Philippe Prokocimer

Phase 2, Randomized, Double-Blind, Dose-Ranging Study Evaluating the Safety, Tolerability, Population Pharmacokinetics, and Efficacy of Oral Torezolid Phosphate in Patients with Complicated Skin and Skin Structure Infections

ABSTRACT Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections. S. aureus, the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials.

In Vitro, In Vivo, and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions

ABSTRACT Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety, tedizolid, has improved potency against Gram-positive pathogens and pharmacokinetics, allowing once-daily administration. Given linezolid warnings for drug-drug and drug-food interactions mediated by monoamine oxidase (MAO) inhibition, including sporadic serotonergic toxicity, these studies evaluated tedizolid for potential MAO interactions. In vitro, tedizolid and linezolid were reversible inhibitors of human MAO-A and MAO-B; the 50% inhibitory concentration (IC50) for tedizolid was 8.7 μM for MAO-A and 5.7 μM for MAO-B and 46.0 and 2.1 μM, respectively, with linezolid. Tedizolid phosphate was negative in the mouse head twitch model of serotonergic activity. Two randomized placebo-controlled crossover clinical studies assessed the potential of 200 mg/day tedizolid phosphate (at steady state) to enhance pressor responses to coadministered oral tyramine or pseudoephedrine. Sensitivity to tyramine was determined by comparing the concentration of tyramine required to elicit a ≥30-mmHg increase in systolic blood pressure (TYR30) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR30/tedizolid phosphate TYR30) was 1.33; a ratio of ≥2 is considered clinically relevant. In the pseudoephedrine study, mean maximum systolic blood pressure was not significantly different when pseudoephedrine was coadministered with tedizolid phosphate versus placebo. In summary, tedizolid is a weak, reversible inhibitor of MAO-A and MAO-B in vitro. Provocative testing in humans and animal models failed to uncover significant signals that would suggest potential for hypertensive or serotonergic adverse consequences at the therapeutic dose of tedizolid phosphate. Clinical studies are registered at www.clinicaltrials.gov as NCT01539473 (tyramine interaction study conducted at Covance Clinical Research Center, Evansville, IN) and NCT01577459 (pseudoephedrine interaction study conducted at Vince and Associates Clinical Research, Overland Park, KS).

Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers

Plasma concentrations of antimicrobial drugs have long been used to correlate exposure with effect, yet one cannot always assume that unbound plasma and tissue concentrations are similar. Knowledge about unbound tissue concentrations is important in the development of antimicrobial drugs, since most infections are localised in tissues. Therefore, a clinical microdialysis study was conducted to evaluate the distribution of tedizolid (TR-700), the active moiety of the antimicrobial prodrug tedizolid phosphate (TR-701), into interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissues following a single oral 600 mg dose of tedizolid phosphate in fasting conditions. Twelve healthy adult subjects were enrolled. Two microdialysis probes were implanted into the thigh of each subject, one into the vastus medialis muscle and one into subcutaneous adipose tissue. Probes were calibrated using retrodialysis. Dialysate samples were collected every 20 min for 12h following a single oral dose of 600 mg tedizolid phosphate, and blood samples were drawn over 24h. Unbound tedizolid levels in plasma were similar to those in muscle and adipose tissue. The ratios of unbound (free) AUC in tissues over unbound AUC in plasma (fAUC(tissue)/fAUC(plasma)) were 1.1 ± 0.2 and 1.2 ± 0.2 for adipose and muscle tissue, respectively. The median half-life was 8.1, 9.2 and 9.6h for plasma, adipose tissue and muscle tissue, respectively. Mean protein binding was 87.2 ± 1.8%. The study drug was very well tolerated. The results of this study show that tedizolid distributes well into ISF of adipose and muscle tissues. Unbound levels of tedizolid in plasma, adipose tissue and muscle tissue were well correlated. Free plasma levels are indicative of unbound levels in the ISF of muscle and adipose tissues.

Characterization of the haematological profile of 21 days of tedizolid in healthy subjects

