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Dalbavancin Population Pharmacokinetic Modeling and Target Attainment Analysis
Timothy J Carrothers1, Jason T Chittenden2, Ian Critchley3
1Allergan plc, Madison, NJ, USA.
Clinical Pharmacology in Drug Development
|May 16, 2019
Summary
Dalbavancin effectively treats skin infections. Updated pharmacokinetic modeling shows >99% of patients achieve therapeutic targets against gram-positive bacteria, even at higher minimum inhibitory concentrations (MICs).
Area of Science:
- Pharmacology
- Infectious Diseases
- Pharmacometrics
Background:
- Dalbavancin is approved for acute bacterial skin and skin structure infections.
- Population pharmacokinetics (popPK) and target attainment are crucial for optimizing dosing.
- Preclinical pharmacokinetic/pharmacodynamic (PK/PD) targets have been revised.
Purpose of the Study:
- To update the population pharmacokinetics (popPK) model for dalbavancin.
- To simulate target attainment based on revised preclinical targets (fAUC/MIC).
- To evaluate dalbavancin's efficacy against susceptible gram-positive microorganisms.
Main Methods:
- Utilized data from a single-dose safety and efficacy study.
- Developed a 3-compartment distribution model with first-order elimination.
- Performed target attainment simulations using updated nonclinical PK/PD targets.
Main Results:
- The popPK model showed typical dalbavancin clearance of 0.05 L/h and volume of distribution of ~15 L.
- Creatinine clearance, weight, and albumin had modest, statistically significant impacts on clearance.
- Dose adjustments are recommended only for severe renal impairment.
- Simulations projected >99% of subjects achieving the nonclinical target at MICs up to 2 mg/L.
Conclusions:
- The updated popPK model accurately describes dalbavancin's disposition.
- Dalbavancin demonstrates a high probability of target attainment against susceptible pathogens.
- The drug is likely effective at the revised target for infections with MICs up to 2 mg/L.
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