In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents

Rajith K.R. Rajoli, David J. Back, Steve Rannard, Caren L Meyers, Charles Williams Flexner, Andrew Owen, Marco Siccardi

Research output: Contribution to journalArticle

Abstract

Background and Objectives: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3–18 years) using physiologically-based pharmacokinetic modelling. Methods: Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations. Results: Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg. Conclusions: The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalClinical Pharmacokinetics
DOIs
StateAccepted/In press - May 24 2017

Fingerprint

Rilpivirine
Computer Simulation
Pharmacokinetics
Injections
Physiological Phenomena
Weights and Measures
Drug Costs

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents. / Rajoli, Rajith K.R.; Back, David J.; Rannard, Steve; Meyers, Caren L; Flexner, Charles Williams; Owen, Andrew; Siccardi, Marco.

In: Clinical Pharmacokinetics, 24.05.2017, p. 1-12.

Research output: Contribution to journalArticle

@article{9258e39f14924ed8b2c87b482af67f2b,
title = "In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents",
abstract = "Background and Objectives: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3–18 years) using physiologically-based pharmacokinetic modelling. Methods: Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations. Results: Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg. Conclusions: The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.",
author = "Rajoli, {Rajith K.R.} and Back, {David J.} and Steve Rannard and Meyers, {Caren L} and Flexner, {Charles Williams} and Andrew Owen and Marco Siccardi",
year = "2017",
month = "5",
day = "24",
doi = "10.1007/s40262-017-0557-x",
language = "English (US)",
pages = "1--12",
journal = "Clinical Pharmacokinetics",
issn = "0312-5963",
publisher = "Adis International Ltd",

}

TY - JOUR

T1 - In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents

AU - Rajoli, Rajith K.R.

AU - Back, David J.

AU - Rannard, Steve

AU - Meyers, Caren L

AU - Flexner, Charles Williams

AU - Owen, Andrew

AU - Siccardi, Marco

PY - 2017/5/24

Y1 - 2017/5/24

N2 - Background and Objectives: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3–18 years) using physiologically-based pharmacokinetic modelling. Methods: Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations. Results: Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg. Conclusions: The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.

AB - Background and Objectives: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3–18 years) using physiologically-based pharmacokinetic modelling. Methods: Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations. Results: Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg. Conclusions: The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.

UR - http://www.scopus.com/inward/record.url?scp=85019621899&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019621899&partnerID=8YFLogxK

U2 - 10.1007/s40262-017-0557-x

DO - 10.1007/s40262-017-0557-x

M3 - Article

SP - 1

EP - 12

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

SN - 0312-5963

ER -