WO2015054246A1 - Methods of treating subjects with renal impairment using tedizolid - Google Patents

Abstract

The present disclosure is related to the administration of tedizolid to special patient populations, for example subjects suffering from renal impairment, for purposes of treating infections.

Description

BACKGROUND

Field of the I vention

[0001] The present disclosure relates to the administration of tedizolid to subjects suffering from renal impairment for purposes of treating infections.

Description of the Related Art

[0002] The management of infections due to gram-positive pathogens, including strains resistant to older antibiotics, continues to pose challenges. Currently available therapeutic options include older generic antibiotics and newer agents such as linezolid, daptomycin, telavancin, and ceftaroline, although drug resistance trends, safety issues, and requirements for dose adjustments in special patient populations may complicate the use of these options.

[0003] Tedizolid ((5i?)-3-{3-fluoro-4-[6-(2-methyl-2H-te1razol-5-yl)pyridra-3- yl]phenyl}-5-(hydrox methyl)-l,3-oxazoiidin-2-one) is an oxazolidinone antibiotic. Tedizolid phosphate, the water-soluble prodmg of the active moiety tedizolid, is rapidly converted to tedizolid in the presence of endogenous phosphatases. The antibacterial activity of tedizolid is believed to result from its interaction with the 23S ribosomal ribonucleic acid (rRNA) of the bacterial ribosome to inhibit protein synthesis, thereby preventing the initiation of translation by inhibiting formation of the initiation complex. Tedizolid shows potent in vitro activity against Gram-positive pathogens, including those resistant to other antimicrobial agents.

[0004] Dose adjustments, or a switch to alternate treatment options, need to be considered for the appropriate clinical use of many antibiotics when their distribution, metabolism, or excretion are altered in ways that may impact clinical efficacy or adverse event profiles. Notably, dose adjustments (either amount or frequency, or both) are required for many antibiotic classes in special patient populations, including patients with renal or hepatic insufficiency. Since renal and hepatic impairment are common comorbidities in patients requiring therapy for serious gram-positive infections, it is important to evaluate the potential need for dose adjustments with antibiotics used in this clinical setting. For example, chronic kidney disease is associated with increased overall and postsurgical infection risk and greater adverse outcomes, necessitating careful antibiotic use in these patients. With aging populations, the prevalence of chronic kidney disease (CKD) increases in both the community and hospitalized patients, with up to 50% CKD among nursing home residents. Dose adjustment calculations based on renal function are available, but achieving adequate target levels while avoiding adverse effects remains challenging. The reported prevalence of chronic liver disease (CLD) has also increased over time. Chronic liver disease may be a risk factor for high vancomycin MIC methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections and MRSA infections caused by the SCCmec- IV strain, which is often community acquired. Like CKD, CLD is associated with increased antibiotic adverse events. Serious liver disease can cause complex changes to drug metabolism and elimination through hepatic as well as renal pathways,

[0005] Accordingly, to achieve safe and successful treatment outcomes, it is desirable to understand the potential need for antibiotic dose adjustments in special patient populations.

SUMMARY

[0006] Provided herein are methods of treating bacterial infections in subjects with renal impairment, wherein the subject is being treated with dialysis. In some embodiments, the subject has severe renal impairment with eGFR < 30.0 mL/min/1.73m². In some embodiments, the subject has end-stage renal disease (ESRD) with eGFR. < 15.0 m.L/min/1 ,73m^".

[0007] In one aspect, provided herein is a method for treating an infection in a subject with renal impairment, wherein the method comprises: identifying a subject with renal insufficiency; and administering a pharmaceutical composition comprising tedizolid to the subject. The degree of the renal insufficiency of the subject may vary. For example, the subject may have severe renal impairment, or suffer from ESRD. In some embodiments, the subject is being treated with dialysis. [0008] In some embodiments, the pharmaceutical composition is administered intravenously. For example, the pharmaceutical composition comprising tedizolid can be administered to the subject in a single TV infusion of tedizolid 200 mg daily. In some embodiments, the pharmaceutical composition is administered orally.

[0009] In some embodiments, the tedizolid is in the form of tedizolid hydrogen phosphate.

[0010] In some embodiments, the infection is caused by gram-positive pathogens, for example, Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus), and Enterococcus faecal is (vaneomycin-susceptible isolates). In some embodiments, the Staphylococcus aureus is methicillin-resistant (MRSA) or methicillin- susceptible (MSSA) Staphylococcus aureus. In some embodiments, the infection is an acute bacterial skin and skin structure infection (ABSSSI). In some embodiments, the Enterococcus faecalis is a vaneomycin-susceptible isolate.

[0011] In some embodiments, the patient is being treated with hemodialysis.

[0012] In some embodiments, the infection is hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP).

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figures 1 A-B show plasma tedizolid concentration in subjects with severe renal impairment and matched controls in linear scale (1A) and in semi-logarithmic scale (IB).

[0014] Figures 2A-B show plasma tedizolid concentration in subjects with impaired hepatic function and matched controls in linear scale (2A) and in semi-logarithmic scale (2B).

[0015] Figure 3 shows total plasma exposure, i.e. the area under the concentration-time curve (AUG), of tedizolid in evaluated special patient populations and relevant controls. [0016] Figure 4 shows peak plasma concentration (C_max) in evaluated special patient populations and relevant controls.

[0017] Figure 5 shows tedizolid AUG and C_max geometric mean ratios (with 90% Cis) in evaluated special populations. Open circles ^::: maximum concentration (C_max); solid circles = area under the curve (AUG) from time zero to infinity. Geometric mean ratio = (Geometric mean test)/(Geometric mean reference), where the test group is the special population,

DETAILED DESCRIPTION

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material set forth herein is only incorporated to the extent that no conflict, arises between that incorporated material and the present disclosure material. As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. The use of "or" or "and" means "and/or" unless stated otherwise.

[0019] The present disclosure relates to the treatment of an infection in a patient with organ impairment, for example, a patient with renal impairment, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of tedizolid. As described herein, the pharmacokinetics and safety of tedizolid were investigated in subjects with varying degree of renal function and in subjects with end-stage renal disease (ESRD) on hemodialysis. Provided herein are specific dosing and administration regimens of tedizolid that are safe and effective in patients with renal impairment.

