Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis. Issue 3 (9th October 2020)

• Record Type: Journal Article
• Authors: Cloesmeijer, Michael E.; van Esdonk, Michiel J.; Lynn, Anne M.; Smits, Anne; Tibboel, Dick; Daali, Youssef; Olkkola, Klaus T.; Allegaert, Karel; Mian, Paola
• Is Part Of: British journal of clinical pharmacology. Volume 87:Issue 3(2021)
• Page Start: 1443
• Page End: 1454
• Publication Date: 2020-10-09
• Subjects: adults -- analgesia -- ketorolac -- paediatrics -- population pharmacokinetics; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.14547
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : 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 EC50‐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.