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Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis
Author(s) -
Cloesmeijer Michael E.,
Esdonk Michiel J.,
Lynn Anne M.,
Smits Anne,
Tibboel Dick,
Daali Youssef,
Olkkola Klaus T.,
Allegaert Karel,
Mian Paola
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14547
Subject(s) - ketorolac , pharmacokinetics , enantiomer , analgesic , population , nonmem , pharmacology , chemistry , pharmacodynamics , bioavailability , medicine , anesthesia , stereochemistry , environmental health
Aims Ketorolac is a nonsteroidal anti‐inflammatory racemic drug with analgesic effects only attributed to its S‐enantiomer. The aim of this study is to quantify enantiomer‐specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants. Methods Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry‐based enantiomer‐specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S‐ and R‐ketorolac exposure. Results S‐ and R‐ketorolac PK were best described with a 3‐ and a 2‐compartment model, respectively. The allometry‐based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S‐ketorolac concentration of 0.057 mg/L, but a mean S‐ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S‐ketorolac‐concentration (0.057 mg/L) in typical infants, the EC 50‐racemic should be increased to 0.41 mg/L. Conclusion Enantiomer‐specific changes in ketorolac PK yield different concentrations and S‐ and R‐ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.