[0020] As used herein, the term "tedizolid" refers to (5 ?)-3- {3-fluoro-4-[6-(2- methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl} -5-(hydroxymethyl)- 1 ,3-oxazolidin-2-one in a free-base or salt form, preferably a hydrogen phosphate form. In some embodiments, tedizolid is in its salt form, for example, a hydrogen phosphate form. This form has tht following formula:

[ 0021] in some embodiments, tedizolid is in the form of disodium salt of tedizolid phosphate, and this form has the following structure:

[0022] Tedizolid is eliminated in excreta, primarily as a non-circulating and biologically inactive sulfate conjugate. Following single oral administration of C³⁴~labeled tedizolid phosphate under fasted conditions, the majority of elimination occurred via the liver, with 81 .5% of the radioactive dose recovered in feces and 18.0% in urine, with most of the elimination (> 85%) occurring within 96 hours. Less than 3%) of tedizolid phosphate administered dose is excreted as active tedizolid.

Tedizolid dosing and administration regimens

[0023] Provided herein, in some embodiments, are tedizolid dosing and administration regimens for the treatment of an infection in a patient with renal impairment. Examples of the patient with renal impairment include, but are not limited to, patients suffering from severe renal impairment without hemodialysis and patients experiencing end- stage renal disease (ESRD) undergoing hemodialysis.

[0024] The pharmaceutical composition comprising tedizolid can be in various forms. For example, the pharmaceutical composition can be in the form of tablet. In some embodiments, each tablet of the pharmaceutical composition contains 200 mg of tedizolid phosphate, and inactive ingredients including, but not limited to, microcrystailine cellulose, mamiitol, povidone, crospovidone and magnesium stearate. In some embodiments, the pharmaceutical composition comprising tedizolid comprises a film coating that contains inactive ingredients including, but not limited to, polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, and yellow iron oxide.

[Ό025] The pharmaceutical composition comprising tedizolid can also be an injectable form. In some embodiments, the pharmaceutical composition is an amount of white to off white sterile lyophilized powder for intravenous (IV) infusion which contains 210 nig of tedizolid phosphate to allow delivery of 200 mg after reconstitution with 4 rtiL of Sterile Water for injection. The injectable form of the pharmaceutical composition comprising tedizolid can also contain inactive ingredients including, but not limited to, mannitol, sodium hydroxide, and hydrochloric acid, which is used in minimal quantities for pH adjustment.

[0026] Typically, the pharmaceutical composition comprising tedizolid is administered orally or intravenously. For example, a single 200 mg dose of tedizolid can be administered as an oral dosage form (such as an oral solution) or intravenously. Higher doses of tedizolid may also be used, such as about 300 mg or about 400 mg. In some embodiments, the pharmaceutical composition is orally administered at about 200 mg tedizolid once-a-day. In some embodiments, the pharmaceutical composition is intravenously administered as an infusion, such as a 60~minute infusion. In some embodiments, the pharmaceutical composition comprising tedizolid is administered to the subject at about 200 mg once daily for six days either orally (with or without food) or as an intravenous (TV) infusion . The pharmaceutical composition comprising tedizolid can also be administered to the subject for shorter or longer period of time, for example 2 days, 3 days, 4 days, 5 days, 7 days, 8 days, 9 days, 10 days, or longer.

[0027] Some preferred dosage and administration embodiments of the pharmaceutical composition comprising tedizolid for ABSSSI are described in Table 1 . Table 1. Dosage of Tedizolid

[0028] Pharmaceutical compositions of tedizolid can be obtained by reacting the free acid dihydrogen phosphate with inorganic or organic bases such as sodium hydroxide or magnesium hydroxide. In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein (e.g. , as made in situ during the manufacture of an intravenous formulation) are provided. Exemplary compositions for lyophilization and injection can be found in US Patent Publication No. 20100227839. For example, tedizolid phosphate can be formulated in situ as the disodrum salt using sodium hydroxide. A compounding solution for lyophilization was prepared containing mannitol as a bulking agent, sodium hydroxide for in situ salt formation, hydrochloric acid for pH adjustment and water as a manufacturing solvent, which is removed during lyophilization. For instance, a vial of the lyophilized composition may contain a 200 mg/viai dose of tedizolid phosphate. The lyophilized material may be reconstituted, for example with 0.9% sodium chloride in water for injection. Renal Impairment

[0029] As described herein, following administration of a single 200 mg IV dose of tedizolid to 8 subjects with severe renal impairment (defined as eGFR <30.0 mL min/1.73 m ); the C_raax was basically unchanged and AUCo-_∞ was changed by less than 10% compared to 8 matched healthy subject controls. It was also found that hemodialysis did not result in meaningful removal of tedizolid from, systemic circulation, as assessed in subjects with end- stage renal disease (ESRD, eGFR <I5 mL/min/1.73 m"). Accordingly, no dosage adjustment of tedizolid is necessary in patients with severe renal impairment or ESRD patients on hemodialysis as compared to the patients with normal renal function.

