The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis

Baba S. Mohammed; Thomas Engelhardt; Ahmed F. Hawwa; Garry A. Cameron; James S. McLay

doi:10.1111/jphp.12418

The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis

Baba S. Mohammed
, Thomas Engelhardt
, Ahmed F. Hawwa
, Garry A. Cameron
, James S. McLay^*

^*Corresponding author for this work

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

6 Citations (Scopus)

Abstract

OBJECTIVE: To describe the effect of age and body size on enantiomer selective pharmacokinetic (PK) of intravenous ketorolac in children using a microanalytical assay.

METHODS: Blood samples were obtained at 0, 15 and 30 min and at 1, 2, 4, 6, 8 and 12 h after a weight-dependent dose of ketorolac. Enantiomer concentration was measured using a liquid chromatography tandem mass spectrometry method. Non-linear mixed-effect modelling was used to assess PK parameters.

KEY FINDINGS: Data from 11 children (1.7-15.6 years, weight 10.7-67.4 kg) were best described by a two-compartment model for R(+), S(-) and racemic ketorolac. Only weight (WT) significantly improved the goodness of fit. The final population models were CL = 1.5 × (WT/46)(0.75) , V1 = 8.2 × (WT/46), Q = 3.4 × (WT/46)(0.75) , V2 = 7.9 × (WT/46), CL = 2.98 × (WT/46), V1 = 13.2 × (WT/46), Q = 2.8 × (WT/46)(0.75) , V2 = 51.5 × (WT/46), and CL = 1.1 × (WT/46)(0.75) , V1 = 4.9 × (WT/46), Q = 1.7 × (WT/46)(0.75) and V2 = 6.3 × (WT/46)for R(+), S(-) and racemic ketorolac.

CONCLUSIONS: Only body weight influenced the PK parameters for R(+) and S(-) ketorolac. Using allometric size scaling significantly affected the clearances (CL, Q) and volumes of distribution (V1 , V2 ).

Original language	English
Pages (from-to)	1179-1187
Number of pages	9
Journal	Journal of Pharmacy and Pharmacology
Volume	67
Issue number	9
Early online date	16 Apr 2015
DOIs	https://doi.org/10.1111/jphp.12418
Publication status	Published - Sept 2015

Bibliographical note

Funding
Funding for this study was provided from institutional source.

Acknowledgements
This work was carried out under the auspices of the Scottish Children Research Network (ScotCRN), a centre for mounting clinical trials and addressing the knowledge gaps in support of the effective and safe use of medicines in children. R(+) and S(−) ketorolac were kindly donated as research compounds by F. Hoffman-La Roche Ltd, Basel, Switzerland.

Funding

This work was carried out under the auspices of the Scottish Children Research Network (ScotCRN), a centre for mounting clinical trials and addressing the knowledge gaps in support of the effective and safe use of medicines in children. R(+) and S(-) ketorolac were kindly donated as research compounds by F. Hoffman-La Roche Ltd, Basel, Switzerland.

Keywords

allometry
enantiomer
ketorolac
paediatric
pharmacokinetic
postoperative pain
tromethamine
infants
morphine
humans
paracetamol
metabolism
model
size
administration
intravenous
adolescent
body weight
child
child, preschool
female
infant
male
nonlinear dynamics
stereoisomerism

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@article{b6ff965d5ad24f3ea8316b77e9e9fda9,

title = "The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis",

abstract = "OBJECTIVE: To describe the effect of age and body size on enantiomer selective pharmacokinetic (PK) of intravenous ketorolac in children using a microanalytical assay.METHODS: Blood samples were obtained at 0, 15 and 30 min and at 1, 2, 4, 6, 8 and 12 h after a weight-dependent dose of ketorolac. Enantiomer concentration was measured using a liquid chromatography tandem mass spectrometry method. Non-linear mixed-effect modelling was used to assess PK parameters.KEY FINDINGS: Data from 11 children (1.7-15.6 years, weight 10.7-67.4 kg) were best described by a two-compartment model for R(+), S(-) and racemic ketorolac. Only weight (WT) significantly improved the goodness of fit. The final population models were CL = 1.5 × (WT/46)(0.75) , V1 = 8.2 × (WT/46), Q = 3.4 × (WT/46)(0.75) , V2 = 7.9 × (WT/46), CL = 2.98 × (WT/46), V1 = 13.2 × (WT/46), Q = 2.8 × (WT/46)(0.75) , V2 = 51.5 × (WT/46), and CL = 1.1 × (WT/46)(0.75) , V1 = 4.9 × (WT/46), Q = 1.7 × (WT/46)(0.75) and V2 = 6.3 × (WT/46)for R(+), S(-) and racemic ketorolac.CONCLUSIONS: Only body weight influenced the PK parameters for R(+) and S(-) ketorolac. Using allometric size scaling significantly affected the clearances (CL, Q) and volumes of distribution (V1 , V2 ).",

keywords = "allometry, enantiomer, ketorolac, paediatric, pharmacokinetic, postoperative pain, tromethamine, infants, morphine, humans, paracetamol, metabolism, model, size, administration, intravenous, adolescent, body weight, child , child, preschool, female , infant, male, nonlinear dynamics, stereoisomerism",

