Effect of ibuprofen on the pharmacokinetics of intravenous flucloxacillin in healthy adults

Abstract

Objective: Ibuprofen is frequently co-administered with antibiotics for its analgesic effect when treating infections. In vitro studies have shown that ibuprofen exhibits concentration-dependent inhibition of organic anion transporters (OAT) 1 and OAT3, and therefore may reduce clearance of β-lactams, including flucloxacillin, in a similar manner to probenecid. We therefore aimed to evaluate the effect of ibuprofen on the pharmacokinetics (PK) of flucloxacillin in healthy volunteers.

Methods: A single-site PK study of 10 healthy adult volunteers was carried out. Over a 3-d intervention period, participants received intravenous (IV) flucloxacillin 2000 mg twice daily with oral ibuprofen 400 mg twice daily on days 2 and 3. Total and unbound flucloxacillin plasma concentrations were collected at predefined time points. A population PK model was developed using a non-linear mixed-effects modelling approach, and ibuprofen was assessed as a covariate in the final model.

Results: Ten participants with a median age of 24.4 y (range 18.8-54.5 y) and median weight of 68.3 kg (range 50.5-85.7 kg) were included. A median of 51.5 (range 34-52) samples was collected per participant. The final two-compartment model included saturable protein binding and allometric scaling of weight on clearance. Ibuprofen was not found to be a significant covariate on K_d (binding dissociation constant), B_max (maximum binding capacity), or clearance.

Conclusion: Orally administered ibuprofen had no measurable effect on plasma flucloxacillin PK in healthy adults. Given the lack of drug-drug interaction, there is no benefit to prescribing ibuprofen alongside flucloxacillin to increase flucloxacillin exposure.

Keywords: Antibacterial agents; Floxacillin; Healthy volunteers; Pharmacokinetics; β-lactam.