Method of Treatment

[0030] Non-limiting examples of bacterial infections that can be treated by the methods disclosed herein include infections caused by gram-positive bacteria, including but are not limited to. Staphylococcus, Streptococcus, Enterococcus, Clostridium, Haemophilus, Listeria, Corynehacterium, Bifidobacterium, Eubacterium, Lactobacillus, Leuconostoc, Pediococcus, Pepiostreptococcus, Propionibacterium, and Actinomyces , For example, the methods disclosed herein can be used, for example, for the treatment of acute bacterial skin and skin structure infections (ABS8SI) caused by gram-positive bacteria including, but not limited to Staphylococcus bacteria (e.g., Staphylococcus aureus (including methiciilin- resistant (MRSA) and methici!lin-susceptible (MSSA) S. aureus). Staphylococcus epidermidis, Staphylococcus haemolyticus , Staphylococcus lugdunensis. Staphylococcus hominis, Staphylococcus saprophytics, and Staphylococcus epidermidis), Streptococcus bacteria (e.g., Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sangius, Streptococcus pneumoniae, Streptococcus agalactiae. Streptococcus pyogenes, and Streptococcus anginosus Group (e.g., Streptococcus anginosus. Streptococcus intermedins and Streptococcus consteUatus)), Enterococcus jaecalis (e.g., vancornycin-susceptible isolates), Enterococcus faecium, Clostridium bacteria (e.g., Clostridium difficile, Clostridium closlridioforme, Clostridium innocuura, Clostridium perfringens, and Clostridium ramosum), Listeria monocytogenes, Corynehacterium jeikeium, Eubacterium aerofaciens, Eubacterium lentum, Lactobacillus bacteria (e.g., Lactobacillus acidophilus, Lactobacillus casei, and Lactobacillus plantarum), Pepiostreptococcus bacteria (e.g., Pepiostreptococcus anaerohius, Pepiostreptococcus asaccarolyticus, Pepiostreptococcus magnus, Pepiostreptococcus micros, Pepiostreptococcus prevotii, and Pepiostreptococcus productus), and Propionibacterium acnes.

[ΘΘ31] In some embodiments, bacterial infection resulting from Staphylococcus aureus, including niethiciliin-resistant S. aureus (MSSA and MRSA) isolates is treated or controlled using the methods disclosed herein. The MRSA isolate can be MRSA clone USA 300, or community-acquired methicilliii-resistant S. aureus (CA-MRSA). In some embodiments, the method is used to treat infection caused by one or more of Staphylococcus haemolyticus, Staphylococcus lugdunensis, coagulase-negative staphylococci, enterococcal (Enterococcus faecalis and Enterococcus faecium, including vancomycin-resistant enterococci (VRE)), and streptococcal species (Streptococcus pyogenes. Streptococcus agalactiae. Streptococcus dysgalactiae, including penicillin-susceptible Streptococcus pneumoniae (PSSP), penicillin-resistant S pneumoniae (PRSP), and multidrug-resistant (MDR) strains). In some embodiments, the method is used to treat an infection caused by one or more bacteria of the Streptococcus anginosus milled group (including Streptococcus anginosus, Streptococcus intermedins, and Streptococcus constellatus).

[0032] The method disclosed herein is used, in some embodiments, to treat an infection caused by a bacteria that is resistant to one or more ribosome-targeting antibiotics. Non-limiting examples of the ribosome-targeting antibiotics include, but are not limited to, linezolid, clindamycin, streptogramins, phenicols, 16-membered macrolides, and pleuromutilins.

[0033] In some embodiments, the method disclosed herein is used to treat an infection caused by vaneomycin-resistant and linezolid-resistant staphylococcal and enterococcai clinical isolates (including heteroresistant isolates) that possess the virulence factors Panton- Valentine leukoeidin toxin fPVL), pore-forming cytotoxins, and phenol- soluble modulins (PSM), cytotoxins that allow enhanced virulence, higher infectivity, and destruction of white blood cells (WBCs).

[0034] In some embodiments, the method disclosed herein is used to treat acute bacterial skin and skin structure infection (ABSSSI) in adults and adolescents. Non-limiting examples of clinical syndromes of ABSSSI include cellulitis, burns, major abscesses, infected ulcers, and wound infections. In some embodiments, the method disclosed herein is used to treat ventilated nosocomial pneumonia (VNP). Non-limiting examples of VNP include ventilator-associated bacterial pneumonia (VABP) and hospital-acquired bacterial pneumonia (HABP). HABP is an acute infection of the pulmonary parenchyma, associated with clinical signs and symptoms such as fever or hypothermia, chills, rigors, cough, purulent sputum production, chest pain, or dyspnea, accompanied by a new or progressive infiltrate on a chest radiograph in a patient hospitalized for more than 48 hours or that develops within 7 days after hospital discharge. VABP is associated with the same clinical syndrome as hospital-acquired bacterial pneumonia (HABP) with increased oxygen requirements in patients receiving mechanical ventilation via. an endotracheal tube for at least 48 hours. The method disclosed herein can be used to treat M S A nosocomial pneumonia. [0035] In one aspect, provided herein is a method for treating an infection in patient with renal impairment, wherein the method comprises identifying a patient with renal insufficiency, and administering a pharmaceutical composition comprising tedizolid to the patient. In some embodiments, identifying the patient with renal insufficiency comprises evaluating the degree of renal insufficiency of the patient. A number of methods are known to assess kidney function of a patient, including but are not limited to, blood urea nitrogen (BUN) test, ereatinine-blood test, creatinine clearance test, creatinine-urine test. In the BUN test, the amount of urea nitrogen in the blood is measured to assess kidney function and the normal results are generally from 6 to 20 mg/dL. Creatinine is a breakdown product of creatine, which is an important part of muscle. The amount of creatinine in the blood or urine can be determined to assess kidney function of a patient. The normal results for the amount of creatinine in the blood are generally from 0.7 to 1.3 mg/dL for men and 0.6 to 1 .1 mg/dL for women. The normal results for urine creatinine test are generally from 14 to 26 mg per kg of body mass per day for men and 1 1 to 20 mg per kg of body mass per day for women. The normal results for creatinine clearance test are generally from. 97 to 137 ml min for men and from 88 to 128 ml/min for women. A healthcare provider can evaluate the degree of renal insufficie cy of a patient using one or more methods known in the art.

[0036] In one aspect, provided herein is a method for treating ventilator- associated bacterial pneumonia (VABP) and hospital-acquired bacterial pneumonia (HABP) in patient, with renal impairment, wherein the method comprising identifying a patient with renal insufficiency, and administering a pharmaceutical composition comprising tedizolid to the patient, wherein the patient also suffers from HABP or VABP.

Pharmaceutical Compositions with Instructions for Use

[0037] The present disclosure provides for a kit format which comprises package units having doses and administration routes of tedizolid for treating an infection in a subject with rental insufficiency, for example a subject with severe rental insufficiency (eGFR < 30.0 rnL/rnin/1 .73m²), or a subject with end-stage renal disease (eGFR < 15.0 mL/m.in/1 .73m²),

[0038] The package label can include, for example, instructions to take tedizolid antibiotic for 6 days for the treatment of a bacterial infection in patients with renal insufficiency. The package label can also include instructions for reconstitution and dilution in diluents/carrier for IV administration (e.g., water for injection, saline, Ringer's solution).

