scholarly journals Oritavancin Population Pharmacokinetics in Healthy Subjects and Patients with Complicated Skin and Skin Structure Infections or Bacteremia

2009 ◽  
Vol 53 (10) ◽  
pp. 4422-4428 ◽  
Author(s):  
Christopher M. Rubino ◽  
Scott A. Van Wart ◽  
Sujata M. Bhavnani ◽  
Paul G. Ambrose ◽  
Jill S. McCollam ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Study Phase ◽  
Phase 2 ◽  
Skin Structure ◽  
Complicated Skin

ABSTRACT Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or Staphylococcus aureus bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single- and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data (n = 6,290 oritavancin plasma concentrations from 560 subjects) was obtained using a three-compartment model with zero-order i.v. infusion and first-order elimination. The model was parameterized using total clearance (CL), volume of central compartment (Vc), distributional clearances from the central to both the first and second peripheral compartments, and volumes of distribution for both the first and second peripheral compartments. Weight and study phase (phase 1 versus phase 2/3) were identified as significant predictors of the interindividual variability in CL, while body surface area and age were significant for Vc. These results suggest that dose modification may be warranted in patients weighing >110 kg. However, the mild nature of the observed relationships for Vc suggest that dosing adjustments are not necessary for elderly patients.

scholarly journals Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Laura L. Kovanda ◽  
Sean M. Sullivan ◽  
Larry R. Smith ◽  
Amit V. Desai ◽  
Pete L. Bonate ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Binding Model ◽  
Saturable Binding ◽  
Drug Concentrations ◽  
Over Time

ABSTRACT VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days. Plasma samples were collected throughout the dosing intervals. Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time were increased less than dose proportionally for doses above 30 mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment nonlinear saturable binding model fit the data well. Clearance increased with dose, and mean values ranged from 0.4 liters/h at 3 mg to 8.5 liters/h at 1,200 mg. Mean volume in the central compartment ranged from 4.8 to 6.9 liters across doses. In the first 24 h, once-daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/liter, regardless of dose, with slow clearance over time. Administration of 300 mg every 8 h achieved concentrations above 1 mg/liter over an entire 24-h period. There was a significant relationship between body surface area and clearance. The data suggest that VL-2397 has nonlinear saturable binding kinetics. Protein binding is the likely primary source of the nonlinearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.

scholarly journals In VitroActivity and Microbiological Efficacy of Tedizolid (TR-700) against Gram-Positive Clinical Isolates from a Phase 2 Study of Oral Tedizolid Phosphate (TR-701) in Patients with Complicated Skin and Skin Structure Infections

2012 ◽  
Vol 56 (9) ◽  
pp. 4608-4613 ◽  
Author(s):  
Philippe Prokocimer ◽  
Paul Bien ◽  
Carisa DeAnda ◽  
Chris M. Pillar ◽  
Ken Bartizal
Keyword(s):  
Clinical Efficacy ◽  
Phase 2 ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Double Blind ◽  
Content Type ◽  
Skin Structure ◽  
Phase 2 Trial ◽  
Complicated Skin

ABSTRACTTedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistantStaphylococcus aureus(MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines thein vitroactivity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% wereS. aureus, and of these, 76% were MRSA. The MIC50and MIC90of tedizolid against both methicillin-susceptibleS. aureus(MSSA) and MRSA were 0.25 μg/ml, compared with a MIC50of 1 μg/ml and MIC90of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n= 7), viridans group streptococci (n= 15), and beta-hemolytic streptococci (n= 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n= 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potentin vitroactivity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.

scholarly journals Population Pharmacokinetic Analyses for BC-3781 Using Phase 2 Data from Patients with Acute Bacterial Skin and Skin Structure Infections

2014 ◽  
Vol 59 (1) ◽  
pp. 282-288 ◽  
Author(s):  
C. M. Rubino ◽  
B. Xue ◽  
S. M. Bhavnani ◽  
W. T. Prince ◽  
Z. Ivezic-Schoenfeld ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Size ◽  
Phase 1 ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Data Set ◽  
Skin Structure ◽  
Population Pk

ABSTRACTBC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.)

scholarly journals Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial

2020 ◽  
Vol 86 (5) ◽  
pp. 595-606
Author(s):  
Hong Xiang ◽  
Lucy Liu ◽  
Yuying Gao ◽  
Ago Ahene ◽  
Monica Macal ◽  
...  
Keyword(s):  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Receptor Occupancy ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Mixed Effect

Abstract Purpose To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab. Methods Nonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target Ctrough in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma. Results Bemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab Ctrough of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial. Conclusion A projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.

scholarly journals Population Pharmacokinetics of Telavancin in Healthy Subjects and Patients with Infections

