XENLETA Solution for injection / Film-coated tablet Ref.[10114] Active ingredients: Lefamulin

The 24 h free-drug AUC to minimal inhibitory concentration (MIC) ratio has been shown to be the best Pharmacokinetic-Pharmacodynamic (PK-PD) index for the antibacterial activity of lefamulin in animal infection models of Streptococcus pneumoniae and Staphylococcus aureus pneumonia.

Cardiac Electrophysiology

The QTcF interval prolongation risk of XENLETA was evaluated using 2 randomized, double-blind, double-dummy, active controlled (moxifloxacin 400 mg once daily), parallel group, trials (Trials 1 and 2) in adult patients with CABP. A concentration dependent QTc prolongation effect of XENLETA was observed. The mean change from baseline QTcF (90% two-sided upper confidence interval) values around T_max on day 3 or 4 were 13.6 ms (15.5 ms) for 150 mg injection administered twice daily as infusion and 9.3 ms (10.9 ms) for 600 mg tablet administered twice daily. The mean change from baseline QTcF (90% two-sided upper confidence interval) values around T_max for the moxifloxacin randomized comparison arm on day 3 or 4 were 16.4 ms (18.3 ms) for 400 mg injection administered once daily as infusion and 11.6 ms (13.2 ms) for 400 mg tablet administered once daily.

Following single-dose intravenous administration, the AUC of lefamulin increased approximately dose-proportionally while the C_max of lefamulin increased less than dose-proportionally over a dose range of 25 mg (0.17 times the approved dose) to 400 mg (2.67 times the approved dose). Following single-dose oral administration, the AUC of lefamulin increased more than dose proportionally over a dose range of 500 mg (0.8 times the approved dose) to 750 mg (1.25 times the approved dose).

Pharmacokinetic (PK) parameters of lefamulin following administration of XENLETA Injection or Tablets to patients with CABP are listed in Table 4.

The mean lefamulin AUC_0-24h and C_max in patients with CABP were 73% and 30% higher, respectively, compared with healthy subjects.

Table 4. Pharmacokinetic (PK) Parameters of Lefamulin Following Single or Multiple Dose (Every 12 Hours) XENLETA Administered as 150 mg (Infused Over 60 Minutes) Intravenously (IV) or 600 mg Orally in Patients with CABP^a:

^a Based on population PK modeling (Trial 1 for IV administration and Trial 2 for oral administration)
^b C_max=maximum plasma concentration; C_min=trough plasma concentration; AUC_0–24h=area under the plasma concentration-time curve from time zero to 24 hours
^c Dose administered under fasting conditions (1 hour before or 2 hours after a meal)

Absorption

The mean oral bioavailability of XENLETA Tablets is approximately 25% and peak lefamulin plasma concentration occurred 0.88 to 2 hours after administration to healthy subjects.

Effect of Food

The concomitant administration of a single oral dose of 600 mg XENLETA Tablets with a high fat (approximately 50% of total calories from fat), high calorie breakfast (approximately 800-1000 calories) slightly reduced bioavailability. The mean relative reduction for oral XENLETA (fasted vs. fed) was on average 22.9% [90% CI: 12.2; 32.3] for the C_max and 18.43% [90% CI: 11.7; 24.7] for the AUC_0-inf.

Distribution

Mean plasma protein binding of lefamulin ranges from 94.8% at 2.35 mcg/mL to 97.1% at 0.25 mcg/mL in healthy adults.

The mean (min to max) steady state volume of distribution of lefamulin is 86.1 L (34.2 to 153 L) in patients with CABP after administration of XENLETA Injection.

Following a single IV administration of lefamulin 150 mg to healthy subjects, the highest lefamulin epithelial lining fluid (ELF) concentrations were observed at the end of infusion. The mean ELF and plasma AUC_0-8 was 3.87 mcg·h/mL and 5.27 mcg·h/mL, respectively. The estimated ratio of ELF AUC to unbound plasma AUC is approximately 15.

Elimination

The mean (min to max) total body clearance of lefamulin is 11.9 L/h (2.94 to 30.0 L/h) in patients with CABP after XENLETA Injection administration.

The mean (min to max) elimination half-life of lefamulin is approximately 8 hours (3 to 20 h) in patients with CABP.