[0039] In some embodiments, the package label includes instructions to treat a bacterial infection in patients with severe renal disease (eGFR < 30.0 mL/min/1.73m ) in which a dose of 200 mg tedizolid is administered daily for six days via an intravenous (IV) infusion.

[0040] In some embodiments, the package label includes instructions to treat a bacterial infection in patients suffering from end-stage renal disease (eGFR < 15.0 mL/min/1.73m²) with hemodialysis in which a dose of 200 mg tedizolid is administered daily for six days via an intravenous (IV) infusion. In some embodiments, the package label includes instructions to treat a bacterial infection in patients suffering from end stage renal disease (eGFR < 15.0 mL/min/1.73m²) with hemodialysis in which a first dose of 200 mg tedizolid is administered via an intravenous (IV) infusion and a second dose of 200 mg tedizolid is administered via an IV infusion at least 7 days after the first dose of tedizolid is administered.

[0041] Packaged compositions are also provided that comprises a therapeutically effective amount of an antibiotic composition comprising tedizolid and a pharmaceutically acceptable carrier or diluents as well as instructions on how to treat a patient suffering from or susceptible to an infection, wherein the patient has renal insufficiency.

Examples

[0042] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

Example 1

Preparation of Tedizolid Phosphate

[0043] Tedizolid phosphate can be obtained using methods described in US patent publication No. 20100093669, which is incorporated herein by reference in its entirety and particularly for the purpose of describing tedizolid phosphate and methods for making it. In some embodiments of methods of making tedizolid compositions, tedizolid is reconstituted in normal sterile saline (0.9% NaCl), to a. concentration of 200 mg/vial for tedizolid. Solutions can be stored at 25°C (77°F) until use. [0044] According to US 20100093669, tedizolid phosphate can be prepared as follows: A 5-L, jacketed round-bottom flask is equipped with an overhead, mechanical stirrer, addition funnel, thermocouple, nitrogen inlet, and a circulating chiller unit. The flask is charged with (R)-3-(4-(2-(2-methyltetrazoi-5-yl)pyridin-5-yl)-3-fluorophenyl)-5- hydroxymethyl oxazolidin-2-one (70.0 g, 0. 89 mol), THF (1.4 L, 20 vol), and triethylamine (58.2 g, 0.575 mol, 3 eq). The slurry is stirred and the jacket temperature is set to 0°C. The addition funnel is charged with phosphorus oxychloride (87.0 g, 0.567 mol, 3 eq) in THF (70 mL, 1 vol). Once the internal temperature reaches 1°C, the POCI₃ solution is added dropwise over 44 minutes. The maximum internal temperature is 2.2°C. The mixture is stirred for 3 hours at 1 -2°C at which point HPLC analysis indicates that <0.5% of the (R)-3-(4-(2-(2- methyltetrazoI-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one remains. A 5-L, three-neck, round-bottom flask equipped with a Teflon diaphragm pump is charged with water (1.4 L, 20 vol) and is cooled to 3.8 °C. in an ice, salt water bath. The reaction mixture is pumped into the quench water subsurface over 1 hour. The maximum temperature during the quench is 1 1.9° C. The reactor and pump lines are rinsed with water (-2 0 mL) into the quench vessel. The yellow slurry is stirred overnight. The slurry is filtered through Whatman paper, and the filter cake is rinsed with water (700 mL, 10 vol) and methanol (700 mL, 10 vol). The product tedizolid phosphate is dried at room temperature in a vacuum oven until a constant weight is obtained.

[0045] Pharmaceutical compositions comprising one or more drug substances or excipients can be prepared in a variety of ways, including, for example, blending and lyophilization (also known as "co-lyophilization"). As is known to those skilled in the art, lyophiiization is a process of freeze-drying in which water is sublimed from a frozen solution of one or more solutes. Specific methods of lyophilization are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990).

Examples 2-5

[0046] Tedizolid is 4-16 folds more potent in vitro than linezolid against gram- positive pathogens, including methicillin-resistant Staphylococcus aureus and strains resistant to linezolid or vancomycin^1"3 and is rapidly bactericidal in vivo⁴. In clinical studies, tedizolid has demonstrated a favorable pharmacokinetic (PK) profile in healthy volunteers, including a. long half-life, minimal accumulation over time, high oral bioavailability (> 80%), and low inter-patient variability in drug exposure levels^"'. Once daily dosing regimens of 200 mg, 300 nig, or 400 mg tedizolid phosphate resulted in similar efficacy outcomes in a Phase 2 study^1,6. In two recent, well-controlled Phase 3 trials, a 6-day course of tedizolid phosphate 200 mg once/day demonstrated non-inferior efficacy to a 10-day course of linezoiid 600 mg twice/day for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), with improved gastrointestinal toierability and less impact on hematological parameters than linezoiid''⁸',

[0047] As described in Examples 2-4, three open-label, single-dose, parallel- group studies were conducted to characterize the pharmacokinetics (PK) properties of tedizolid and the safety of the prodrug tedizolid phosphate in various special patient populations, including elderly subjects and subjects with impaired organs of clearance relative to matched control subjects (for example, subjects with moderately to severely impaired hepatic or severely impaired renal function). As described in Example 5, a two-part, open-label study characterizing the PK of tedizolid in adolescent subjects was conducted. Within each study described in Examples 2-5, tedizolid PK parameters were compared between the special population and the control population. Adolescents were compared to control results from multiple studies, since the study did not include a control population. These comparisons included calculation of PK parameter geometric mean ratios and associated 90% confidence intervals (Cis). A descriptive comparison of results was also obtained from special populations, controls from those studies as well as results from a multipart Phase 1 study of tedizolid phosphate conducted in healthy volunteers'". The multi-part Phase I study comprised several subsequent stages: single ascending IV dose (Part A), multiple IV dose (Part B), and cross-over oral and IV bioavailability study (Part C).

