Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Nabriva Therapeutics Ireland DAC, Alexandra House, Office 225/227, The Sweepstakes Ballsbridge, Dublin 4, D04 C7H2, Ireland
Pharmacotherapeutic group: antibacterials for systemic use, pleuromutilins
ATC code: J01XX12
Lefamulin is a pleuromutilin antibacterial agent. It inhibits bacterial protein synthesis by interacting with the A- and P-sites of the peptidyl transferase centre (PTC) in the central part of domain V of the 23S rRNA of the 50S ribosomal subunit, preventing correct positioning of the tRNA.
Resistance to lefamulin in normally susceptible species may be due to mechanisms that include specific protection or modification of the ribosomal target by ABC-F proteins such as vga (A, B, E), Cfr methyl transferase, or by mutations of ribosomal proteins L3 and L4 or in domain V of 23S rRNA.
Cfr generally confers cross-resistance with oxazolidinones, lincosamides, phenicols and group A streptogramins. ABC-F proteins can confer cross-resistance with lincosamides and group A streptogramins.
Organisms resistant to other pleuromutilin class antibacterial agents are generally cross-resistant to lefamulin.
The activity of lefamulin is not affected by mechanisms that confer resistance to beta-lactams, macrolides, quinolones, tetracyclines, folate-pathway inhibitors, mupirocin and glycopeptides.
Inherent resistance to lefamulin occurs in Enterobacterales (e.g. Klebsiella pneumoniae) and non-fermenting Gram-negative aerobes (e.g. Pseudomonas aeruginosa, Acinetobacter baumannii).
In vitro studies demonstrated no antagonism between lefamulin and amikacin, azithromycin, aztreonam, ceftriaxone, levofloxacin, linezolid, meropenem, penicillin, tigecycline, trimethoprim/sulfamethoxazole, and vancomycin.
The Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommended interpretive criteria are:
| Organism | Minimum Inhibitory Concentrations (mg/L) | |
|---|---|---|
| Susceptible (≤S) | Resistant (>R) | |
| Streptococcus pneumoniae | 0.5 | 0.5 |
| Staphylococcus aureus | 0.25 | 0.25 |
The antimicrobial activity of lefamulin against S. pneumoniae and S. aureus correlated best with the ratio of the area under the concentration-time curve of free drug over 24 hours to the minimum inhibitory concentration (24-h AUC/MIC ratio).
Efficacy has been demonstrated in clinical studies against pathogens susceptible to lefamulin in vitro listed under each indication:
Community-acquired Pneumonia
Gram-positive bacteria:
Streptococcus pneumoniae
Staphylococcus aureus
Gram-negative bacteria:
Haemophilus influenzae
Legionella pneumophila
Other bacteria:
Mycoplasma pneumoniae
Chlamydophila pneumoniae
Clinical efficacy has not been established against the following pathogens that are relevant to the approved indications although in vitro studies suggest that they would be susceptible to lefamulin in the absence of acquired mechanisms of resistance:
Gram-negative bacteria:
Haemophilus parainfluenzae
Moraxella catarrhalis
The European Medicines Agency has deferred the obligation to submit the results of studies with Xenleta in one or more subsets of the paediatric population in community-acquired pneumonia (see section 4.2 for information on paediatric use).
In a post-hoc, subgroup analysis from two Phase 3 trials in patients with community-acquired pneumonia, the clinical cure rates at a post-treatment visit in patients with any of a positive sputum culture, positive blood culture or positive urinary antigen test for S. pneumoniae were lower for patients treated with lefamulin compared to patients treated with moxifloxacin. When treatment commenced by the intravenous route the cure rates were 28/36 [77.8%; (95% confidence intervals (CIs) 60.8% to 89.9%)] for lefamulin vs. 26/31 [83.9%; (95% CI 66.3% to 94.6%)] for moxifloxacin. When treatment commenced by the oral route, the cure rates were 19/25 (76%; 95% CI 55.9% to 90.6%) vs. 30/32 (93.8%; 95% CI 79.2% to 99.2%), respectively.
After oral administration of an immediate-release 600 mg tablet formulation, oral bioavailability of lefamulin under fasted conditions was 25.8%. Exposure on Day 1 (AUC0-12h) was equivalent to the exposure obtained with lefamulin 150 mg administered intravenously.
The concomitant administration of a high-fat, high calorie breakfast with a single oral dose of 600 mg lefamulin (immediate release tablet) resulted in a slightly reduced absolute bioavailability (21.0%).
