Abstract
Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p < 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p < 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.
Highlights
Racemic ketoprofen is a chiral 2-arylpropionic acid derivative nonsteroidal anti-inflammatory drug (NSAID) with antiinflammatory and antipyretic properties
In this work, we aimed to explore the influence of several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g., CYP or UGT) or transporters (e.g., ATP Binding Cassette (ABC) or solute carrier transporters (SLC)) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription
Bioequivalence clinical trials offer a controlled setting for the evaluation of pharmacokinetic variability based on genetic polymorphism or demographics as confounding factors are avoided. These results can be considered preliminary and further studies are needed to confirm the hypotheses that were raised in the study. This candidate gene study is, to our knowledge, the only one published to date (n 85) with a comprehensive genotype screening strategy based on a robust dataset, which lays the foundation for exploring dexketoprofen pharmacogenetics in the future
Summary
Racemic ketoprofen is a chiral 2-arylpropionic acid derivative nonsteroidal anti-inflammatory drug (NSAID) with antiinflammatory and antipyretic properties. The (S)(+)-enantiomer (dexketoprofen) is active, while (R)(−)-ketoprofen is completely inactive (Barbanoj et al, 2001). Maximum daily dose is 75 mg, being 25 mg/8 h, 12.5 mg/4 h or 12.5 mg/6 h the recommended doses. Those with hepatic or renal impairment, the maximum daily dose should be reduced and patients should be closely monitored. Administered as a water-soluble salt (dexketoprofen trometamol), dexketoprofen reaches the maximum concentration (Cmax) 30 min (15–60 min) after drug intake; absorption is delayed by the presence of food. It is extensively glucuronized to conjugates and eliminated in urine in this form (Barbanoj et al, 2001; Agencia Española del Medicamento y Productos Sanitarios (AEMPS), 2021)
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