E ample 2

Pharmacokinetics (PK) and Safety of Tedizolid in Elderly Subjects

[0048] In this example, the PK profile of a single oral dose of tedizolid phosphate 200 mg in healthy elderly subjects (> 65 years; n = 14) was compared with younger control subjects (age 18 to 45 years; n = I4)^y. Materials and Methods for Examples 3 and 4

[0049] Studies were conducted in accordance with current FDA regulations, international Conference on Harmonisation Good Clinical Practice guidelines, and the Basic Principles of the Declaration of Helsinki. Clinical studies are registered at www.clinicaltrials.gov as NCT01452828 (renal impairment study) and NCT01431833 (hepatic impairment study).

Study subjects

[ΘΘ50] Individuals with impaired renal or hepatic function and matched controls were enrolled in two open-label phase I trials to assess the pharmacokinetics of tedizolid. Subjects between the ages of 18 and 75 years (renal impairment study) and 18 and 70 years (hepatic impairment study) with a body mass index (BMI) between! 8.0 and 40.0 kg/m² were eligible. Screening procedures included assessment of the degree of organ dysfunction by estimated glomerular filtration rate (eGFR) for the renal impairment study and by Child-Pugh classification for the hepatic impairment study. The presence of stable disease and absence of additional confounding factors were determined through assessment of medical history, physical examination, laboratory findings, and electrocardiogram (ECG) results.

[0051] Subjects were excluded if they were being treated with monoamine oxidase inhibitors or serotonergic agents within 14 days prior to the first tedizolid phosphate dose, or with direct or indirect sympathomimetic agents within 48 hours prior to the first tedizolid phosphate dose. Lifestyle restrictions included avoidance of high-tyramine diets, alcohol, and strenuous exercise 48 hours prior to tedizolid phosphate administration through to the follow up visit.

[0052] In the renal impairment study, subjects with severely impaired renal function group not on hemodialysis had to have an eGFR < 30 mL/min/1.73 m^z using the Modification of Diet in Renal Disease 4- Variable (MDRD-4) formula, stable hemoglobin and hematocrit values for the past, 3 months, and stable medication doses for the past month. Subjects with end-stage renal disease (ESRD) requiring chronic hemodialysis had to have a 3 month history of stable urea clearance during dialysis (> 1.2 of total body water). [0053] Additional exclusion criteria for the hepatic impairment study included alanine transaminase (ALT) > 5x the upper limit of normal (ULN) for moderate and > 8x ULN for severe disease, hemoglobin concentration < 10 rng/dL for moderate and < 9 mg/dL for severe disease, and total bilirubin > 5 for moderate disease (there was no limit for severe disease). Evidence of acute deterioration of hepatic function within 8 weeks prior to screening, creatinine clearance < 50 mL/min, and ECG abnormalities (including QTc interval > 500 ms) were additional exclusion criteria.

Overall study design

[0054] Screening visits were conducted within 21 days (for renal impairment) or 28 days (for hepatic impairment) prior to the first dose of tedizolid phosphate. Subjects were admitted to the study center one day before the first dose. They remained in the center for 72 hours (renal impairment study) or 5 days (hepatic impairment study) after the last dose of tedizolid phosphate was administered, for routine collection of blood and urine samples. A final safety follow up visit took place 7 days (± 1 day) after the last dose. Additional design elements for the individual studies are described below.

Renal impairment study design

[0055] The P properties of a single 200 mg IV dose of tedizolid phosphate were compared between healthy matched control subjects, subjects with severe renal impairment, and subjects with ESRD requiring chronic hemodialysis. Tedizolid phosphate was administered IV to patients with severe renal impairment to maximize the capacity for identifying potential effects of uremic proteins on drug disposition, including both metabolic and transporter effects. Cohort assignments (8 subjects per group) included the control group (eGFR > 80.0 mL/min/1.73 m ^") that was matched (by age, sex, and body mass index) to severe renally impaired subjects (eGFR < 30.0 mL/min/1.73 m ) and a third group with ESRD requiring hemodialysis (eGFR < 15.0 mL/miR<'L73 m ^').

[0056] individuals in both the control group and the nondialyzed severe renal impairment group received a single 60-minute infusion of 200 mg tedizolid phosphate. Those in the ESRD group received 2 separate 60-minute infusions of 200 mg tedizolid phosphate in a non-randomized crossover design, with half of all subjects first receiving an infusion starting 1 to 1.5 hours prior to hemodialysis (using high flux hemodialysis and non-reuse filters) and the other half initially receiving an infusion starting within I hour of completion of hemodialysis. All subjects subsequently underwent the reverse sequence to the one to which they were initially assigned, with a minimum 7-day washout period required between infusions.

Hepatic impairment study design

[0057] Controls and subjects with hepatic impairment were matched to compare the PK properties of a single dose of 200 mg tedizolid phosphate administered orally. Cohort assignments (8 subjects in each group) were as follows: moderate hepatic impairment (Child- Pugh classification B; score of 7-9); severe hepatic impairment (Child-Pugh classification C; score of 10-15); and 16 controls (8 subjects matched to the moderate hepatic control group, 8 matched to the severe hepatic impairment control group) with normal hepatic function. Control subjects were matched for age, sex, and BMi to each of the hepatic impairment groups. Group enrollment was sequential; the moderate hepatic impairment group was enrolled before the severe impairment group. Study drug was administered to subjects in a fasted (for at least 8 hours) state.

Sample collection

[0058] Serial plasma samples were collected from predose through 72 hours postdose for the renal impairment study and predose through 96 hours postdose for the hepatic impairment study. Afferent and efferent plasma samples and clialysate samples (ESRD group only) were collected prehemodialysis and every 30 minutes during hemodialysis. Samples were extracted with acetonitrile and precipitated with hydrochloric acid, followed by low-speed (3,800 ^x g) centrifugation at room temperature for 5 minutes. Supematants were evaporated to dryness and reconstituted in methanol/ ater (3:7, v/^'v). Tedizolid and tedizolid phosphate were separated by high-power liquid chromatography ( 1200 series; Agilent Technologies, Santa Clara, CA) with a Hypersil GOLD aQ column (50 x 3 mm, 5 -micron particle size) (Thermo Fisher Scientific, Waltham, MA). Samples were eluted using a gradient from 80% 20 mM ammonium phosphate (pH 9.0)/20% methanol to 80% methanol over 4.5 minutes at a flow rate of 0.5 mL/min. The column eluent was directed to an API 4000 triple quadrupole mass spectrometer (AB SCTEX, Framingham, MA) for compound quantification. Data were processed using the Analyst 1 .4.1 software package (AB SCIEX) and the Watson LIMS laboratory information management system (Thermo Fisher Scientific).

