Extrapolation and dosing recommendations for raxibacumab in children from birth to age <18 years

Abstract

What is already known about this subjecto Raxibacumab is recommended for administration in adult patients as a single intravenous dose of 40 mg/kg, with paediatric doses ranging from 40 mg/kg to 80 mg/kg. These doses have been selected under the assumption that drug disposition across the overall paediatric population varies primarily due to developmental growth What this study addso This study assesses whether maturation processes in neonates, infants, and toddlers, affect raxibacumab disposition and consequently the systemic exposure in this group of patients.o While mAb pharmacokinetics are known to vary due to body weight, dosing regimens in paediatrics need to consider maturation processes to ensure optimized exposure.

Population pharmacokinetics and dose rationale for aciclovir in term and pre‐term neonates with herpes

“…Although pharmacokinetic data remains limited in the neonatal patient population, the current investigation aimed to evaluate the effect of developmental growth, organ function and disease severity on the disposition of aciclovir to better understand interindividual differences in exposure and consequently confirm the dose rationale for this age group based on pharmacokinetic‐pharmacodynamic principles. 11 , 12 , 13 In addition, our analysis has shown how exposure in neonates compares with older infants, children, adolescents and adult patients. 14 , 29 …”

“…Although pharmacokinetic data remains limited in the neonatal patient population, the current investigation aimed to evaluate the effect of developmental growth, organ function and disease severity on the disposition of aciclovir to better understand interindividual differences in exposure and consequently confirm the dose rationale for this age group based on pharmacokinetic-pharmacodynamic principles. [11][12][13] In addition, our analysis has shown how exposure in neonates compares with older infants, children, adolescents and adult patients. 14,29 Even though there is limited understanding of the mechanisms associated with the maturation processes and the effect of renal dysfunction on the clearance of aciclovir in pre-term and term neonates, we believe that the current results provide further insight into the role of age-and disease-related factors on the disposition properties in this small group of patients.…”

“…The dose rationale for neonates, and in particular in pre‐term new‐borns, has been based on empirical evidence of efficacy and safety, without further consideration of the different factors that may determine drug disposition and overall exposure to the active moiety. Although pharmacokinetic data remains limited in the neonatal patient population, the current investigation aimed to evaluate the effect of developmental growth, organ function and disease severity on the disposition of aciclovir to better understand interindividual differences in exposure and consequently confirm the dose rationale for this age group based on pharmacokinetic‐pharmacodynamic principles 11–13 . In addition, our analysis has shown how exposure in neonates compares with older infants, children, adolescents and adult patients 14,29 …”

“…Yet, there has not been any systematic attempt to establish how exposure in neonates compares across the overall population. 11 , 12 Besides, available pharmacokinetic models do not include the effect of disease and organ function to better understand interindividual differences in exposure and consequently establish the dose rationale for this age group. 13 Of note has been the lack of covariates that describe the maturation of renal function (i.e., glomerular filtration and active tubular secretion) over the first few weeks after birth.…”

“…Such a rationale raise an interesting point, namely, that if aciclovir had been developed according to current guidelines for pediatric drug development, 9,10 its efficacy in neonates could have been extrapolated from adults and older pediatric patients based on a dosing regimen that yields exposure comparable to the efficacious range observed in the reference population. Yet, there has not been any systematic attempt to establish how exposure in neonates compares across the overall population 11,12 . Besides, available pharmacokinetic models do not include the effect of disease and organ function to better understand interindividual differences in exposure and consequently establish the dose rationale for this age group 13 .…”