Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans

Abstract

CP-65,207 is a new broad-spectrum penem antimicrobial agent that is a 1:1 mixture of two stereoisomers. Five minutes after a 10-min intravenous infusion of 1 g of CP-65,207 to volunteers, mean concentrations in serum were 33 ,ug of the R isomer per ml and 29 tig of the S isomer per ml. Following rapid distribution, half-lives of the isomers were 53 and 55 min, respectively. Concentrations in urine exceeded 800 ,ug of each isomer per ml. Recovery of the S isomer in urine (46%) was much greater than recovery of the R isomer (26%). The serum kinetics of the S isomer (volume of distribution, 319 ml/kg; total clearance, 315 ml/min; elimination rate constant, 0.80 h-1) were similar when it was given alone and when it was contained in 207, demonstrating that the presence of the R isomer has little effect on the serum kinetics of the S isomer. However, when the S isomer was given alone, the urinary recovery of intact S isomer (36%) was substantially lower than that when it was given with the R isomer as 207 (57%). Administration of the S isomer alone did not produce the unpleasant sulfurous odor in urine that was observed following administration of 207. Oral doses of a prodrug, which contained 1 g of CP-65,207, produced peak concentrations in serum of 1.6 ,ug of the R isomer per ml and 1.8 ,ug of the S isomer per ml. Approximately 36% of the S-isomer component was absorbed, and 20% of this isomer was recovered in urine. A 1-g oral dose of the prodrug of the single S isomer provides concentrations in serum above 1.0 ,ig/ml (the MIC for 90% of over 1,000 hospital pathogens) for 3.5 h, suggesting that the drug given orally will prove to be efficacious against many infections.Carbapenem and penem antimicrobial agents are betalactams that usually demonstrate a broad spectrum of activity and a high potency in vitro. However, penems and carbapenems also are susceptible to hydrolysis by the renal dehydrodipeptidase found in the brush border cells of animal and human kidneys (9,11,14). Thus, a renal dipeptidase inhibitor is coadministered with imipenem, the first member of this group of antimicrobial agents to be used commercially (14). Some penems are orally absorbed either as the parent molecule (9, 13) or after incorporation into a prodrug (5,16). Given the potent antibacterial activity of penems and carbapenems, research continues in an effort to find new agents with potential clinical utility (10, 12).CP-65,207 (2) is a potent broad-spectrum antibacterial agent with activity comparable to that of imipenem, with the exception that it has significantly lower activity against Pseudomonas aeruginosa (8). The MIC for 90% of over 1,000 hospital pathogens was approximately 1.0 jig/ml (8).CP-65,207 is a mixture of a more polar R isomer (CP-65,207-R) and a less polar S isomer (CP-65,207-S; also called 429) in approximately a 1:1 ratio (Fig. 1). While the isomers have very similar antibacterial activities, in vitro studies and animal experiments indicate that the S isomer is more resistant to hydrolysis by the renal dipetidase e...

Antibiotics in the clinical pipeline as of December 2022

“…Compounds in phase-III trials (Table 3, Fig. 4) Sulopenem (6) (CP-70,429), which is a synthetic thiopenem BL first developed by Pfizer (New York, NY, USA) in the 1990s [65][66][67][68], and its prodrug sulopenem etzadroxil (7) (PF-03709270; po) are being developed as treatments for G-ve infections by Iterum Therapeutics (Dublin, Ireland).…”

“…VenatoRx have revealed that cefepime-taniborbactam had a superior primary efficacy endpoint to the carbapenem meropenem (66) in this trial with a similar safety profile [328], and plan to submit an NDA to the US FDA in 2023 [329]. The taniborbactam (62) + cefepime (41) combination has activity against E. coli, K pneumoniae, carbapenemase-producing Enterobacterales and P. aeruginosa [330][331][332].…”

In vitro activity of sulopenem and comparator agents against Enterobacterales and anaerobic clinical isolates collected during the SENTRY Antimicrobial Surveillance Program

“… 10 Oral administration of the prodrug sulopenem etzadroxil demonstrates increased absorption whereas IV administration of sulopenem (comprised of the stable S isomer) leads to significant active concentration in the urine. 11 , 12 With activity against both Gram-positive and -negative species, sulopenem inhibits peptidoglycan cross-linking thus preventing bacterial cell wall synthesis. 13 , 14 Notably, susceptibility reports for this compound indicate activity against fluoroquinolone-resistant, ESBL-producing and MDR Enterobacterales.…”

Prodrug Study of Plinabulin Using a Click Strategy Focused on the Effects of a Replaceable Water-Solubilizing Moiety

“…The stereochemistries of the auxiliaries of 2 and 12 were opposite, which was also capable of having affected the hydrolysis rate. [33][34][35][36] The presence of an asymmetric center at the water-solubilizing moiety is generally avoided to reduce structural complexity, however, the stereochemistry of the substrate did affect the enzyme reaction, [37][38][39][40] suggesting that this feature may be significant. In our case, the asymmetric center in the water-solubilizing moiety, which was derived from a natural amino acid, may have adjusted the prodrug half-life while improving the water solubility.…”