دورية
Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug
| العنوان: | Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug |
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| المؤلفون: | McLeay, Sarah C., Vis, Peter, van Heeswijk, Rolf P. G., Green, Bruce |
| المصدر: | Antimicrobial Agents and Chemotherapy; June 2014, Vol. 58 Issue: 9 p5315-5324, 10p |
| مستخلص: | ABSTRACTBedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosisinfections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 00664804 10986596 |
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| DOI: | 10.1128/AAC.01418-13 |