12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

NUZYRA is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

Based on the nonclinical and clinical data, including electrocardiogram evaluation in the phase 3 clinical trials, one of which had moxifloxacin as a control group, no clinically relevant QTc prolongation was observed at the maximum recommended dose of omadacycline.

Cardiac Physiology-Increase in Heart Rate

In phase 1 studies conducted in healthy volunteers, reversible dose-dependent increases in heart rate have been observed following administration of single and multiple doses of omadacycline. The clinical implication of this finding is unknown [see Adverse Reactions (6.1)].

In a standard radiolabeled ligand binding assays, omadacycline was shown to inhibit binding of H-scopolamine to the M2 subtype of the muscarinic acetylcholine receptor. In the heart, muscarinic M2 receptors serve as mediators of the parasympathetic input that normally is received via the vagus nerve and stimulation of the receptor increases membrane potassium conductance through the acetylcholine-dependent channel, which slows depolarization and reduces pacemaker activity in the sinoatrial node.

12.3 Pharmacokinetics

The pharmacokinetic parameters of NUZYRA after single and multiple oral and intravenous doses are summarized in Table 6.

Table 6: Mean (SD) Pharmacokinetic Parameters of NUZYRA in Healthy Adult Subjects
Dose and Route of Administration		100 mg IV	300 mg Oral	450 mg Oral
C max= maximum plasma concentration, AUC = area under concentration-time curve, IV = intravenous, ND = not determined, T max= time to C max
* All PK parameters presented as mean (standard deviation), Number of Subjects, unless otherwise specified † Presented as AUC (0-inf) ‡ Presented as AUC (0-24) § Presented as apparent clearance or volume of distribution ¶ Following administration of radiolabeled omadacycline
PK Parameters *
C maxng/mL	Single dose	1507 (582) (n=63)	548 (146) (n=103)	874 (232) (n=24)
C maxng/mL	Steady state	2116 (680) (n=41)	952 (420) (n=43)	1077 (269) (n=24)
AUCh*ng/mL	Single dose †	9358 (2072) (n=62)	9399 (2559) (n=102)	13504 (3634) (n=24)
AUCh*ng/mL	Steady state ‡	12140 (3223) (n=41)	11156 (5010) (n=43)	13367 (3469) (n=24)
Accumulation	Accumulation ratio 1.5
Absorption
Bioavailability	34.5% following single 300 mg dose of NUZYRA
T maxMedian (min, max)	Single dose	0.6 (0.3, 0.7) (n=63)	2.5 (1, 4.1) (n=103)	2.5 (1.5, 3) (n=24)
T maxMedian (min, max)	Steady state	0.5 (0, 1) (n=41)	2.5 (0, 8) (n=43)	2.5 (1.5, 4) (n=24)
Distribution
Plasma Protein Binding	20%; not concentration dependent
Volume of DistributionL	Single dose	256 (66) (n=62)	794 §(188) (n=27)	914 §(821.9) (n=23)
Volume of DistributionL	Steady state	190 (53) (n=41)	440 §(262) (n=34)	607 §(197.4) (n=24)
Elimination
Elimination Half-Lifeh	Single dose	16.4 (2.1) (n=62)	15.0 (2.5) (n=81)	13.45 (1.7) (n=23)
Elimination Half-Lifeh	Steady state	16.0 (3.5) (n=41)	15.5 (1.7) (n=21)	16.83 (1.4) (n=23)
Systemic ClearanceL/h	Single dose	11.24 (2.7) (n=62)	34.6 §(10.7) (n=27)	43.4 §(49.8) (n=23)
Systemic ClearanceL/h	Steady state	8.8 (2.2) (n=41)	18.3 §(8.3) (n=34)	21.2 §(8.9) (n=24)
Renal ClearanceL/h	3.1 (0.69) (n=8)
Metabolism	Omadacycline is not metabolized
Excretion(% dose)	Urine	27 (3.5) (n=8)	14.4 ¶(2.3) (n=6)	ND
Excretion(% dose)	Feces	ND	81.1 ¶(2.3) (n=6)	ND

Absorption

The exposure to omadacycline is similar between a 300 mg oral dose and a 100 mg intravenous dose of NUZYRA in healthy fasted subjects.

Effect of Food

Ingestion of a standard high-fat nondairy meal (855 calories; 59% calories from fat) and standard high-fat meal including dairy (985 calories; 60% calories from fat) 2-hours before administration of a single 300 mg oral dose of NUZYRA decreased the rate (Cmax) and extent of absorption (AUC) by 40% and 42%, and 59% and 63%, respectively compared to administration of NUZYRA under fasting conditions. The rate and extent of absorption of NUZYRA were not substantially decreased when a high-fat nondairy meal (800-1000 calories; 50% calories from fat) was ingested 4 hours pre-dose.

Following ingestion of either a light non-fat (300-350 calories; ≤5% calories from fat), or a standard low-fat (800-1000 calories; 30% calories from fat), or a standard high fat (800-1000 calories; 50% calories from fat) meal 2 hours post-dose, the AUC and C maxwere not substantially altered, as compared to fasting conditions.

Distribution

Plasma protein binding of omadacycline is approximately 20% and is not concentration dependent. The mean (% CV) volume of distribution of omadacycline at steady-state following IV administration of NUZYRA in healthy subjects was 190 (27.7) L.

Elimination

Renal clearance of omadacycline following IV administration of NUZYRA ranged from 2.4 to 3.3 L/h in healthy subjects.

Metabolism

In vitrostudies using human liver microsomes and hepatocytes demonstrated that omadacycline is not metabolized.