OBJECTIVES Tedizolid is a novel oxazolidinone antibacterial. Oxazolidinones carry concerns for time-dependent myelosuppression. To further explore tedizolids haematological tolerability, we analysed data from a 21 day study comparing safety and pharmacokinetics of tedizolid and linezolid. METHODS This was a Phase 1 study in healthy volunteers comparing five treatments (each n = 8) over 21 days: tedizolid at 200, 300 or 400 mg once daily; linezolid at 600 mg twice daily; and placebo. Routine laboratory haematological parameters (platelet, absolute neutrophil, white blood cell, red blood cell and reticulocyte counts) were compared between groups. Adverse haematological outcomes were pre-specified as any parameter below the standard lower limits of normal (LLN), substantially abnormal (<50% LLN for neutrophils; <75% LLN for other parameters) or ≥50% below baseline (platelets only). ClinicalTrials.gov identifier: NCT00671814. RESULTS During the 21 day study period, pre-specified adverse platelet outcomes were observed in the linezolid (n = 2), tedizolid 300 mg (n = 1) and tedizolid 400 mg (n = 3) groups. Mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with higher doses being similar to linezolid. The magnitude of platelet count decreases from baseline was influenced by unbound drug trough plasma concentrations, which were generally higher in subjects with at least a 20% decrease in platelet count. Substantially abnormal haematological parameters were only observed with linezolid and tedizolid 400 mg. One linezolid and two tedizolid 400 mg subjects discontinued due to meeting criteria for pre-specified adverse haematological outcomes. CONCLUSIONS Although limited to small groups of healthy volunteers, these exploratory results support clinical study of extended treatment durations with tedizolid at 200 mg once daily.

Pharmacokinetics of Tedizolid in Obese and Nonobese Subjects

Obesity, defined as body mass index (BMI) 30 kg/m2, is a growing problem worldwide; the prevalence is 38% in the US adult population.1 Obesity is a risk factor for infection and is associated with antimicrobial treatment failure2 and worse clinical outcomes.3 Communityacquired pneumonia and skin and soft-tissue infections are themost common indications for prescribing outpatient antibiotics for obese patients.4 Obesity can affect the ability of antimicrobial agents to attain therapeutic levels.5,6 Changes in clearance and volume of distribution that may occur in obese patients can alter the dose– exposure relationship with some drugs, resulting in the need to adjust the dose in this patient population.7 With the emergence of antibiotic resistance, dosing decisions become increasingly important. Tedizolid phosphate, the prodrug of the novel oxazolidinone tedizolid, has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in a number of countries, among them the United States and countries in the European Union.8,9 Tedizolid phosphate is rapidly and extensively converted by endogenous phosphatases to its microbiologically active moiety, tedizolid, after administration.10,11 Tedizolid is generally at least 4-fold more potent in vitro than linezolid, the only other currently marketed oxazolidinone antibacterial, against staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci, and enterococci (including vancomycinresistant strains).10,12,13 In 2 recent phase 3 trials in patients with ABSSSIs, tedizolid (200 mg once daily for 6 days) demonstrated noninferior efficacy to linezolid (600 mg twice daily for 10 days) and was generally well tolerated.14,15 The pharmacokinetics (PK) of tedizolid allow for once-daily administration, either orally or intravenously, at equivalent doses.11 Available data suggest that systemic exposure to linezolid is lower in obese than in nonobese patients, which suggests that body weight and/or BMI may be important factors.16–18 The reason for this difference remains undetermined, as does whether linezolid dose modification is warranted for obese patients. In studies of tedizolid, exposure in elderly adults, adolescents, and subjects with severe hepatic or renal impairment (including those requiring hemodialysis) was similar to that in control groups following administration of oral or intravenous tedizolid 200 mg.19,20 The PK in obese subjects were not explicitly studied during the development of tedizolid, but approximately 28% of subjects in phase 1 studies were obese. Thus, a retrospective comparison of the extensive PK data obtained in obese and nonobese subjects would provide useful knowledge of tedizolid PK in obese patients, which could assist in dosing; this is the basis for the current investigation.

Clinician-reported lesion measurements in skin infection trials: Definitions, reliability, and association with patient-reported pain

OBJECTIVES Outcome assessments as clinical trial endpoints should be well-defined, reliable, and reflect meaningful treatment benefits. For acute bacterial skin and skin structure infections (ABSSSI) trials, recent recommendations suggest a primary endpoint of reduction in skin lesion area. Objectives were: evaluate ABSSSI lesion area measurement reliability, evaluate impact of various lesion area definitions on treatment effect size, and explore relationships between lesion area and pain. METHODS Data from two randomized, double-blinded Phase 3 trials comparing tedizolid to linezolid in ABSSSI and one open-label, non-comparative Phase 2 study of tedizolid in cellulitis/erysipelas and skin abscess were analyzed. Repeated lesion area measurements were prospectively obtained in all studies. In the open-label study, lesion area was measured by two investigators, using four different definitions. Repeated pain assessments using two patient-reported outcome instruments (Visual Analog Scale [VAS] and Faces Rating Scale [FRS]) were elicited in the randomized trials. RESULTS At baseline, lesion size did not correlate with pain intensity: r=0.02 for VAS and r<0.01 for FRS pain scores. However, decreasing lesion size and decreasing pain were strongly associated over time, regardless of initial lesion size or pain intensity (r=0.20 for VAS and r=0.21 for FRS scores at Day 10-13). Each lesion area definition demonstrated high inter-observer reliability (intra-class correlation coefficient>0.95). CONCLUSIONS Decreasing lesion area (indirect clinician-reported measure of benefit) and pain (direct patient-reported measure of benefit) were strongly associated over time, and lesion area measurements were reliable, regardless of their definition. These findings support both measures as outcome assessments in ABSSSI clinical trials. REGISTRATION Clinicaltrials.govNCT01519778, NCT01170221, and NCT01421511.

