Pharmacokinetic/pharmacodynamic modelling of the plasma bactericidal activity of NXL103 against Streptococcus pneumoniae and Staphylococcus aureus in phase I studies
Abstract number: 1733_291
Merdjan H., Lowther J., Girard A-M., Delachaume C., Rangaraju M.
Objective: NXL103 is a novel oral streptogramin antibiotic associating 2 components RPR202868 (PI) and RPR132552 (PII). The objective of this study was to characterise the relationship between the plasma bactericidal activity against S. pneumoniae and S. aureus strains, and PI and PII plasma concentrations measured in samples collected in 2 phase I studies.
Methods: The dataset for building the PK/PD model was composed of 1067 plasma samples from a phase I repeated (10-day) oral administration study in healthy male volunteers. Four cohorts of 10 subjects (8 received NXL103 and 2 placebo) received 0.5 g bid, 0.75 g bid, 1.5 g oad, or 1 g bid. Blood samples were taken on 7 occasions from day 1 to day 11. PI and PII concentrations were measured in plasma by LC-MS/MS. Separate aliquots of the same samples were serially diluted into a growth medium/control plasma mixture, and incubated with S. pneumoniae (030MV1 strain) and S. aureus (011HT18 strain) to measure bactericidal activity. For the purpose of PK/PD modelling, cidality data were recoded as 0 (no activity) or 1 (cidal activity), irrespective of the intensity of effect. Fits were performed using WinNonlin®.
Results: The model predicted bactericidal activity on S. pneumoniae if both PI and PII were more than 0.175 mg/L and 0.523 mg/L, respectively. Breakpoints for S. aureus were 0.123 mg/L and 0.081 mg/L, respectively. The descriptive performance of the model was 93.5% and 83.9% accurate against S. pneumoniae and S. aureus, respectively. The predictive performance of the model was assessed on a separate validation dataset composed of 416 human plasma samples collected in a previous study, where 32 healthy male volunteers received a single oral dose of either 0.5 g, 1 g, 1.5 g or 2 g of NXL103. Plasma concentrations of PI and PII, and bactericidal activity were measured as above. Model-predictions were 91.8% and 93.5% accurate against S. pneumoniae and S. aureus, respectively, the remainder being evenly distributed between false positive and false negative predictions.
Conclusion: A PK/PD model was built that predicts the plasma bactericidal activity against two pathogens of therapeutic interest. These results should be taken into account in defining dose(s) for phase II trial(s).
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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