Statistical, analysis

[0059] Standard noncompartmental analysis was conducted using WinNonlin Professional edition (Version 5.2; Pharsight Corporation, St. Louis, MO), and the following PK parameters were calculated for tedizoiid and tedizoiid phosphate when applicable: peak concentration in plasma Cmax (_,ug<'niL), time at peak plasma concentration T_max (hr), area under the concentration-time curve AUCo-t ^g-hr/mL), AUCo-∞ ^g-hr/mL), and apparent terminal half-life t}/₂ (hr). The geometric mean ratios for tedizoiid C_max, AUQ , and AUCo- _∞and corresponding 90% confidence intervals (CI) were determined for each study group and their corresponding controls using analysis of variance models. For each comparison, the log- transformed PK parameter was the response variable, group was the fixed factor, and subject was the random effect. Plasma concentration-time profiles were generated for individuals receiving tedizoiid phosphate, and median or mean plasma concentration-time profiles (linear and semilogarithmic scales) were generated for each treatment group.

Example 3

Pharmacokinetics (PK) and Safety of Tedizoiid in Subjects with Severe Renal Impairment

[0060] A previously conducted mass balance study in healthy individuals showed that overall tedizoiid elimination in urine is low (3% of total dose) and that total renal excretion is only -18% of the total administered dose. Since non-renal clearance can be altered in renally impaired subjects, an empirical study specifically conducted in this population is still necessar' to assess a potential need for dose adjustments. By comparison, renal elimination of linezoiicl is -80% of the administered dose (including 30% as linezolid, 40% as the metabolite PNU-142586, and 10% as the metabolite P U-142300). While linezolid PK is not consistently altered by renal insufficiency, a recent study confirmed that patients with hematologic abnormalities on linezolid therapy have lower estimated glomerular filtration rates and almost 2-fold higher linezolid C_m._n levels. Linezolid-associated thrombocytopenia rates are higher in patients with severe renal impairment and may be related to drug or metabolite accumulation, since renal insufficiency is also associated with significant increases in linezolid plasma metabolite levels. [0061] Additional dosing considerations come into play when hemodialysis support is required, due to the faster clearance of small -molecular- weight compounds during dialysis. In contrast to the low (-30%) protein binding of linezolid, tedizolid demonstrates greater protein binding, even in patients with severe renal impairment. Because dialysis clearance is associated with the free drug fraction, it, is no surprise that the tedizolid clearance during hemodialysis (i.e., ~10% of the administered dose) is less than the -30% clearance for linezolid during dialysis. It is suggested that linezolid doses only be given after dialysis. Use of tedizolid phosphate, on the other hand, may allow for more flexible timing of dose administration in hemodialysis patients.

[0062] In this example, the P profile of an IV infusion of tedizolid phosphate in subjects with severe renal impairment (eGFR < 30.0 mL/min'1.73m²) without dialysis support (n ^::: 8) was compared to matched controls with normal renal function (n ^::: 8). Subjects with severe renal impairment requiring chronic hemodialysis (eGFR < 15,0 niL/min/ 1.73m²; n = 8) were studied with dialysis occurring before and after drug infusion. Hemodialyzed subjects were also compared to the controls matched to nondialyzed subjects¹⁰. The effect of hemodialysis on tedizolid pharmacokinetics was determined in a separate cohort of subjects on chronic hemodialysis. One subject in the dialysis group only completed one arm of the crossover study design and was subsequently withdrawn due reasons other than an adverse event. The individual study groups were balanced in terms of age, gender, and BMI (Table 2).

[0063] Each participant with severe renal impairment without dialysis received a single 60-minute IV infusion of tedizolid phosphate 200 mg. Each participant with severe renal impairment with chronic hemodialysis received two 60-minute IV infusions of tedizolid phosphate 200 mg separated by a minimum of 7 days and examined for tedizolid pharmacokinetics before and after dialysis in a cross-over fashion. Each participant, with normal renal function received a singl e 60-minute IV infusion of tedizol id phosphate 200 mg. Table 2: Renal impairment study: baseline demographies

a Demographic data are presented as the mean ± SD or as the number and percentage of the study population.

° The estimated calculation of GFR using the MDRD-4 calculation can overestimate glomerular filtration rate as a result of fluctuating plasma creatinine levels during and between dialysis sessions.

Renal impairment study— pharmacokinetics

[0064] Tedizolid pharmacokinetics remained essentially unchanged in subjects with severe renal impairment compared to healthy controls (Table 3, Figures 1A-B). Comparison of the geometric mean P exposure parameters between the severe renal impairment and control groups revealed no meaningful difference in either C_max or AUC (C„_i3X geometric mean ratio 0.994, 90% CI 0.777 to 1 .273; AUC₀__∞ 0.925; 90% CI 0.698 to 1.227). When tedizolid kinetics were compared between tedizolid phosphate infusions administered prior to and after hemodialysis, both C_max and AUC were slightly lower than observed in the control or severe renal impairment groups (Table 3), but there were no meaningful differences in the geometric mean values for Cmax or AUC when post-dialysis and pre-dialysis infusion data was compared (C_max geometric mean ratio 1.148, 90% CI 1.053 to 1.252; AUCo-oo geometric mean ratio 0.953, 90% CI 0.827 to 1 .007). When samples were collected during high flux hemodialysis from subjects who received their tedizolid infusion prior to dialysis, <50% of the administered tedizolid dose was removed by 4 hours of hemodialysis (data not shown). Mean tedizolid protein binding was similar (73,2% to 76,8%) across all treatment groups.