Pharmacokinetics, Safety, and Tolerability of Tedizolid Phosphate in Elderly Subjects

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We evaluated the pharmacokinetics of tedizolid in elderly subjects to guide dosing recommendations. In an open‐label phase 1 study (ClinicalTrials.gov identifier NCT01496677), 14 elderly (≥65 years) and 14 younger control (18–45 years) subjects each received a single oral dose of tedizolid phosphate 200 mg. Blood samples were collected before dose and more than 72 hours after dose. The pharmacokinetic parameters of tedizolid after a single dose were similar in both age groups. Geometric mean ratios (elderly/younger controls) and corresponding 90% confidence intervals were maximum observed plasma concentration (Cmax), 1.091 (0.917–1.297); AUC from time 0 extrapolated to infinity (AUC0–∞), 1.132 (0.954–1.343). Tedizolid plasma exposure was similar in elderly and younger control subjects. The findings indicated that after intravenous or oral administration of tedizolid phosphate 200 mg once daily, no dose adjustment was warranted in elderly subjects to achieve therapeutic levels.

Early Clinical Response as a Predictor of Late Treatment Success in Patients With Acute Bacterial Skin and Skin Structure Infections: Retrospective Analysis of 2 Randomized Controlled Trials

In the treatment of acute bacterial skin and skin structure infections, pooled data from 2 clinical trials (N = 1333 patients) showed that programmatic and investigator-assessed early treatment success both had a high positive predictive value (94.3%–100.0%) for late clinical cure, including among hospitalized patients. The negative predictive value of programmatic early success was <20%. These exploratory findings require prospective real-world evaluation. Clinical Trials Registration. NCT01170221; NCT01421511.

Effects of therapeutic and supratherapeutic doses of oral tedizolid phosphate on cardiac repolarisation in healthy volunteers: a randomised controlled study

Drug-induced prolongation of the QT interval on the electrocardiogram (ECG) infrequently results in Torsades de pointes, a potentially fatal arrhythmia. Therefore, thorough QT analysis of new drugs is a regulatory requirement. The objective of this phase 1 study was to assess the effects of oral tedizolid phosphate on the QT interval corrected with Fridericias formula (QTcF) in healthy adult subjects. A single therapeutic dose (200 mg) and a supratherapeutic dose (1200 mg) of tedizolid phosphate were administered to characterise QTc changes following typical systemic exposure and with markedly higher exposures, respectively. This was a four-way crossover study with 48 subjects randomly assigned to receive therapeutic and supratherapeutic doses of tedizolid phosphate, moxifloxacin (positive control for QT interval prolongation) and placebo (negative control). A continuous 12-lead ECG was recorded from 1 h before drug administration to 23 h after administration. Adverse events, which were generally mild, occurred most frequently with moxifloxacin or with a supratherapeutic dose of tedizolid phosphate; however, all treatments were well tolerated. This study demonstrated that therapeutic or supratherapeutic doses of the antibacterial tedizolid had no clinically significant effect on QT interval in healthy adults [ClinicalTrials.gov registration no.: NCT01461460].

Clinical safety and tolerability of tedizolid phosphate in the treatment of acute bacterial skin and skin structure infections

ABSTRACT Background: We evaluated safety and tolerability of tedizolid phosphate at the 200-mg once-daily dose approved for 6-day treatment of skin and skin-structure infections. Research design and methods: Clinical adverse event (AE) and laboratory data were pooled across completed clinical studies (13 phase 1, two phase 2, and two phase 3), for all participants who received ≥1 dose of tedizolid 200 mg, linezolid 600 mg (phase 3 only), or placebo (phase 1 only). Results: 1280 participants received tedizolid (phase 1: n = 355; phase 2/3: n = 925). In total, 13% received >6 doses of tedizolid (range: 7–21); in phase 2/3, 94% of participants received ≥5 doses (range: 5–10). Drug-related AEs occurred in 27% of participants (most commonly gastrointestinal reactions in 13% of participants and headache in 4%). Most AEs were mild-moderate in severity; <1% of participants discontinued treatment due to AEs. Tedizolid and linezolid had similar frequency, severity, and types of drug-related AEs. Tolerability in clinically important subpopulations (obese, n = 346; elderly, n = 99; renal impairment, n = 40; hepatic disease/impairment, n = 294) appeared comparable to the overall population. Conclusions: Tedizolid, given orally or intravenously at 200 mg, has a favorable safety profile. Clinical trial and postmarketing experience with treatment ≥7 days is limited.