Lefamulin is moderate to highly bound to plasma proteins (alpha-1 acid glycoprotein > human serum albumin) within a range of 88-97% at a concentration of 1 μg/mL, 83-94% at 3 μg/mL, and 73-86% at 10 μg/mL (depending on assay), demonstrating saturable, non-linear binding between 1-10 μg/mL. The steady-state volume of distribution (Vss) is approximately 2.5 L/kg. Rapid tissue distribution of lefamulin into skin and soft tissues was demonstrated using microdialysis, and into the epithelial lining fluid (ELF) using bronchoalveolar lavage.
In plasma, between 24 and 42% of lefamulin is metabolised primarily by CYP3A phase I reactions, leading mainly to hydroxylated metabolites devoid of antibacterial properties, most notably the main metabolite BC-8041 (2R-hydroxy lefamulin). BC-8041 is the only metabolite in plasma accounting for >10% (13.6% to 17.3%) of total drug related material after oral dosing while no metabolites exceeded 10% (≤6.7%) after intravenous dosing.
Elimination was multiphasic and the terminal t1/2 ranged between 9-10 h after a single oral or intravenous administration. Overall, lefamulin was primarily eliminated via the non-renal route. Between 9.6%-14.1% of an intravenous dose of lefamulin was excreted as unchanged drug in the urine. The total body clearance and the renal clearance following 150 mg intravenous infusion were approximately 20 L/h and 1.6 L/h, respectively.
No clinically significant differences in the pharmacokinetics of lefamulin were observed based on gender, race, or weight.
In CAP patients there was a trend of increasing lefamulin exposure with increasing age, with a~50% increase in AUC0-24 at steady-state in patients aged ≥85 years compared to patients aged <65 years.
A study was conducted to compare lefamulin pharmacokinetics following intravenous administration of 150 mg in 8 subjects with severe renal impairment and 7 matched healthy control subjects. Another 8 subjects requiring haemodialysis received 150 mg lefamulin intravenously immediately before dialysis (on-dialysis) and on a non-dialysis day (off-dialysis). The AUC, Cmax, and CL of lefamulin and its main metabolite were comparable between subjects with severe renal impairment and matched healthy subjects, and in subjects requiring haemodialysis whether on- or off-dialysis. Lefamulin and its main metabolite were not dialyzable. Renal impairment did not impact lefamulin elimination.
A study was conducted to compare lefamulin pharmacokinetics following intravenous administration of 150 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B), 8 subjects with severe hepatic impairment (Child-Pugh Class C), and 11 matched healthy control subjects. No clinically meaningful changes in the total AUC, Cmax, and CL of lefamulin and its main metabolite were observed between subjects with moderate or severe hepatic impairment and matched healthy control subjects. Hepatic impairment did not meaningfully impact lefamulin elimination. Plasma protein binding decreased with increased impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, and genotoxicity.
In rats, there were no effects on male or female fertility that were considered related to lefamulin. Lefamulin/metabolites are excreted into the milk of lactating rats. Maximal concentrations of radioactivity in plasma and milk were 3.29 and 10.7 μg equivalents/g, respectively, following a single dose of 30 mg/kg radio-labelled lefamulin. Lefamulin/metabolites crossed the placenta in pregnant rats. In the plasma of suckling rat pups, lefamulin exposure was demonstrated in only 1 of 3 litters of treated dams in each of the mid and high dose groups on post-natal day 4. No test item was quantified in pup’s plasma on post-natal day 20.
Adverse reactions seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
In the rat embryo-foetal development study of lefamulin during organogenesis (GD 6-17) there were 1, 0, 2, and 1 malformed foetuses in control, low, mid, and high dose groups, respectively. Findings included malformations (cleft palate, short lower jaw, vertebral and rib malformations, and a cyst in the neck region) at the mid and high doses, but the relationship to treatment is considered equivocal. Decreased or no ossification in a number of skeletal elements in all treated groups may indicate treatment-related developmental delay at all doses evaluated.
In the rabbit embryo-foetal development study of lefamulin during organogenesis (GD 6-18), low numbers of live foetuses in utero in treated groups limited the interpretation of the study. Additional findings in the high dose group included decreased foetal weight and decreased or no ossification of skeletal elements, which may be indicative of developmental delay.
In a prenatal and postnatal development study in rats the pup live birth index was reduced (87.4%) in the high dose group. In the absence of related findings at the same dose level in the rat embryo-foetal development study, stillbirth was considered to be a late stage pregnancy or delivery effect.
Evidence of dose-dependent regenerative anaemia in both species indicated lefamulin was potentially haemolytic at concentrations that are higher than the concentration of the infusion solution which will be used clinically. This effect was not apparent from an in vitro evaluation of blood compatibility using human blood at a concentration of 0.6 mg/mL.
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