l-084 and tebipenem

Topics: Administration, Oral; Anti-Bacterial Agents; Carbapenems; Humans; Monobactams; Prodrugs; Pyelonephritis; Urinary Tract Infections

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.. 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.. 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.. 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.

Topics: Communicable Diseases; Diabetes Mellitus; Diabetic Foot; Healthy Volunteers; Humans; Microdialysis; Monobactams; Tissue Distribution

Tebipenem pivoxil (TBPM-PI) has been developed as the first oral carbapenem drug in the world to treat otolaryngological and respiratory infections in pediatric patients. Due to its structural properties and external factors, some related impurities, which may cause side effects in patients, might be formed during the synthesis and storage of TBPM-PI. It was vital to rapidly separate and identify the related impurities to guarantee the safe use of TBPM-PI.. A method using ultra-high-performance liquid chromatography (UHPLC) coupled with quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) was developed to separate and detect TBPM-PI and related impurities in an oral pharmaceutical formulation. LC/MS and MS/MS spectra of these compounds in the formulation were acquired to confirm their elemental compositions and propose their structures based on LC/MS data and fragmentation pathways of available reference substances.. LC/MS parameters and MS/MS fragmentation pathways of reference substances of TBPM-PI and related impurities were summarized in detail. Based on this, a total of 23 related impurities were found and characterized in the oral pharmaceutical formulation. Eight of these were verified by comparison with reference substances and the structures of the other 15 were proposed for the first time. In addition, four of these compounds were produced by the reaction of excipients and pre-existing related impurities.. A UHPLC/QTOF-MS method was established and used for the separation and identification of 23 related impurities in a TBPM-PI oral pharmaceutical formulation. Moreover, it was proved that new related impurities could be produced by the reaction of excipients in the pharmaceutical formulation and related impurities in the corresponding active pharmaceutical ingredient (API).

Topics: Carbapenems; Chromatography, High Pressure Liquid; Dosage Forms; Drug Contamination; Models, Molecular; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry