12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

The AUC/minimum inhibitory concentration (MIC) was shown to best correlate with tedizolid activity in animal infection models.

In the mouse thigh infection model of S. aureus, antistaphylococcal killing activity was impacted by the presence of granulocytes. In granulocytopenic mice (neutrophil count <100 cells/mL), bacterial stasis was achieved at a human-equivalent dose of approximately 2000 mg/day; whereas, in non-granulocytopenic animals, stasis was achieved at a human-equivalent dose of approximately 100 mg/day. The safety and efficacy of SIVEXTRO for the treatment of neutropenic patients (neutrophil counts <1000 cells/mm3) have not been evaluated.

Cardiac Electrophysiology

In a randomized, positive- and placebo-controlled crossover thorough QTc study, 48 enrolled subjects were administered a single oral dose of SIVEXTRO at a therapeutic dose of 200 mg, SIVEXTRO at a supratherapeutic dose of 1200 mg, placebo, and a positive control; no significant effects of SIVEXTRO on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. Therefore, SIVEXTRO does not affect cardiac repolarization.

12.3 Pharmacokinetics

Tedizolid phosphate is a prodrug that is converted by phosphatases to tedizolid, the microbiologically active moiety, following oral and intravenous administration. Only the pharmacokinetic profile of tedizolid is discussed further due to negligible systemic exposure of tedizolid phosphate following oral and intravenous administration. Following multiple once-daily oral or intravenous administration, steady state concentrations are achieved within approximately three days with tedizolid accumulation of approximately 30% (tedizolid half-life of approximately 12 hours). Pharmacokinetic (PK) parameters of tedizolid following oral and intravenous administration of 200 mg once daily tedizolid phosphate are shown in Table 5.

Table 5: Mean (Standard Deviation) Tedizolid Pharmacokinetic Parameters Following Single and Multiple Oral and Intravenous Administration of 200 mg Once-Daily Tedizolid Phosphate
Pharmacokinetic Parameters of Tedizolid*	Oral		Intravenous
Pharmacokinetic Parameters of Tedizolid*	Single Dose	Steady State	Single Dose	Steady State
* Cmax, maximum concentration; Tmax, time to reach Cmax; AUC, area under the concentration-time curve; CL, systemic clearance; CL/F, apparent oral clearance † Median (range) ‡ AUC is AUC0-∞ (AUC from time 0 to infinity) for single-dose administration and AUC0-24 (AUC from time 0 to 24 hours) for multiple-dose administration
Cmax (mcg/mL)	2.0 (0.7)	2.2 (0.6)	2.3 (0.6)	3.0 (0.7)
Tmax (hr)†	2.5 (1.0 - 8.0)	3.5 (1.0 - 6.0)	1.1 (0.9 - 1.5)	1.2 (0.9 - 1.5)
AUC (mcg∙hr/mL)‡	23.8 (6.8)	25.6 (8.5)	26.6 (5.2)	29.2 (6.2)
CL or CL/F (L/hr)	7.5 (2.3)	6.9 (1.7)	6.4 (1.2)	5.9 (1.4)

Absorption

Peak plasma tedizolid concentrations are achieved within approximately 3 hours following oral administration under fasting conditions or at the end of the 1 hour intravenous infusion of tedizolid phosphate. The absolute bioavailability is approximately 91% and no dosage adjustment is necessary between intravenous and oral administration.

Tedizolid phosphate (oral) may be administered with or without food as total systemic exposure (AUC0-∞) is unchanged between fasted and fed (high-fat, high-calorie) conditions.

Distribution

Protein binding of tedizolid to human plasma proteins is approximately 70 to 90%. The mean steady state volume of distribution of tedizolid in healthy adults following a single intravenous dose of tedizolid phosphate 200 mg ranged from 67 to 80 L (approximately twice total body water). Tedizolid penetrates into the interstitial space fluid of adipose and skeletal muscle tissue with exposure similar to free drug exposure in plasma.

Elimination

Metabolism

Other than tedizolid, which accounts for approximately 95% of the total radiocarbon AUC in plasma, there are no other significant circulating metabolites in humans.

There was no degradation of tedizolid in human liver microsomes indicating tedizolid is unlikely to be a substrate for hepatic CYP450 enzymes.

In vitro studies showed that conjugation of tedizolid is mediated via multiple sulfotransferase (SULT) isoforms (SULT1A1, SULT1A2, and SULT2A1).

Excretion

Following single oral administration of 14C-labeled tedizolid phosphate under fasted conditions, the majority of elimination occurred via the liver, with 82% of the radioactive dose recovered in feces and 18% in urine, primarily as a non-circulating and microbiologically inactive sulfate conjugate. Most of the elimination of tedizolid (>85%) occurs within 96 hours. Less than 3% of the tedizolid phosphate-administered dose is excreted in feces and urine as unchanged tedizolid.

Specific Populations

Based on the population pharmacokinetic analysis, there are no clinically relevant demographic or clinical patient factors (including age, gender, race, ethnicity, weight, body mass index, and measures of renal or liver function) that impact the pharmacokinetics of tedizolid.

Patients with Hepatic Impairment

Following administration of a single 200 mg oral dose of SIVEXTRO, no clinically meaningful changes in mean tedizolid Cmax and AUC0-∞ were observed in adult patients with moderate (n=8) or severe (n=8) hepatic impairment (Child-Pugh Class B and C) compared to 8 matched healthy control subjects. No dose adjustment is necessary for patients with hepatic impairment.

Patients with Renal Impairment

Following administration of a single 200 mg intravenous dose of SIVEXTRO to 8 adult subjects with severe renal impairment defined as eGFR <30 mL/min/1.73 m2, the Cmax was essentially unchanged and AUC0-∞ was decreased by less than 10% compared to 8 matched healthy control adult subjects. Hemodialysis does not result in meaningful removal of tedizolid from systemic circulation, as assessed in subjects with end-stage renal disease (eGFR <15 mL/min/1.73 m2). No dosage adjustment is necessary in patients with renal impairment or patients on hemodialysis.

Geriatric Patients

The pharmacokinetics of tedizolid were evaluated in a Phase 1 study conducted in elderly healthy volunteers (age 65 years and older, with at least 5 subjects at least 75 years old; n=14) compared to younger control subjects (25 to 45 years old; n=14) following administration of a single oral dose of SIVEXTRO 200 mg. There were no clinically meaningful differences in tedizolid Cmax and AUC0-∞ between elderly subjects and younger control subjects. No dosage adjustment of SIVEXTRO is necessary in elderly patients.

Male and Female Patients

The impact of gender on the pharmacokinetics of SIVEXTRO was evaluated in clinical trials of adult healthy males and females and in a population pharmacokinetics analysis. The pharmacokinetics of tedizolid were similar in males and females. No dosage adjustment of SIVEXTRO is necessary based on gender.

Pediatric Patients

Compared to adult patients, tedizolid exposures are higher in pediatric patients 12 to <18 years of age following multiple dose administration of IV or oral SIVEXTRO (geometric mean Cmax 3.13 vs. 2.00 mcg/mL, AUC24h 28.6 vs. 21.0 mcg*h/mL); however, this increase in exposure is not considered clinically significant.

Drug Interaction Studies

Drug Metabolizing Enzymes

Transformation via Phase 1 hepatic oxidative metabolism is not a significant pathway for elimination of SIVEXTRO.

Neither SIVEXTRO nor tedizolid detectably inhibited or induced the metabolism of selected CYP enzyme substrates, suggesting that drug-drug interactions based on oxidative metabolism are unlikely.

Membrane Transporters

The potential for tedizolid or tedizolid phosphate to inhibit transport of probe substrates of important drug uptake (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2) and efflux transporters (P-gp and BCRP) was tested in vitro. No clinically relevant interactions are expected to occur with these transporters except BCRP.

Coadministration of multiple oral doses of SIVEXTRO (200 mg once daily) increased the Cmax and AUC of rosuvastatin (10 mg single oral dose), a known BCRP substrate, by approximately 55% and 70%, respectively, in healthy adult subjects [see Drug Interactions (7)].

Monoamine Oxidase Inhibition

Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro. The interaction with MAO inhibitors could not be evaluated in Phase 2 and 3 trials, as subjects taking such medications were excluded from the trials.

Adrenergic Agents

Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oral SIVEXTRO at steady state to enhance pressor responses to pseudoephedrine and tyramine in healthy adults. No meaningful changes in blood pressure or heart rate were seen with pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure of ≥30 mmHg from pre-dose baseline was 325 mg with SIVEXTRO compared to 425 mg with placebo. Palpitations were reported in 21/29 (72.4%) adult subjects exposed to SIVEXTRO compared to 13/28 (46.4%) exposed to placebo in the tyramine challenge study.

Serotonergic Agents

Serotonergic effects at doses of tedizolid phosphate up to 30-fold above the human equivalent dose did not differ from vehicle control in a mouse model that predicts serotonergic activity. In Phase 3 trials, subjects taking serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine (5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded.

12.4 Microbiology

Mechanism of Action

The antibacterial activity of tedizolid is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis. Tedizolid inhibits bacterial protein synthesis through a mechanism of action different from that of other non-oxazolidinone class antibacterial drugs; therefore, cross-resistance between tedizolid and other classes of antibacterial drugs is unlikely. The results of in vitro time-kill studies show that tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci.

Resistance

Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to tedizolid. In the limited number of Staphylococcus aureus strains tested, the presence of the chloramphenicol-florfenicol resistance (cfr) gene did not result in resistance to tedizolid in the absence of chromosomal mutations. Mutations in 23SrRNA (G2576T mutation) have been associated with tedizolid resistance in S. aureus isolates.

Spontaneous mutations conferring reduced susceptibility to tedizolid occur in vitro at a frequency rate of approximately 10-10.

Interaction with Other Antimicrobial Drugs

In vitro drug combination studies with tedizolid and aztreonam, ceftriaxone, ceftazidime, imipenem, rifampin, trimethoprim/sulfamethoxazole, minocycline, clindamycin, ciprofloxacin, daptomycin, vancomycin, gentamicin, amphotericin B, ketoconazole, and terbinafine demonstrate neither synergy nor antagonism.

Antimicrobial Activity

Tedizolid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in Indications and Usage (1).

Aerobic bacteria

: Gram-positive bacteria
: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates)
: Streptococcus pyogenes
: Streptococcus agalactiae
: Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus)
: Enterococcus faecalis

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

Aerobic bacteria

Gram-positive bacteria

: Staphylococcus epidermidis (including methicillin-susceptible and methicillin-resistant isolates)
: Staphylococcus haemolyticus
: Staphylococcus lugdunensis
: Enterococcus faecium

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