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

Research output: Contribution to journalArticle

5 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 languageEnglish
Pages (from-to)1179-1187
Number of pages9
JournalJournal of Pharmacy and Pharmacology
Volume67
Issue number9
Early online date16 Apr 2015
DOIs
Publication statusPublished - Sep 2015

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

Cite this

The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis. / Mohammed, Baba S.; Engelhardt, Thomas; Hawwa, Ahmed F.; Cameron, Garry A.; McLay, James S.

In: Journal of Pharmacy and Pharmacology, Vol. 67, No. 9, 09.2015, p. 1179-1187.

Research output: Contribution to journalArticle

@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 = "9",
doi = "10.1111/jphp.12418",
language = "English",
volume = "67",
pages = "1179--1187",
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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

VL - 67

SP - 1179

EP - 1187

JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

SN - 0022-3573

IS - 9

ER -