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Published on: September 9, 2015
Extended-duration dosing and distribution of dalbavancin into bone and articular tissue
Michael W Dunne1, Sailaja Puttagunta2, Craig R Sprenger3
1Durata Therapeutics, Inc., Branford, Connecticut, USA mdunne@duratatx.com.
Abstract:
Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC90 for Staphylococcus aureus of 0.06 μg/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 μg/g and 2 weeks later were 4.1 μg/g. A two-dose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed.
Insights
Dalbavancin, an effective antibiotic for Gram-positive infections, shows promising pharmacokinetics for treating bone and heart infections. A novel two-dose regimen may offer extended treatment with less frequent intravenous administration.
Area of Science:
- Pharmacology
- Infectious Diseases
- Drug Development
Background:
- Dalbavancin is a lipoglycopeptide antibiotic effective against Gram-positive pathogens.
- Its long terminal half-life (>14 days) suggests potential for infrequent dosing regimens.
- Treating osteomyelitis and endocarditis often requires prolonged, daily intravenous antibiotic therapy.
Purpose of the Study:
- To evaluate the pharmacokinetics of dalbavancin over an extended dosing interval.
- To determine dalbavancin distribution into bone and articular tissue.
- To support a rationale for novel, infrequent dosing regimens for dalbavancin.
Main Methods:
- Two Phase I clinical trials were conducted.
- Pharmacokinetic modeling was performed.
- Dalbavancin concentrations in cortical bone were measured after a single 1,000-mg intravenous infusion.
Main Results:
- A regimen of 1,000 mg on day 1 followed by 500 mg weekly for seven weeks was well tolerated and showed no drug accumulation.
- Bone concentrations were 6.3 μg/g at 12 hours and 4.1 μg/g two weeks after a single 1,000-mg dose.
- The proposed regimen provides tissue exposure above the MIC for Staphylococcus aureus for 8 weeks.
Conclusions:
- A two-dose, once-weekly dalbavancin regimen is proposed.
- This regimen maximizes initial drug exposure while minimizing intravenous therapy frequency.
- It offers a potential strategy for extended treatment of difficult-to-treat Gram-positive infections.
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