Pharmacokinetics and soft-tissue distribution of tebipenem pivoxil hydrobromide using microdialysis: a study in healthy subjects and patients with diabetic foot infections

Abstract Objective Tebipenem pivoxil hydrobromide is a novel oral carbapenem prodrug of tebipenem, the active moiety. We assessed tebipenem steady-state pharmacokinetics in the skin and soft tissue in healthy subjects and infected patients with diabetes using in vivo microdialysis. Methods Six healthy subjects and six patients with an ongoing diabetic foot infection (DFI) received tebipenem pivoxil hydrobromide 600 mg orally every 8 h for three doses. A microdialysis probe was inserted in the thigh of healthy subjects or by the wound margin in patients. Plasma and dialysate samples were obtained immediately prior to the third dose and sampled over 8 h. Results Tebipenem plasma protein binding (mean ± SD) was 50.2% ± 2.4% in healthy subjects and 53.5% ± 5.6% in infected patients. Mean ± SD tebipenem pharmacokinetic parameters in plasma for healthy subjects and infected patients were: maximum free concentration (fCmax), 3.74 ± 2.35 and 3.40 ± 2.86 mg/L, respectively; half-life, 0.88 ± 0.11 and 2.02 ± 1.32 h; fAUC0–8, 5.61 ± 1.64 and 10.01 ± 4.81 mg·h/L. Tebipenem tissue AUC0–8 was 5.99 ± 3.07 and 8.60 ± 2.88 mg·h/L for healthy subjects and patients, respectively. The interstitial concentration–time profile largely mirrored the free plasma profile within both populations, resulting in a penetration ratio of 107% in healthy subjects and 90% in infected patients. Conclusions Tebipenem demonstrated excellent distribution into skin and soft tissue of healthy subjects and patients with DFI following oral administration of 600 mg of tebipenem pivoxil hydrobromide.