Lefamulin

Lefamulin is an antibacterial drug.

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 lefamulin 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 lefamulin 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 lefamulin injection or tablets to patients with CABP are listed in the table below.

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

Pharmacokinetic (PK) Parameters of Lefamulin Following Single or Multiple Dose (Every 12 Hours) Lefamulin 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 lefamulin 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 lefamulin 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 lefamulin (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 lefamulin 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 lefamulin 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 lefamulin, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of lefamulin 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 lefamulin 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 lefamulin tablets. Thus, lefamulin tablets are not recommended in patients with moderate or severe hepatic impairment.

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 lefamulin injection. Additionally, oral rifampin reduced the mean lefamulin AUC_0-inf and C_max by 72% and 57%, respectively, when administered concomitantly with lefamulin 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 lefamulin injection. Additionally, oral ketoconazole (strong inhibitor) increased the lefamulin AUC_0-inf and C_max by 165% and 58%, respectively, when administered concomitantly with lefamulin 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 lefamulin 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 lefamulin tablets.

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

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 lefamulin 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.