Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia.

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.

In vivo pharmacodynamics of lefamulin, the first systemic pleuromutilin for human use, in a neutropenic murine thigh infection model.

OBJECTIVES: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of lefamulin in the neutropenic murine thigh infection model to ascertain (i) which PK/PD index best correlates with efficacy and (ii) whether the magnitude of the index that drives efficacy varies for different pathogens. METHODS: We evaluated the in vivo PK/PD of lefamulin against five Streptococcus pneumoniae and five Staphylococcus aureus strains using a neutropenic murine thigh infection model. The relationships between bacterial burden in the thigh of normal and neutropenic mice after 24 h of lefamulin treatment and various PK/PD indices were determined. RESULTS: The kinetics of the three doses was linear by AUC. Rate of killing was maximal at concentrations near the MIC; suppression of regrowth was dose dependent, with a post-antibiotic effect of 3.0-3.5 and 1.0-1.5 h against S. pneumoniae and S. aureus, respectively. The efficacy of lefamulin correlated most strongly with the AUC0-24/MIC ratio; coefficient of determination was 79.9% for S. pneumoniae and 78.3% for S. aureus. The magnitude of the 24 h AUC/MIC of total drug required ranged from 9.92 to 32.1 for S. pneumoniae and 40.2 to 82.5 for S. aureus, corresponding to free drug values (∼20% free fraction) of 1.98-6.42 and 8.04-16.5, respectively. CONCLUSIONS: Lefamulin, the first systemically available pleuromutilin in humans, exhibits time- and concentration-dependent killing. The presence of white blood cells had only a slight effect in enhancing the activity of the drug, indicating a leucocyte-independent effect. The identified driver of efficacy, the AUC0-24/MIC ratio and the ratios determined against various S. aureus and S. pneumoniae strains, will inform further non-clinical and clinical trials.

Pharmacokinetics/pharmacodynamics of lefamulin in a neutropenic murine pneumonia model with Staphylococcus aureus and Streptococcus pneumoniae.

OBJECTIVES: To present results of preclinical studies that supported further development of lefamulin for treating patients with community-acquired bacterial pneumonia (CABP). METHODS: The effect of bovine lung surfactant on the antibacterial activity of lefamulin against Streptococcus pneumoniae and Staphylococcus aureus was determined by broth microdilution assay. In vitro accumulation of lefamulin was evaluated in J774 mouse macrophages. Pharmacokinetics was assessed in female BALB/c (Bagg albino) mice treated with subcutaneous lefamulin (35 or 70 mg/kg). In neutropenic lung infection experiments, BALB/c mice received intraperitoneal cyclophosphamide before challenge with single S. pneumoniae or S. aureus strains; subcutaneous lefamulin (1.25-160 mg/kg) was given twice daily post-infection. Hill models described relationships between AUC/MIC ratios and changes in log10 cfu. RESULTS: Lung surfactant did not significantly increase lefamulin MIC values against test strains. Lefamulin uptake in macrophages was rapid (a plateau was reached in ∼3 h). In mice, distribution of lefamulin [plasma to epithelial lining fluid (ELF)] was rapid, showing an ∼2-fold increase in lefamulin exposure in the ELF during the 5.5 h period. Median plasma AUC/MIC ratios associated with 1 and 2 log10 cfu reductions from baseline were 1.37 and 2.15, respectively, for S. pneumoniae and 2.13 and 6.24 for S. aureus. Corresponding ELF results were 14.0 and 22.0 for S. pneumoniae and 21.7 and 63.9 for S. aureus. CONCLUSIONS: Overall, lefamulin displays desirable pharmacokinetic/pharmacodynamic relationships that are predictive of the clinical effectiveness of lefamulin and other antibacterial agents used to treat CABP.

Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.

Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic.

The emergence and spread of antimicrobial resistance have led to a global public health emergency requiring development of new antimicrobial classes. Lefamulin (formally BC-3781) is a novel pleuromutilin antibiotic currently undergoing Food and Drug Administration review for community-acquired bacterial pneumonia (CABP) as intravenous (IV) and oral (PO) formulations. Although pleuromutilin antibiotics were first developed in the 1950s, lefamulin is the first to be used for systemic treatment of bacterial infections in humans. Lefamulin exhibits a unique mechanism of action through inhibition of protein synthesis by binding to the peptidyl transferase center of the 50S bacterial ribosome, thus preventing the binding of transfer RNA for peptide transfer. Lefamulin displays activity against gram-positive and atypical organisms associated with CABP (i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae), with an expanded gram-positive spectrum including Staphylococcus aureus (i.e., methicillin-resistant, vancomycin-intermediate, and heterogeneous strains) and vancomycin-resistant Enterococcus faecium. Lefamulin was also shown to retain activity against multidrug-resistant Neisseria gonorrhoeae and Mycoplasma genitalium. Lefamulin exhibits time-dependent killing, and the pharmacodynamic target best associated with antibacterial activity is ƒAUC0-24 /MIC (minimum inhibitory concentration [MIC]). Preclinical and phase II trials indicate that lefamulin concentrates in lung tissue are well tolerated at an IV dose of 150 mg twice/day over 1 hour or a PO dose of 600 mg twice/day, and preliminary phase III data suggest similar efficacy when compared with moxifloxacin with or without linezolid in CABP. Documented resistance and cross-resistance with other gram-positive antibacterials remains low. Additional published in vitro, in vivo, and preclinical trial data suggest further exploration of lefamulin in various infectious disease states (e.g., acute bacterial skin and skin structure infections, and sexually transmitted infections). This review discusses the pertinent bacterial spectrum of activity, preclinical and ongoing clinical data, and potential roles in therapy for lefamulin.