Metabolism

Lefamulin is primarily metabolized by CYP3A4.

Excretion

In healthy adult subjects, the mean % of total radioactivity excreted in feces was 77.3% (4.2% to 9.1% unchanged) and 88.5% (7.8% to 24.8% unchanged), and in urine was 15.5% (9.6% to 14.1% unchanged) and 5.3% (unchanged not determined) following 150 mg IV or 600 mg oral XENLETA, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of XENLETA were observed based on age, sex, race, weight, or renal impairment including patients receiving hemodialysis.

Patients with Hepatic Impairment

The disposition of lefamulin was evaluated in non-infected subjects with normal hepatic function and with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment following administration of XENLETA Injection. The half-life of lefamulin is prolonged in subjects with severe hepatic impairment compared to that in subjects with normal hepatic function (17.5 h versus 11.5 h). Protein binding of lefamulin is reduced in subjects with hepatic impairment. Therefore, unbound (biologically active) lefamulin concentrations increased with the degree of hepatic impairment. On average, unbound lefamulin plasma AUC_0-inf was increased 3-fold in subjects with severe hepatic impairment compared to that in subjects with normal hepatic function. There is no information to evaluate the effect of hepatic impairment on the disposition of lefamulin following administration of XENLETA Tablets. Thus, XENLETA Tablets are not recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Effect of Other Drugs on the Pharmacokinetics of Lefamulin:

Strong CYP3A inducers or P-gp inducers: oral rifampin (strong inducer) reduced the mean lefamulin AUC_0-inf and C_max by 28% and 8%, respectively, when administered concomitantly with XENLETA Injection. Additionally, oral rifampin reduced the mean lefamulin AUC_0-inf and C_max by 72% and 57%, respectively, when administered concomitantly with XENLETA Tablets.

Strong CYP3A inhibitors or P-gp inhibitors: oral ketoconazole (strong inhibitor) increased the mean lefamulin AUC_0-inf and C_max by 31% and 6%, respectively, when administered concomitantly with XENLETA Injection. Additionally, oral ketoconazole (strong inhibitor) increased the lefamulin AUC_0-inf and C_max by 165% and 58%, respectively, when administered concomitantly with XENLETA tablets.

Effect of Lefamulin on the Pharmacokinetics of Other Drugs:

CYP3A Substrates: No clinically significant differences in the pharmacokinetics of midazolam were observed when administered concomitantly with XENLETA Injection. Mean AUC_0-inf and C_max of midazolam were increased by approximately 200% and 100%, respectively, when oral midazolam (CYP3A substrate) was administered concomitantly with and at 2 or 4 hours after administration of XENLETA Tablets.

P-gp substrates: No clinically significant differences in the pharmacokinetics of digoxin (P-gp substrate) were observed when administered concomitantly with XENLETA Tablets.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Lefamulin inhibited CYP2C8 (IC₅₀=37.0 mcg/mL), BCRP (Breast Cancer Resistance Protein) (IC₅₀=21.4 mcg/mL), and MATE1 (IC₅₀=0.15 mcg/mL).

Mechanism of Action

XENLETA is a systemic pleuromutilin antibacterial. It inhibits bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center (PTC) in domain V of the 23s rRNA of the 50S subunit. The binding pocket of the bacterial ribosome closes around the mutilin core for an induced fit that prevents correct positioning of tRNA.

XENLETA is bactericidal in vitro against S. pneumoniae, H. influenzae and M. pneumoniae (including macrolide-resistant strains), and bacteriostatic against S. aureus and S. pyogenes at clinically relevant concentrations.

XENLETA is not active against Enterobacteriaceae and Pseudomonas aeruginosa.

Resistance

The resistance frequency to XENLETA due to spontaneous mutations in vitro at 2-8 times the MIC was 2 × 10^-9 to <2 × 10 ^-11 for S. aureus, <1 × 10^-9 to <3 × 10^-10 for S. pneumoniae, and <4 × 10^-9 to <2 × 10^-10 for S. pyogenes. Resistance development at sub-MIC concentrations required greater than 1 mutational step with no resistant clones detected at ≥4-times MIC.

