD Xu Hong H Li Zhi-Ping ZP

The Journal of international medical research 20200801 8

<h4>Objective</h4>Sirolimus has been used to treat paediatric kaposiform haemangioendothelioma patients. However, there is considerable pharmacokinetic variability among individuals, and it is difficult to develop an initial dosing regimen. The goal of the present study is to recommend an initial sirolimus dose in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics.<h4>Methods</h4>This was a retrospective clinical study. A population pha ...[more]

PMID: 32815764

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Project description:BackgroundVenous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population.ObjectiveThe objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0-18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients.MethodsExperimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration-time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations.ResultsSimulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However, pharmacokinetic values in infants and preschool children (body weight <40 kg) were lower than the 90 % confidence interval threshold of the adult reference model and, therefore, indicated that doses in these groups may need to be increased to achieve the same plasma levels as in adults. For children with body weight between 40 and 70 kg, simulated plasma pharmacokinetic parameters (C max, C 24h and AUC) overlapped with the values obtained in the corresponding adult reference simulation, indicating that body weight-related exposure was similar between these children and adults. In adolescents of >70 kg body weight, the simulated 90 % prediction interval values of AUC and C 24h were much higher than the 90 % confidence interval of the adult reference population, owing to the weight-based simulation approach, but for these patients rivaroxaban would be administered at adult fixed doses of 10 and 20 mg.ConclusionThe paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients.

Project description:The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex.Sirolimus concentration-time data were collected from an ongoing prospective trial in children with NF1. An iterative 2-stage Bayesian method was used for the PK parameter analyses.Data from 44 patients with NF1 were included in the analyses. Mean age was 8.4 years (SD 4.5, range 3-18), and mean weight was 29.8 kg (SD 16.7, range 12-85.8). Mean sirolimus clearance was 11.8 L/h (SD 4.6, range 2.2-24.1), and the mean dose to obtain a target trough concentration of 10-15 ng/mL was 2.0 mg/m administered twice daily (SD 0.72, range 0.77-3.85). A nonlinear relationship between age and clearance was observed. Total body weight and BSA were strong predictors of sirolimus clearance (r = 0.67 and 0.65, respectively).Sirolimus clearance in children with NF1 is comparable with that in pediatric transplant patients. Clearance was most associated with body size parameters (BSA and total body weight) in children with NF1. When normalized for size, an age effect on clearance was observed in the youngest patients, most likely because of the maturational changes in drug absorption and metabolism. A mean dose of 2.0 mg/m twice a day was required for attainment of target trough concentrations of 10-15 ng/mL in children greater than 3 years of age who have NF1. The updated model will allow PK-guided individualized dosing of sirolimus in patients with NF1.

Dataset Information

Initial dose recommendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics.

Publications

Initial dose recommendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics.

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