Investigating PXR (NR1I2) genetic polymorphisms as possible determinants of the magnitude of the clindamycin-rifampicin pharmacokinetic interaction.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.