Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis

Abstract

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 Sand R-ketorolac exposure. Results: Sand 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 Sand R-ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.

Retinal and Systemic Toxicity of Vigabatrin Is Driven by the S-Enantiomer in the Long Evans Rat

“…That enantiomers may have different kinetic profiles and may even be best described using different compartment models has been seen for other compounds such as S- and R-ketorolac. 23…”

Efficacy and Safety of NSAIDs in Infants: A Comprehensive Review of the Literature of the Past 20 Years

“…Overview of studies published after 2000 [ 17 , 25 – 28 , 33 , 34 , 38 , 39 , 41 , 42 , 46 , 51 , 52 , 63 , 64 , 67 , 71 , 72 , 273 , 274 , 277 – 280 , 317 , 318 ] No. of patients Age (range) Body weight [kg] Dose [mg/kg] Compartment absorption elimination PK parameters References F [%] AUC [mg⋅h/L] C max [mg/L] T max [h] t ½ [h] V d / F [L/kg] CL/ F [L/h] Metabolism Ibuprofen 9 4.2 ± 1.9 weeks (1–7 weeks) 4.4 ± 0.6 19.0 ± 1.6 RECT NA NA 299 ± 69 49.2 ± 20.7 1.9 ± 1.2 h 4.6 ± 5.1 NA NA CYP2C8 CYP2C9 UGT2B7 [ 278 ] 8 16.1 ± 6.9 weeks (8–25 weeks) 6.7 ± 1.4 …”

“…This dosing regimen is in agreement with current practice. Recently, it was shown that S-enantiomers produce different concentrations between infants and adults, and therefore requires further research as this difference in S-enantiomer concentration may have an important effect on analgesia since the S-enantiomer is solely responsible for the analgesic effect [ 51 ]. When clinical and patient covariates were assessed for effects on PK, it was found that no covariates were statistically significant when accounted for body size [ 52 ].…”

Stellate Ganglion Block: Comparison of Different Doses of Ketorolac After Breast Cancer Surgeries

“…There is also a low risk of gastrointestinal and operative site bleeding and acute renal insufficiency. Some people also experience itching, diarrhea, sweating, self-limiting wheezing, edema and hyperkalemia (17) . Interestingly, the current study compared the first request analgesia and total analgesia between studied groups.…”