Probenecid effects on cephalexin pharmacokinetics and pharmacodynamics in healthy volunteers

We evaluated the effects of probenecid on the Pharmaco Kinetics (PK) and pharmacodynamics (PD) of oral cephalexin in healthy volunteers.

Cephalexin 1000 mg was administered orally to 11 healthy volunteers following a standardized meal, with and without probenecid 500 mg orally, on two separate days one week apart. Total plasma concentrations of cephalexin and probenecid over a 12 h period were measured by liquid chromatography tandem mass spectrometry. Standard pharmacokinetic measures and contemporary PK/PD targets were compared.

Probenecid increased the mean (95% CI) cephalexin area under the concentration-time curve (AUC_0-∞) 1.73-fold (1.61-1.85, p < 0.0001), peak concentration 1.37-fold (1.16-1.58, p < 0.01), time to peak concentration 1.45-fold (1.1-1.8, p < 0.01)_, and half-life 1.33-fold (1.03-1.62, p < 0.05). The effects resulted in clinically meaningful increases in the probability of PK/PD target attainment (PTA). As an example, the PTA of total concentrations above the minimum inhibitory concentration required to inhibit methicillin-susceptible Staphylococcus aureus isolates (MIC ≤ 8 mg/L) for 70% of a 6 h dose interval approached 100% for cephalexin + probenecid while for cephalexin alone it was <15%.

Probenecid prolonged and flattened the plasma concentration-time curve, enhancing the probability of attaining PK/PD targets. Co-administration of probenecid may expand the clinical benefits of oral cephalexin.