author = "Mohammed, \{Baba S.\} and Thomas Engelhardt and Hawwa, \{Ahmed F.\} and Cameron, \{Garry A.\} and McLay, \{James S.\}",

note = "Funding Funding for this study was provided from institutional source. Acknowledgements This work was carried out under the auspices of the Scottish Children Research Network (ScotCRN), a centre for mounting clinical trials and addressing the knowledge gaps in support of the effective and safe use of medicines in children. R(+) and S(−) ketorolac were kindly donated as research compounds by F. Hoffman-La Roche Ltd, Basel, Switzerland.",

year = "2015",

month = sep,

doi = "10.1111/jphp.12418",

language = "English",

volume = "67",

pages = "1179--1187",

journal = "Journal of Pharmacy and Pharmacology",

issn = "0022-3573",

publisher = "Oxford University Press",

number = "9",

}

TY - JOUR

T1 - The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis

AU - Mohammed, Baba S.

AU - Engelhardt, Thomas

AU - Hawwa, Ahmed F.

AU - Cameron, Garry A.

AU - McLay, James S.

N1 - Funding Funding for this study was provided from institutional source. Acknowledgements This work was carried out under the auspices of the Scottish Children Research Network (ScotCRN), a centre for mounting clinical trials and addressing the knowledge gaps in support of the effective and safe use of medicines in children. R(+) and S(−) ketorolac were kindly donated as research compounds by F. Hoffman-La Roche Ltd, Basel, Switzerland.

PY - 2015/9

Y1 - 2015/9

N2 - OBJECTIVE: To describe the effect of age and body size on enantiomer selective pharmacokinetic (PK) of intravenous ketorolac in children using a microanalytical assay.METHODS: Blood samples were obtained at 0, 15 and 30 min and at 1, 2, 4, 6, 8 and 12 h after a weight-dependent dose of ketorolac. Enantiomer concentration was measured using a liquid chromatography tandem mass spectrometry method. Non-linear mixed-effect modelling was used to assess PK parameters.KEY FINDINGS: Data from 11 children (1.7-15.6 years, weight 10.7-67.4 kg) were best described by a two-compartment model for R(+), S(-) and racemic ketorolac. Only weight (WT) significantly improved the goodness of fit. The final population models were CL = 1.5 × (WT/46)(0.75) , V1 = 8.2 × (WT/46), Q = 3.4 × (WT/46)(0.75) , V2 = 7.9 × (WT/46), CL = 2.98 × (WT/46), V1 = 13.2 × (WT/46), Q = 2.8 × (WT/46)(0.75) , V2 = 51.5 × (WT/46), and CL = 1.1 × (WT/46)(0.75) , V1 = 4.9 × (WT/46), Q = 1.7 × (WT/46)(0.75) and V2 = 6.3 × (WT/46)for R(+), S(-) and racemic ketorolac.CONCLUSIONS: Only body weight influenced the PK parameters for R(+) and S(-) ketorolac. Using allometric size scaling significantly affected the clearances (CL, Q) and volumes of distribution (V1 , V2 ).

AB - OBJECTIVE: To describe the effect of age and body size on enantiomer selective pharmacokinetic (PK) of intravenous ketorolac in children using a microanalytical assay.METHODS: Blood samples were obtained at 0, 15 and 30 min and at 1, 2, 4, 6, 8 and 12 h after a weight-dependent dose of ketorolac. Enantiomer concentration was measured using a liquid chromatography tandem mass spectrometry method. Non-linear mixed-effect modelling was used to assess PK parameters.KEY FINDINGS: Data from 11 children (1.7-15.6 years, weight 10.7-67.4 kg) were best described by a two-compartment model for R(+), S(-) and racemic ketorolac. Only weight (WT) significantly improved the goodness of fit. The final population models were CL = 1.5 × (WT/46)(0.75) , V1 = 8.2 × (WT/46), Q = 3.4 × (WT/46)(0.75) , V2 = 7.9 × (WT/46), CL = 2.98 × (WT/46), V1 = 13.2 × (WT/46), Q = 2.8 × (WT/46)(0.75) , V2 = 51.5 × (WT/46), and CL = 1.1 × (WT/46)(0.75) , V1 = 4.9 × (WT/46), Q = 1.7 × (WT/46)(0.75) and V2 = 6.3 × (WT/46)for R(+), S(-) and racemic ketorolac.CONCLUSIONS: Only body weight influenced the PK parameters for R(+) and S(-) ketorolac. Using allometric size scaling significantly affected the clearances (CL, Q) and volumes of distribution (V1 , V2 ).

KW - allometry

KW - enantiomer

KW - ketorolac

KW - paediatric

KW - pharmacokinetic

KW - postoperative pain

KW - tromethamine

KW - infants

KW - morphine

KW - humans

KW - paracetamol

KW - metabolism

KW - model

KW - size

KW - administration

KW - intravenous

KW - adolescent

KW - body weight

KW - child

KW - child, preschool

KW - female

KW - infant

KW - male

KW - nonlinear dynamics

KW - stereoisomerism

U2 - 10.1111/jphp.12418

DO - 10.1111/jphp.12418

M3 - Article

C2 - 25880462

SN - 0022-3573

VL - 67

SP - 1179

EP - 1187

JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

IS - 9

ER -

The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis

Abstract

Bibliographical note

Funding

Keywords

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