Demonstrating In Vitro Activity, Efficacy Of Prodrugs In Osteomyelitis Models

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Prodrugs In Osteomyelitis Models

Targanta Therapeutics released detailed data from two studies highlighting the in vitro activity and in vivo efficacy of its proprietary prodrugs in osteomyelitis models.

Results are being presented today at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) taking place in Chicago, IL and represent the first data sets from this proprietary platform.

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Osteomyelitis is an acute or chronic bone infection predominantly caused by staphylococci, requiring treatment through prolonged parenteral antibiotic administration and, often, surgical intervention. There are currently no antibiotics approved to treat osteomyelitis, which has been designated by the U.S. Food and Drug Administration (FDA) as a significant unmet medical need. Targanta has developed a novel drug discovery platform through which it tethers bone-targeting bisphosphonates to approved antibiotics to generate molecules that deliver the antibiotics directly to the bone, targeting the site of infection.

In the first study, entitled, "Preparation and In Vitro Evaluation of Fluoroquinolone Prodrugs for the Prevention and Treatment of Osteomyelitis," researchers synthesized a total of 45 bisphosphonated fluoroquinolone prodrugs by tethering ciprofloxacin, gatifloxacin or moxifloxacin to a bisphosphonate via cleavable linkers. The affinity of the prodrugs for bone was determined by exposing individual compounds to a suspension of bovine bone powder. Most were found to bind near quantitatively to bone powder and released the parent fluoroquinolone at various rates. In this in vitro study, the high affinity displayed by the compounds for bone powder and their ability to regenerate active parent compound over time suggests they could be used to concentrate antibacterial fluoroquinolones into the bone via systemic administration.

In the second study, entitled "In Vivo Efficacy of a New Osteotropic Prodrug in a Rabbit Model of Chronic Osteomyelitis," researchers reported on the pharmacokinetics of a rifabutin-bisphosphonate prodrug (TT99000647) and its in vivo efficacy versus both gatifloxacin and rifabutin alone. In the study, osteomyelitis was created in rabbits by injecting Staphylococcus aureus into the medullar cavity of the tibia. Tibiae were harvested 14 days after the end of 28 days of therapy, ground and their bacterial loads determined by plating bone homogenates.

The pharmacokinetic study of TT99000647 revealed a Cmax at 303 mcg/g of bone and a terminal half-life of 131 hours in bone. In the efficacy study, treatments resulted in the following proportion of sterilized tibia: 14% (untreated controls); 86% (gatifloxacin, 56 doses of 40 mg/kg); 43% (rifabutin, 10 doses of 30 mg/kg); 43%, 57% and 100% (TT99000647, 4, 7 and 10 doses of 30 mg/kg rifabutin equivalent, respectively). The efficacy demonstrated by rifabutin-bisphosphonate in the rabbit osteomyelitis model in this study suggests further development as a possible therapy for osteomyelitis.

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