Table 3: Renal impairment study: mean tedizolid pharmacokinetics"

a Pharmacokinetic parameters are presented as the mean ± SD, except for T_max, which is presented as median (range),

C_max, maximum concentration observed with 200 mg dose; T_raax, time to reach maximum concentration; AUCo-t, integrated area under the curve based on samples from time 0 to the last collected sample; AUCo-», the area under the curve based on terminal rate constant; t_½, tedizolid half-life.

[Ό065] Therefore, tedizolid PK parameters were comparable between controls and subjects with severe renal impairment, including those with ES D. Since uremia is known to alter several aspects of non-renal drag clearance (including membrane transport functions) and because anomalous adverse event profiles have been noted when orally administered linezolid was studied in renal insufficiency, the administration of IV tedizolid phosphate in the present study allowed for a more sensitive assessment of tedizolid metabolism and excretion under ESRD conditions.

Renal impairment study— tolerabilitv and safety

[0066] Tedizolid phosphate was generally well tolerated in subjects with severe renal impairment. Less than half of all treated subjects experienced at least one treatment- emergent adverse event, (TEAE); this included 3 subjects in the control group, 5 in the non- dialysis group, and 3 in the dialysis group. The only adverse event experienced by more than one subject per group was headache. Most of the TEAEs were mild or moderate in severity; 2 severe TEAEs (nausea and vomiting) were reported for one subject with severe renal impairment. No serious adverse events were reported,

[0067] Clinically significant, abnormal ECG results were not observed in any participant at any time point. Five subjects in the ESRD group and 4 in the severe renal impairment group had abnormal ECG results that were not clinically significant. None had a Bazett-corrected QT interval (QTcB) increase > 30 msec from predose. One subject in the ESRD group (diaiyzed postinfusion) had a postdose absolute QTcB interval > 500 msec, which had not changed from baseline.

[0068] There were no substantial hematology abnormalities beyond the diminished red blood cell levels associated with renal impairment. There were no significant coagulation panel changes. The majority of subjects in the 2 renal impairment groups had abnormalities on multiple chemistry laboratory tests at baseline and during follow-up (creatinine and electrolyte imbalances were common), but these were deemed typical of this population.

Example 4

Pharmacokinetics (PK) and Safety of Tedizolid in Subjects with Moderate and Severe

Hepatic Impairment

[0069] The liver is an important site for dmg biotransformation (through phase 1 oxidative processes and/or phase 2 conjugation reactions) that can also influence PK through altered plasma protein binding or biliary excretion. With progressive liver impairment, phase 1 metabolism tends to be adversely affected earlier in the course of disease, while phase 2 metabolism is more likely to be affected in severe liver disease. Preclinical studies demonstrate that tedizolid is primarily metabolized through phase 2 conjugation reactions, in marked contrast to the oxidative metabolism of linezolid, which appears to be mediated through a phase 5 , non-cytochrome P450 mechanism. The present study included subjects with moderate and severe hepatic impairment to fully understand the PK impact of a molecule with extensive hepatic metabolic and excretory features. Overall, AUG or C_max were not appreciably altered in subjects with moderate or severe hepatic dysfunction, compared to their respective control groups. [0070] In clinical practice, chronic liver disease and/or impaired liver function are risk factors for linezolid-associated thrombocytopenia and for isolated cases of delayed, but rapid-onset, lactic acidosis in adults and children. Linezolid PK changes have not been formally evaluated in subjects with severe hepatic impairment, but an increase in linezolid AUC of ~1.3-fold was observed in subjects with mild to moderate hepatic impairment. This effect size is similar to the increase seen with tedizoiicl in subjects with even greater (i.e., severe) hepatic impairment, suggesting that larger increases in linezolid AUC may be expected in subjects with severe hepatic impairment.

[0071] In this example, the PK profile of a single oral dose of tedizolid phosphate 200 rng in subjects with moderate hepatic impairment (Child-Pugh score of 7-9, inclusive; n = 8) and severe hepatic impairment (Child-Pugh score of 10-15, inclusive; n = 8) was compared to the PK profile of the matched control subjects with normal hepatic function (n ^::: 16). Each participant with hepatic impairment received a single oral dose of tedizolid phosphate 200 mg. All subjects completed the study. The individual study groups were balanced in terms of age, gender, and BM1 (Table 4).

Table 4: Hepatic impairnu ;nt study: basel hie demograp hies "

Demographic data are presented as the mean + SD or as the number and percentage of the study population.

CLc_r, creatinine clearance calculated using the Cockcroft-Gault equation. Hepatic impairment study pharmacokinetics.

[0072] Overall, the P of tedizoiicl, following administration of 200 nig oral tedizolid phosphate, were not markedly different between subjects with moderate/severe hepatic impairment and corresponding matched controls with norma] hepatic function (Table 5). Plasma concentration-time profiles were similar between subjects with moderate hepatic impairment and controls, as well as between subjects with severe hepatic impairment and controls (Figures 2A-B). The largest PK differences between subjects with hepatic impairment and controls were seen in AUCo-_∞ , which was approximately 34% higher among those with severe hepatic impairment compared to controls (geometric mean ratio 1.341 , 90% Q 0.927 to 1.939), and 22% higher among those with moderate hepatic impairment compared to controls (geometric mean ratio 1.216, 90% CI 0.862 to 1.716). C_max values were unchanged in patients with moderate or severe hepatic impairment compared to the control groups (moderate impairment geometric mean ratio 1 .093, 90% CI 0.849 to 1.408; severe impairment geometric mean ratio 0.992, 90% CI 0.703 to 1.400). There were no marked changes in unbound PK parameters relative to bound PK parameters or in urinary excretion of tedizolid (a very minor pathway) in either the moderate or severe hepatic impairment groups.