Resistance mechanisms that affect XENLETA include specific protection or modification of the ribosomal target by ABC-F proteins such as vga (A, B, E), lsa(E), sal(A), Cfr methyl transferase, or by mutations of ribosomal proteins L3 and L4. Cfr methyl transferase has the potential to mediate cross-resistance between lefamulin and phenicols, lincosamides, oxazolidinones, and streptogramin A antibacterials.

Some isolates resistant to β-lactams, glycopeptides, macrolides, mupirocin, quinolones, tetracyclines, and trimethoprim-sulfamethoxazole may be susceptible to XENLETA.

Interaction with Other Antimicrobials

In vitro studies demonstrated no antagonism between XENLETA and other antibacterial drugs (e.g., amikacin, azithromycin, aztreonam, ceftriaxone, levofloxacin, linezolid, meropenem, penicillin, tigecycline, trimethoprim/sulfamethoxazole, and vancomycin).

XENLETA has demonstrated synergy in vitro with doxycycline against S. aureus.

Antimicrobial Activity

XENLETA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1.1)]:

Gram-positive Bacteria:

Streptococcus pneumoniae
Staphylococcus aureus (methicillin-susceptible isolates)

Gram-negative Bacteria:

Haemophilus influenzae

Other Bacteria:

Mycoplasma pneumoniae
Chlamydophila pneumoniae
Legionella pneumophila

At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for XENLETA against isolates of similar genus or organism group. However, the safety and efficacy of XENLETA in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria:

Staphylococcus aureus (methicillin-resistant [MRSA] isolates)
Streptococcus agalactiae
Streptococcus anginosus
Streptococcus mitis
Streptococcus pyogenes
Streptococcus salivarius

Gram-negative Bacteria:

Haemophilus parainfluenzae
Moraxella catarrhalis

Long-term carcinogenicity studies have not been conducted with lefamulin.

Lefamulin did not elicit genotoxic potential in an in vivo clastogenicity assay. Valid in vitro mutagenicity assays have not been performed for lefamulin or the main human metabolite of lefamulin (2R-hydroxy lefamulin). At least six impurities have been identified to be possibly genotoxic based on chemical structure, while two others were positive in mutagenicity testing and may contribute to a total amount of genotoxic impurities that exceed the acceptable total daily intake of mutagenic impurities. However, since the duration of clinical dosing is limited to 5-7 days, the clinical implications are unknown.

In rats, there were no effects on male fertility that were considered to be related to lefamulin. Reproductive indices including mating behavior and fertility were not changed in any group in either gender at the highest dose tested (75 mg/kg/day, approximately 0.7 times the mean exposure of CABP patients treated IV, based on AUC_0-24h); that dose was the NOAEL for fertility in male rats. In females, abnormal estrous cycling and increased post-implantation loss were observed at the high dose, making the NOAEL for fertility and early embryonic development in female rats the next highest dose, 50 mg/kg/day (approximately 0.5 times the mean exposure of CABP patients treated IV).

Following IV administration of lefamulin to rats for 4 or 13 weeks, anemia (all doses), increased coagulation times, and lower organ weights and histopathological changes in spleen (decreased peri-arteriolar lymphoid sheath, decreased size of the marginal zone) and thymus (cortical atrophy) were seen in rats at exposures greater than approximately 0.7 times exposure in CABP patients after IV administration in the 4-week study and greater than approximately 0.3 times exposure in CABP patients in the 13-week study.

In cynomolgus monkeys administered IV lefamulin, anemia and pancreatic microvesicular vacuolization of acinar cells were noted at exposures greater than approximately 1.6 times exposure in CABP patients in a 4-week study. In a 13-week study, pancreatic microvesicular vacuolization of acinar cells and minimal alveolar macrophage infiltrates in the lung were observed at all doses, and anemia was noted at exposures greater than approximately 1.0 times clinical exposure.

Lefamulin was evaluated in 4-week oral toxicology studies in rats and cynomolgus monkeys. Findings included partially reversible degenerative changes in the stomach and evidence of lymphoid depletion and hematopoietic cell depletion in rats at exposures greater than approximately 0.6 times exposure following oral administration to CABP patients. Findings in cynomolgus monkeys included myocardial vacuolation and fibrosis at exposures equal to or greater than 0.3 times that in CABP patients.

