Multidose Dalbavancin Population Pharmacokinetic Analysis for Prolonged Target Attainment in Patients Requiring Long-Term Treatment.

Abstract

Introduction: Dalbavancin (DAL) is a long-acting lipoglycopeptide active against Gram-positive bacteria, including multidrug-resistant isolates. A growing body of evidence supports its efficacy in various difficult-to-treat infections. DAL shows time-dependent bactericidal activity in vitro at free drug concentrations equal to 4×MIC values. However, the optimal dosing scheme for achieving the PK/PD target in multidose treatment has not been fully established. Methods: Pharmacokinetic analysis was based on a nonlinear mixed effects modelling approach performed in NONMEM v7.5/Pirana, while R was used for data management and graphical summaries. Final model parameters were used to simulate the plasma disposition of DAL by Monte Carlo simulations to determine the multidose DAL regimen associated with a 90% target attainment of 100% fT > 4×MIC. Results: A two-compartmental model with first-order elimination and allometric-scaled bodyweight best described DAL disposition in patients with CLcr > 30 mL/min. Monte Carlo simulations showed that two 1500 mg DAL doses 7 days apart granted an optimal PTA > 90% of 100% fT > 4×MIC up to 5, 4, and 3 weeks in patients weighting from 40-80 kg, 80-120 kg and 120-200 kg, respectively. An additional third 1500 mg dose at the above time points by weight bands may extend the optimal PTA up to 9, 7, and 6 weeks of total treatment. Conclusions: Two 1500 mg DAL doses administered 7 days apart could be a valuable starting strategy for patients of all weight classes with CLcr > 30 mL/min. In patients requiring long-term DAL treatment, the optimal timing of additional administrations should be guided by routine TDM or empirically through patients' total body weight when TDM is unavailable.