Ranibizumab population pharmacokinetics and free vegf pharmacodynamics in preterm infants with retinopathy of prematurity in the rainbow trial

RAINBOW study group

doi:10.1167/tvst.9.8.43

Ranibizumab population pharmacokinetics and free vegf pharmacodynamics in preterm infants with retinopathy of prematurity in the rainbow trial

RAINBOW study group

Ophthalmology

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Purpose: To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

Original language	English (US)
Article number	43
Pages (from-to)	1-10
Number of pages	10
Journal	Translational Vision Science and Technology
Volume	9
Issue number	8
DOIs	https://doi.org/10.1167/tvst.9.8.43
State	Published - Jul 2020

Keywords

Pharmacokinetics
ROP
Ranibizumab
VEGF

ASJC Scopus subject areas

Biomedical Engineering
Ophthalmology

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10.1167/tvst.9.8.43

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@article{8c9f4b7a365d4a1c90d783796ba13ab5,

title = "Ranibizumab population pharmacokinetics and free vegf pharmacodynamics in preterm infants with retinopathy of prematurity in the rainbow trial",

abstract = "Purpose: To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.",

keywords = "Pharmacokinetics, ROP, Ranibizumab, VEGF",

author = "{RAINBOW study group} and Matthew Fidler and Fleck, {Brian W.} and Andreas Stahl and Neil Marlow and Chastain, {James E.} and Jun Li and Domenico Lepore and Reynolds, {James D.} and Chiang, {Michael F.} and Fielder, {Alistair R.}",

note = "Funding Information: The authors thank Daniel Stiehl, MD, (Novar-tis Pharma AG, Basel, Switzerland) for his expert input on patient safety aspects of the study and for critical review of the manuscript. The authors also acknowledge the editorial support (including compilation and addressal of comments from authors) provided by Lakshmi Deepa Gurajala, PhD, of Novar-tis Healthcare Pvt. Ltd, Hyderabad, India, which was funded by Novartis Pharma AG, Basel, Switzerland. The RAINBOW study investigators (Supplementary Appendix Table S3) lead activity in the study centers and contributed data. Publisher Copyright: {\textcopyright} 2020 The Authors.",

year = "2020",

month = jul,

doi = "10.1167/tvst.9.8.43",

language = "English (US)",

volume = "9",

pages = "1--10",

journal = "Translational Vision Science and Technology",

issn = "2164-2591",

publisher = "Association for Research in Vision and Ophthalmology Inc.",

number = "8",

}

TY - JOUR

T1 - Ranibizumab population pharmacokinetics and free vegf pharmacodynamics in preterm infants with retinopathy of prematurity in the rainbow trial

AU - RAINBOW study group

AU - Fidler, Matthew

AU - Fleck, Brian W.

AU - Stahl, Andreas

AU - Marlow, Neil

AU - Chastain, James E.

AU - Li, Jun

AU - Lepore, Domenico

AU - Reynolds, James D.

AU - Chiang, Michael F.

AU - Fielder, Alistair R.

N1 - Funding Information: The authors thank Daniel Stiehl, MD, (Novar-tis Pharma AG, Basel, Switzerland) for his expert input on patient safety aspects of the study and for critical review of the manuscript. The authors also acknowledge the editorial support (including compilation and addressal of comments from authors) provided by Lakshmi Deepa Gurajala, PhD, of Novar-tis Healthcare Pvt. Ltd, Hyderabad, India, which was funded by Novartis Pharma AG, Basel, Switzerland. The RAINBOW study investigators (Supplementary Appendix Table S3) lead activity in the study centers and contributed data. Publisher Copyright: © 2020 The Authors.

PY - 2020/7

Y1 - 2020/7

N2 - Purpose: To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

AB - Purpose: To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

KW - Pharmacokinetics

KW - ROP

KW - Ranibizumab

KW - VEGF

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U2 - 10.1167/tvst.9.8.43

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JO - Translational Vision Science and Technology

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ER -

Ranibizumab population pharmacokinetics and free vegf pharmacodynamics in preterm infants with retinopathy of prematurity in the rainbow trial

Abstract

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