Evidence of dose-dependent regenerative anemia in both species may indicate that XENLETA was potentially hemolytic at a concentration that is approximately ten times 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.

14.1 Community-Acquired Bacterial Pneumonia

A total of 1289 adults with CABP were randomized in two multicenter, multinational, double-blind, double-dummy, non-inferiority trials (Trial 1 NCT #02559310 and Trial 2 NCT #02813694). Trial 1 compared 5 to 10 days of XENLETA to 7 to 10 days of moxifloxacin ± linezolid. Trial 2 compared 5 days of XENLETA to 7 days of moxifloxacin.

In Trial 1, 276 patients were randomized to XENLETA (150 mg by intravenous [IV] infusion over 60 minutes every 12 hours, with the option to switch to 600 mg orally every 12 hours after at least 3 days of IV treatment) and 275 patients were randomized to moxifloxacin (400 mg IV every 24 hours, with the option to switch to 400 mg orally every 24 hours after at least 3 days of IV treatment). If methicillin-resistant Staphylococcus aureus (MRSA) was suspected at screening, patients randomized to moxifloxacin were to receive adjunctive linezolid (600 mg IV every 12 hours, with the option to switch to 600 mg orally every 12 hours after at least 3 days of IV treatment), and patients randomized to XENLETA were to receive linezolid placebo. Patients were predominantly male (60%) and white (87%). Approximately 72% of patients were PORT Risk Class III and 28% were PORT Risk Class IV or V. Median age was 62 (range 19-91) years, approximately 18% of patients were 75 years or older, and median body mass index (BMI) was 25.8 (range 11-58.4) kg/m². Approximately 53% of patients had creatinine clearance (CrCl) <90 mL/min. Common comorbid conditions included hypertension (41%), asthma/chronic obstructive pulmonary disease (COPD) (17%), and diabetes mellitus (13%).

In Trial 2, 370 patients were randomized to XENLETA (600 mg orally every 12 hours for 5 days) and 368 patients were randomized to moxifloxacin (400 mg orally every 24 hours for 7 days). Patients were predominantly male (52%) and white (74%). Approximately 50% of patients were PORT Risk Class II and 49% were PORT Risk Class III or IV. Median age was 59 (range 19-97) years, approximately 16% of patients were 75 years or older, and median BMI was 26.0 (range 13-63.9) kg/m². Approximately 50% of patients had CrCl <90 mL/min. Common comorbid conditions included hypertension (36%), asthma/COPD (16%), and diabetes mellitus (13%).

In both trials, efficacy was determined by Early Clinical Response (ECR) at 72 to 120 hours after the first dose in the Intent-to-treat (ITT) Analysis Set, which comprised all randomized patients. Patients entered the trials with at least three of four symptoms consistent with CABP (cough, sputum production, chest pain, and/or dyspnea). Response was defined as survival with improvement of at least two symptoms, no worsening of any symptom, and no receipt of non-study antibacterial treatment for CABP. Table 5 summarizes ECR rates in the two trials.

Table 5. Early Clinical Response Rates in Trial 1 and Trial 2 (ITT Analysis Set):

* Trial 1 compared XENLETA to moxifloxacin ± linezolid.
** 95% confidence interval for the treatment difference.

Clinical response was also assessed by the Investigator at the Test of Cure (TOC) Visit 5 to 10 days after the last dose of study drug. Response was defined as survival with improvement of signs and symptoms based on the Investigator’s assessment and no receipt of non-study antibacterial treatment for CABP. Table 6 summarizes Investigator-assessed Clinical Response (IACR) rates at TOC in the ITT Analysis Set, which comprised all randomized patients.

Table 6. Investigator-assessed Clinical Response Rates at TOC in Trial 1 and Trial 2 (ITT Analysis Set):

* Trial 1 compared XENLETA to moxifloxacin ± linezolid.
** 95% confidence interval for the treatment difference.

Table 7 summarizes IACR rates at TOC by the most common baseline pathogens across both trials in the microITT Analysis Set, which comprised all randomized patients with at least 1 baseline pathogen.

Table 7. Investigator-assessed Clinical Response Rates at TOC by Baseline Pathogen in Trial 1 and Trial 2 (microITT Analysis Set):

* Trial 1 compared XENLETA to moxifloxacin ± linezolid.