The pharmacokinetics of dalbavancin in subjects with mild, moderate, or severe hepatic impairment

Introduction

Dalbavancin (DAL) is a semisynthetic lipoglycopeptide in phase 3 development with activity against Gram-positive bacteria. Weekly doses (1 g day 1/0.5 g day 8) are being investigated for the treatment of complicated skin and soft tissue infections. DAL has both renal and nonrenal routes of elimination. A study was performed to assess the need for dosage adjustments in patients with hepatic impairment.

Methods

Subjects received intravenously 1 g DAL on day 1 followed by 0.5 g on day 8. Subjects had mild, moderate, or severe hepatic impairment as defined by Child–Pugh criteria A, B, or C. Age, gender, and weight-matched controls with normal hepatic function were also enrolled. DAL plasma concentrations were determined and pharmacokinetic parameters were calculated. Drug exposure was calculated as the cumulative area under the concentration–time curve through day 15; drug clearance and the elimination half-life were also determined. Safety was assessed by physical examination and adverse event and laboratory monitoring.

Results

Twenty-six subjects were enrolled, received DAL, and had evaluable pharmacokinetics. The drug was well tolerated with no serious adverse events. DAL concentrations and exposures were not increased due to hepatic impairment. The elimination half-life was not affected by hepatic impairment. Slightly lower exposures and higher drug clearance were observed for subjects with moderate and severe hepatic impairment, presumably due to volume changes secondary to ascites and edema. The DAL concentrations observed for these subjects were comparable with the ranges observed in other studies.

Conclusion

DAL concentrations are not increased due to hepatic impairment and no dosage adjustment should be required for patients with mild, moderate, or severe hepatic impairment.