Excretion

Following a 100 mg IV dose of NUZYRA, 27% of the dose was recovered as unchanged omadacycline in the urine. In healthy male volunteers receiving 300 mg oral [ 14C] NUZYRA, 77.5% to 84.0% of the dose was recovered in the feces, approximately 14.4% (range 10.8% to 17.4%) in the urine, with 95.5% of the administered radioactive dose recovered after 7 days.

Lung Penetration

The mean omadacycline concentrations over time for alveolar cells (AC), epithelial lining fluid (ELF), and plasma following IV administration of multiple doses of 100 mg of NUZYRA to healthy volunteers are shown in Figure 1. The steady-state omadacycline AUC 0-24h(302.5 hr*mcg/mL) in AC was 25.8-fold higher than the plasma AUC 0-24h, and the AUC 0-24h(17.2 hr*mcg/mL) in ELF was 1.5-fold higher than the AUC 0-24hin plasma.

Figure 1: Mean (± SD) Concentrations of Omadacycline in Alveolar Cells, Epithelial Lining, and Plasma Following Multiple 100 mg IV Doses of NUZYRA to Healthy Subjects During Bronchoscopy Sampling Times

Specific Populations

No clinically significant differences in the pharmacokinetics of omadacycline were observed based on age, gender, race, weight, renal impairment or end-stage renal disease, and hepatic impairment.

Patients with Renal Impairment

A study was conducted to compare NUZYRA pharmacokinetics following 100 mg IV administration in 8 subjects with end-stage renal disease (ESRD) on stable hemodialysis, with and 8-matched healthy control subjects. In the ESRD subjects, NUZYRA was administered on two separate occasions; immediately prior to dialysis and after dialysis, and the AUC, C max, and CL of NUZYRA were comparable between the renally impaired subjects and the matching healthy subjects. During dialysis, 7.9% of omadacycline was recovered in the dialysate. Renal impairment did not impact NUZYRA elimination.

Patients with Hepatic Impairment

A study was conducted to compare NUZYRA pharmacokinetics following intravenous and oral dosing to 5 subjects with mild hepatic impairment (Child-Pugh Class A), 6 subjects with moderate hepatic impairment (Child-Pugh Class B), and 6 subjects with severe hepatic impairment (Child-Pugh Class C) as compared to 12 matched healthy control subjects. The AUC and C maxof NUZYRA were comparable between the hepatically impaired subjects and the matching healthy subjects, and similar clearance was observed across all cohorts. Hepatic impairment did not impact NUZYRA elimination.

Drug Interaction Studies

Clinical Studies

Administration of oral verapamil (P-gp inhibitor) two hours prior to a single 300 mg oral dose of NUZYRA increased omadacycline AUC by approximately 25% and C max by approximately 9%.

In vitro Studies

In vitro studies in human liver microsomes indicate that omadacycline does not inhibit nor induce metabolism mediated by CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, or UGT1A1. Therefore, NUZYRA is not expected to alter the pharmacokinetics of drugs metabolized by the above stated human hepatic enzymes.

Omadacycline is not an inhibitor of P-gp and organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Omadacycline is a substrate of P-gp (see Clinical Studies above). Omadacycline is not a substrate or inhibitor of the major organic anion transporters (OAT-1 and 3), breast cancer resistance protein (BCRP), or multidrug resistance-associated protein 2 (MRP2). Omadacycline was not an OATP1B1 or OATP1B3 substrate at supra-therapeutic concentrations (5-13 fold higher than clinically relevant concentrations).

12.4 Microbiology

Mechanism of Action

Omadacycline is an aminomethylcycline antibacterial within the tetracycline class of antibacterial drugs. Omadacycline binds to the 30S ribosomal subunit and blocks protein synthesis. In general, omadacycline is considered bacteriostatic; however, omadacycline has demonstrated bactericidal activity against some isolates of S. pneumoniae and H. influenzae.

Resistance

The following in vitro data are available, but their clinical significance is unknown. Omadacycline was active in vitro against Gram-positive bacteria expressing ribosomal protection proteins (TetM) and tetracycline resistance active efflux pumps (TetK and TetL), and in Enterobacteriaceae expressing the TetB efflux pump. Additionally, omadacycline was active against some S. aureus, S. pneumoniae, and H. influenzae strains carrying macrolide resistance genes ( ermA,Band/or C), or ciprofloxacin resistance genes ( gyrAand parC) and beta-lactamase positive H. influenzae.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated antagonism between omadacycline and other commonly used antibacterials (ampicillin, ceftazidime, ceftriaxone, imipenem, piperacillin/tazobactam, gentamicin, vancomycin, daptomycin, linezolid).

Antimicrobial Activity

Omadacycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1, 1.2)] .

Community-Acquired Bacterial Pneumonia (CABP)

Gram-positive bacteria
Streptococcus pneumoniae
Staphylococcus aureus (methicillin-susceptible isolates)

Gram-negative bacteria
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae

Other microorganisms
Chlamydophila pneumoniae
Legionella pneumophila
Mycoplasma pneumoniae

Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

Gram-positive bacteria
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Staphylococcus lugdunensis
Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus pyogenes

Gram-negative bacteria
Enterobacter cloacae
Klebsiella pneumoniae

The following in vitro data are available, but their clinical significance is unknown. At least 90% of isolates of the following bacteria exhibit an in-vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for NUZYRA against isolates of similar genus or organism group. However, the efficacy of NUZYRA in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.

Gram-positive bacteria
Enterococcus faecium(vancomycin-susceptible and -resistant isolates)
Streptococcus agalactiae

Gram-negative bacteria
Enterobacter aerogenes
Escherichia coli
Citrobacter freundii
Citrobacter koseri
Klebsiella oxytoca
Moraxella catarrhalis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.