Investigating PXR (NR1I2) Genetic Polymorphisms As Possible Determinants of the Magnitude of the Clindamycin–rifampicin Pharmacokinetic Interaction

Rifampicin is known to induce clindamycin metabolism via CYP3A4/5, but the magnitude of this interaction varies greatly from one patient to another. Because this metabolic induction results from rifampicin activation of the nuclear pregnane X receptor (PXR), the genetic polymorphisms of its NR1I2 gene and that of CYP3A4/5 might predict the risk of clindamycin underdosage when combined with rifampicin. We therefore conducted a study to determine the possible influence of NR1I2 and CYP3A4/5 gene polymorphisms on baseline and rifampicin-induced clindamycin clearance. Eighty-five patients were included and sequentially received clindamycin by continuous infusion alone and then combined with rifampicin. The clindamycin steady-state concentration (Css) was measured for each patient before and during combination therapy. Clindamycin clearance during the 2 phases was calculated as the infusion rate/Css ratio. Five single nucleotide polymorphisms (SNPs) in the NR1I2, CYP3A4*22 and CYP3A5*3 genes were investigated. Clindamycin clearances alone and with combined rifampicin were 11.29 ± 5.54 and 46.14 ± 60.13 L/h, respectively. The minimal target clindamycin Css of 3 mg/L was not achieved in 31 patients. None of the investigated SNPs had any observed impact. None of the investigated SNPs can be used to predict the risk of clindamycin underdosage when combined with rifampicin. Further research is warranted to advance our understanding of this issue.