Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia
| Autor: | Sujata M. Bhavnani, Christopher M. Rubino, Steven P Gelone, Li Zhang, Paul G. Ambrose, Helio S. Sader, Wolfgang W Wicha, Jeffrey P. Hammel, Justin C Bader |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Staphylococcus aureus medicine.drug_class 030106 microbiology Antibiotics Population Administration Oral Microbial Sensitivity Tests Pharmacology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Streptococcus pneumoniae medicine Pneumonia Bacterial Humans Pharmacology (medical) Computer Simulation Polycyclic Compounds 030212 general & internal medicine Dosing education education.field_of_study Models Statistical Bacteria business.industry Bacterial pneumonia Fasting Staphylococcal Infections medicine.disease Anti-Bacterial Agents Community-Acquired Infections Regimen Infectious Diseases Pharmacodynamics Thioglycolates Supplement Papers Administration Intravenous Diterpenes business Monte Carlo Method |
| Zdroj: | Journal of Antimicrobial Chemotherapy |
| ISSN: | 1460-2091 |
| Popis: | Objectives Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150 mg iv q12h and 600 mg orally q12h under fed and fasted conditions for the treatment of patients with CABP. Methods The analyses undertaken used a population PK model based on Phase 1 PK data, non-clinical PK/PD targets for efficacy and in vitro surveillance data for Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), and Monte Carlo simulation. Percentage probabilities of PK/PD target attainment by MIC on day 1 were determined using median total-drug epithelial lining fluid (ELF) and free-drug plasma AUC:MIC ratio targets associated with 1 and 2 log10 cfu reductions from baseline. Results Percentage probabilities of attaining the total-drug ELF AUC:MIC ratio target for a 1 log10 cfu reduction from baseline for SP were ≥99.2% at the MIC90 of 0.12 mg/L and 96.7%, 82.1% and 96.3% for iv and oral dosing regimens under fed and fasted conditions, respectively, at the MIC99 of 0.25 mg/L. Percentage probabilities of attaining the free-drug plasma AUC:MIC target for the same endpoint at the SP MIC99 were 100% for each regimen. For the SA MIC90 of 0.12 mg/L and AUC:MIC ratio targets for the same endpoint, percentage probabilities were 92.7%–100% for iv and oral dosing regimens. Conclusions These data provide support for lefamulin 150 mg iv q12h and 600 mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions. |
| Databáze: | OpenAIRE |
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