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Crystal structure of tebipenem pivoxil.

ABSTRACT: The mol-ecular structure of the first orally active carbapenem anti-bacterial agent, tebipenem pivoxil (systematic name: (2,2-di-methyl-propano-yloxy)methyl (4R,5S,6S)-3-{[1-(4,5-di-hydro-1,3-thia-zol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hy-droxy-eth-yl]-4-methyl-7-oxo-1-aza-bicyclo-[3.2.0]hept-2-ene-2-carboxyl-ate), C₂₂H₃₁N₃O₆S₂, has been determined and the configurations of the four chiral centers validated. The title compound crystallizes in the triclinic space group P1 with one mol-ecule in the unit cell. Three out of the four rings adopt planar conformations while the thia-zolinyl ring adopts an enveloped conformation. In the crystal, O-H?N hydrogen bonds link the mol-ecules into chains along [10].

SUBMITTER: Tang C

PROVIDER: S-EPMC6127708 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Crystal structure of tebipenem pivoxil.

Tang Chao C Cai Li L Liu Shuai S Zheng Zhiwei Z Li Gen G Chen Jianli J Sui Qiang Q

Acta crystallographica. Section E, Crystallographic communications 20180810 Pt 9

The mol-ecular structure of the first orally active carbapenem anti-bacterial agent, tebipenem pivoxil (systematic name: (2,2-di-methyl-propano-yloxy)methyl (4R,5S,6S)-3-{[1-(4,5-di-hydro-1,3-thia-zol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hy-droxy-eth-yl]-4-methyl-7-oxo-1-aza-bicyclo-[3.2.0]hept-2-ene-2-carboxyl-ate), C22H31N3O6S2, has been determined and the configurations of the four chiral centers validated. T ...[more]

PMID: 30225102

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Project description:Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug being developed for the treatment of serious bacterial infections. The active moiety, tebipenem, has broad-spectrum activity against common Enterobacterales pathogens, including extended-spectrum-β-lactamase (ESBL)-producing multidrug-resistant strains. This study evaluated the intrapulmonary pharmacokinetics (PK) and epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations of tebipenem relative to plasma levels in nonsmoking, healthy adult subjects. Thirty subjects received oral TBP-PI-HBr at 600 mg every 8 h for five doses. Serial blood samples were collected following the last dose. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) 1, 2, 4, 6, or 8 h after the fifth dose of TBP-PI-HBr. The tebipenem area under the concentration-time curve for the 8-h dosing interval (AUC0-8) values in plasma, ELF, and AMs were calculated using the mean concentration at each BAL sampling time. Ratios of AUC0-8 values for total ELF and AMs to those for unbound plasma were determined, using a plasma protein binding value of 42%. Mean values ± standard deviations (SD) of tebipenem maximum (Cmax) and minimum (Cmin) total plasma concentrations were 11.37 ± 3.87 mg/L and 0.043 ± 0.039 mg/L, respectively. Peak tebipenem concentrations in plasma, ELF, and AMs occurred at 1 h and then decreased over 8 h. Ratios of tebipenem AUC0-8 values for ELF and AMs to those for unbound plasma were 0.191 and 0.047, respectively. Four (13.3%) subjects experienced adverse events (diarrhea, fatigue, papule, and coronavirus disease 2019 [COVID-19]); all resolved, and none were severe or serious. Tebipenem is distributed into the lungs of healthy adults, which supports the further evaluation of TBP-PI-HBr for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT04710407.).

Project description:Tebipenem pivoxil (TBPM-PI), an oral carbapenem antibiotic, has shown special advantages in pediatric infections and was in urgent need in China. Although pharmacokinetics, urinary excretion, and metabolite information of its active form tebipenem (TBPM) has been reported, ethnic differences may exist among the Chinese and Japanese population. By now, no systematic pharmacokinetics, urinary excretion, metabolites, or safety information has been revealed to the Chinese population. The purpose of the present work was to investigate abovementioned information of TBPM-PI granules after oral single ascending doses of 100, 200, and 400 mg in Chinese volunteers. Based on the pharmacokinetic study, the urine pharmaco-metabolomic analysis was conducted to reveal metabolomic interruptions and metabolite information. The study design was a single-center, open-label, randomized, single-dose pharmacokinetic study of 36 healthy volunteers (with half of them being male and the other half female). Time to maximum concentration (T max) was reached at 0.50, 0.50, or 0.67 h for 100, 200, or 400 mg, respectively. The linear pharmacokinetic characteristic of maximum plasma concentration (C max) was detected over 100-200 mg. The area under the concentration time curve (AUC) was proportional to the dose in the range of 100-400 mg. The maximum urinary excretion rate was detected at 0-1 or 1-2 h for dose of 100 or 200-400 mg. Cumulative amount of TBPM excreted in urine by 24 h accounted up to 90, 95, and 80% of dose administered for three groups, respectively. The pharmaco-metabolomic analysis revealed urine metabolic trajectory of deviation at 0-1 or 1-2 h and gradually regressing back to the pre-dose group at the following time periods. Urine metabolites from M1 to M4 were identified, indicating ethnic difference in metabolites among the Chinese or Japanese population. The current work proved safety and tolerance of single-dose administration of oral TBPM-PI in Chinese healthy volunteers over doses of 100-400 mg. All these results provide pharmacokinetics, urine excretion, urine metabolomics, urine metabolites, and safety information in healthy Chinese volunteers after oral single ascending doses of TBPM-PI, benefitting further development and clinical utilities.

Project description:Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug being developed for the treatment of serious bacterial infections. This open-label, 3-period, fixed sequence study evaluated the effect of gastric acid-reducing agents, aluminum hydroxide/magnesium hydroxide/simethicone, and omeprazole on the pharmacokinetics (PK) of tebipenem (TBP), the active moiety, following coadministration with immediate release TBP-PI-HBr during fasting. In Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 × 300 mg tablets). In Period 2, subjects received a single oral dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension co-administered with a single dose of TBP-PI-HBr 600 mg. In Period 3, subjects received a single oral dose of omeprazole 40 mg once daily over 5 days, followed by single dose administration of TBP-PI-HBr 600 mg on day 5. In each period, whole blood samples were obtained prior to, and up to 24 h, following TBP-PI-HBr dose administration in order to characterize TBP PK. A 7-day washout was required between periods. Twenty subjects were enrolled and completed the study. Following co-administration of TBP-PI-HBr with either aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole, total TBP exposure (area under the curve [AUC]) was approximately 11% (geometric mean ratio 89.2, 90% confidence interval: 83,2, 95.7) lower, and Cmax was 22% (geometric mean ratio 78.4, 90% confidence interval: 67.9, 90.6) and 43% (geometric mean ratio 56.9, 90% confidence interval: 49.2, 65.8) lower, respectively, compared to administration of TBP-PI-HBr alone. Mean TBP elimination half-life (t1/2) was generally comparable across treatments (range: 1.0 to 1.5 h). Concomitant administration of TBP-PI-HBr with omeprazole or aluminum hydroxide/magnesium hydroxide/simethicone is not expected to impact the efficacy of TBP-PI-HBr, as there is minimal impact on TBP plasma AUC, which is the pharmacodynamic driver of efficacy. Co-administration was generally safe and well tolerated.

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Crystal structure of tebipenem pivoxil.

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Crystal structure of tebipenem pivoxil.

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