Table 5: Hepatic impairment study: mean tedizolid pharmacokinetic parameters'^*

" Pharmacokinetic parameters are presented as the mean + SD, except for T_raax, which is presented as the median (range),

Cmax, maximum concentration observed with 200 mg dose; T_ma¾ time to reach maximum concentration; AUCo-t, integrated area under the curve based on samples from time 0 to the last collected sample; AUC0-∞, the are under the curve based on terminal rate constant; t ½, tedizolid half-life. Hepatic impairment study - tolerability and safety

[0073] Eight subjects with hepatic impairment experienced a total of 5 TEAEs that were deemed to be related to tedizolid phosphate: diarrhea (n = 2), flatulence, transient flushing, and fine downy hair growth on the scalp. No serious or severe events or deaths related to the drug were reported during the study period, and most adverse events were deemed to be mild in severity. There were no serious ECG changes in any group and no subject experienced a QTcB increase > 30 ms, compared to predose values, or an absolute QTcB interval > 500 ms following administration of tedizolid phosphate.

[0074] Four subjects in the severe impairment, 3 in the moderate impairment, and none in the control group had substantially abnormal hematologic laboratory values (abnormal platelet values, n=7; abnormal absolute neutrophil count, n=l ) post-baseline. In all cases, the values were abnormal at baseline and did not worsen with administration of tedizolid phosphate. The majority of the subjects with moderate and severe hepatic impairment had baseline abnormalities on multiple chemistry laboratory tests, but no parameters worsened following tedizolid phosphate administration. The hematologic and chemistry laboratory abnormalities in the subjects with hepatic impairment were considered typical of such individuals. There were no abnormal coagulation panel or urinalysis results considered to be clinically significant among any of the subjects.

Example 5

Pharmacokinetics (PK) and Safety of Tedizolid in Adolescent Subjects

[0075] In this example, a 2-pa.rt, open-label study characterized the PK of tedizolid in adolescent subjects was conducted. The study determined the PK profile of a single 200 mg dose of tedizolid phosphate administered orally (n = 10) or IV (n = 10) in 12-

17 year old healthy adolescent subjects ¹¹.

Results of Examples 2-5:

[0076] Whether administered orally (to subjects with hepatic insufficiency) or IV

(to subjects with renal insufficiency), tedizolid phosphate was rapidly converted to tedizolid, the only metabolite detected in plasma samples from both subject populations. As a result, discussion of study results focuses on the plasma kinetics of tedizolid. [0077] As shown in Figures 3-5, no clinically meaningful changes in the rate and extent of tedizolid exposure were observed in adolescent subjects, elderly subjects, and subjects with impaired renal or hepatic function (including those requiring hemodialysis treatment) as compared to various control groups comprised of healthy volunteers, following oral or IV administration of tedizolid phosphate 200 mg. In addition, tedizolid AUG and C_raax geometric mean ratios (with 90% Cis) were similar across in all evaluated special populations, regardless of administration route.

[0078] Hemodialysis (even if initiated shortly after tedizolid phosphate dose administration) also had no impact on tedizolid pharmacokinetics in subjects with end-stage renal disease. Approximately 10% of the total administered dose was recovered in dialysate as tedizolid.

[0079] These results suggest that tedizolid phosphate dose adjustments are not required for adolescent patients, elderly patients, or patients with any degree of renal or hepatic impairment.

Examples 2-5 references:

1. Prokocimer P et al. Antimicrob Agents Chemother 2012;56:4608-13.

2. Rodriguez-Avial I et al. J Antimicrob Chemother 2012;67: 567-9.

3. Shaw KJ et al. Antimicrob Agents Chemother 2008;52:4442-7.

4. Louie A et al. Antimicrob Agents Chemother 2011;55:3453-60.

5. Flanagan S et al. ICAAC 2013 (Denver, 10-13 Sept). Abstract A-017c.

6. Prokocimer P et al . Antimicrob Agents Chemother 201 1 ;55:583-92.

7. Prokocimer P et al. JAMA 2013;309:559-69.

8. Fang E et al. ECCMID 2013 (Berlin, 27-30 April). Abstract LB2964.

9. Dreskin H et al. ICAAC 2012 (San Francisco, 9-12 Sept). Abstract A-1293.

10. Flanagan S et al. ICAAC 2012 (San Francisco, 9-12 Sept). Abstract A- 1294.

11. Dreskin H et al. ICAAC 2012 (San Francisco, 9-12 Sept). Abstract A-1292.

12. Bien P et al. ICAAC 2010 (Boston, 12-15 Sept). Abstract Al-013. Example 6

Dosing and Administration of Additional Antibiotic composition

[0080] The following Table discloses the results of studies where different antibiotics are administered to patients with varying degrees of renal insuffiency.

Claims

WHAT IS CLAIMED IS:

1. A method for treating an infection in a patient with renal impairment, comprising:

identifying a patient with renal insufficiency, wherein the patient is bei g treated with dialysis; and

administering a pharmaceutical composition comprising tedizolid to the patient.

2. The method of Claim 1 , wherein the pharmaceutical composition is administered intravenously.

3. The method of Claim 2, wherein the pharmaceutical composition comprising tedizolid is administered to the patient in a single intravenous (IV) infusion of tedizolid 200 mg daily.

4. The method of Claim 1 , wherein the pharmaceutical composition is administered orally.

5. The method of any one of Claims 1 to 4, wherein the tedizolid is in the form of tedizolid hydrogen phosphate.

6. The method of any one of Claims 1 to 5, wherein the infection is caused by one or more gram-positive bacteria.

7. The method of Claim 6, wherein the one or more gram-positive bacteria are selected from the group consisting of Staphylococcus aureus, Staphylococcus haemolyticus. Staphylococcus lugdunensis, Streptococcus agalacliae, Streptococcus pyogenes, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus), and Enterococcus faecalis.

8. The method of Claim 7, wherein the Staphylococcus aureus is methieiilin- resistant (MRSA) or methicillin-susceptible (MSSA) isolates.

9. The method of any one of Claims 1 to 8, wherein the infection is an acute bacterial skin and skin structure infection (ABSSS1).

10. The method of any one of Claims 1 to 9, wherein the patient has severe renal impairment with estimated glomerular filtration rate (eGFR) < 30.0 mL/min/1.73nT.

1 1 . The method of any one of Claims 1 to 10, wherein the patient has end stage renal disease (ESRD) with eGFR < 15,0 mL/min/1.73m .

12. The method of any one of Claims 1 to 1 1 , wherein the infection is hospital- acquired bacterial pneumonia (HASP) or ventilator-associated bacterial pneumonia. (VABP).