Doripenem

Doripenem is a broad-spectrum carbapenem antibiotic. It works against aerobic and anaerobic Gram-positive and Gram-negative bacteria.

Doripenem kills bacteria by stopping them from building their cell walls. It binds to several essential penicillin-binding proteins (PBPs), which blocks cell wall synthesis and leads to the death of the cell. In E. coli and P. aeruginosa, doripenem binds to PBP 2, which helps maintain cell shape, as well as to PBPs 3 and 4.

Absorption: After a single 1-hour intravenous infusion of a 500 mg dose in 24 healthy subjects, the mean plasma concentration of doripenem was 23.0 (6.6) pg/mL. When given intravenously over 1 hour, doripenem's Cmax and AUC rise in a straight line across doses from 500 mg to 1 g. With multiple intravenous infusions of either 500 mg or 1 g every 8 hours for 7 to 10 days, doripenem does not build up in people with normal kidney function.

Distribution: About 8.1% of doripenem binds to plasma proteins, and this does not change with the drug concentration in the plasma. In healthy subjects at steady state, the median volume of distribution (range) is 16.8 L (8.09-55.5 L), which is close to the extracellular fluid volume of 18.2 L.

Metabolism: Doripenem is broken down mainly by dehydropeptidase-I into a ring-opened metabolite, doripenem-M1, which has no antibacterial activity. In pooled human liver microsomes, no metabolism of doripenem could be detected in the lab, so doripenem is not a substrate for hepatic CYP450 enzymes.

Excretion: The kidneys remove most doripenem from the body in its unchanged form. In healthy non-elderly adults, the mean plasma terminal elimination half-life is about 1 hour, and plasma clearance is 15.9 (SD 5.3) L/hour. Mean renal clearance is 10.8 (3.5) L/hour. After a single 500 mg dose in healthy adults, an average of 70% of the dose was recovered in urine as unchanged drug and 15% as the ring-opened metabolite within 48 hours.