2012 ◽  
Vol 56 (4) ◽  
pp. 2067-2073 ◽  
Author(s):  
Emil Samara ◽  
Jeng-Pyng Shaw ◽  
Steven L. Barriere ◽  
Shekman L. Wong ◽  
Philip Worboys
Keyword(s):  
Renal Function ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Population Pharmacokinetic ◽  
Phase 3 ◽  
Two Phase ◽  
Complicated Skin ◽  
Hospital Acquired Pneumonia ◽  
Highly Correlated ◽  
Hospital Acquired

ABSTRACTA population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.

scholarly journals 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

2010 ◽  
Vol 55 (2) ◽  
pp. 583-592 ◽  
Author(s):  
P. Prokocimer ◽  
P. Bien ◽  
J. Surber ◽  
P. Mehra ◽  
C. DeAnda ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Gram Positive ◽  
Double Blind ◽  
Skin Structure ◽  
Complicated Skin ◽  
Cure Rates ◽  
Dose Levels

ABSTRACTTorezolid (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-resistantStaphylococcus 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 withS. aureusisolated 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.

scholarly journals Population Pharmacokinetics of Tigecycline in Patients with Complicated Intra-Abdominal or Skin and Skin Structure Infections

2006 ◽  
Vol 50 (11) ◽  
pp. 3701-3707 ◽  
Author(s):  
S. A. Van Wart ◽  
J. S. Owen ◽  
E. A. Ludwig ◽  
A. K. Meagher ◽  
J. M. Korth-Bradley ◽  
...  
Keyword(s):  
Steady State ◽  
Prediction Error ◽  
Clinical Laboratory ◽  
Population Pharmacokinetic ◽  
Phase 3 ◽  
Two Phase ◽  
Data Set ◽  
Skin Structure ◽  
Concentration Time ◽  
Complicated Skin

ABSTRACT Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5- or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward (α = 0.05) and backward (α = 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (P < 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC0-12) were generally unbiased (median prediction error, −1.60% to −3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC0-12 in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.

scholarly journals 1118. Population Pharmacokinetics of Contezolid Acefosamil and Contezolid – Rationale for a Safe and Effective Loading Dose Regimen

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S651-S651
Author(s):  
Jürgen B Bulitta ◽  
Barry Hafkin ◽  
Edward Fang
Keyword(s):  
Diabetic Foot ◽  
Healthy Subjects ◽  
Treatment Options ◽  
Plasma Concentrations ◽  
Sequential Therapy ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Population Pharmacokinetic Modeling ◽  
Diabetic Foot Infections ◽  
Complicated Skin

Abstract Background Contezolid (CZD) is a novel oral oxazolidnone with comparable activity and potentially improved safety compared to current oxazolidinones. The intravenous (IV) double prodrug contezolid acefosamil (CZDa) is converted via MRX-1352 to active CZD. CZDa paired with CZD holds promise as a safe and effective treatment for serious Gram-positive infections such as those caused by methicillin-resistant Staphylococcus aureus. Sequential therapy with CZDa IV followed by CZD oral (PO) offers flexible treatment options in hospital and outpatient settings for conditions such as diabetic foot infections. We aimed to design a CZDa/CZD dosage regimen leveraging population pharmacokinetic modeling (PopPK). Methods PopPK simultaneously fit data from 184 adult subjects. These were 1) plasma concentrations (by LC-MS/MS) of MRX-1352, CZD, and its metabolite MRX-1320 from 66 healthy subjects receiving CZDa (150-2400 mg IV) for up to 10 days, 2) CZD and MRX-1320 concentrations from 44 healthy subjects receiving single CZD PO doses of 400, 800, or 1200 mg with and without food or multiple doses Q12h for up to 28 days, and 3) CZD concentrations from 74 Phase 2 patients receiving CZD 800 mg PO Q12h. PopPK and Monte Carlo simulations were used to optimize CZD exposures. Results CZDa was rapidly converted to MRX-1352, which was converted less rapidly to CZD. CZD was well absorbed and food enhanced its bioavailability. For CZD 800 mg PO with food, apparent total clearance of CZD was 13.1 L/h (22% coefficient of variation) in healthy subjects and 14.5 L/h (53% CV) in patients. The apparent volume of distribution at steady-state was 20.5 L. A loading dose of CZDa 2000 mg IV, then CZDa 1000 mg IV Q12h, and followed by CZD 800 mg PO Q12h achieved areas under the curve (AUC) between 75 and 100 mg*h/L (medians; Figure) on all study days. Compared to CZD AUCs, the MRX-1352 AUCs during IV dosing were higher. While the median MRX-1320 AUCs were lower (18 to 48 mg*h/L), some accumulation was predicted in ~5% of subjects. Conclusion A loading dose of CZDa 2000 mg IV followed by either CZDa 1000 mg IV or CZD 800 mg PO Q12h was predicted to reliably achieve efficacious CZD exposures on day 1 and maintain those exposures throughout therapy. This regimen will be evaluated in Phase 3 studies in complicated skin infections and diabetic foot infections. Disclosures Jürgen B. Bulitta, PhD, MicuRx Pharmaceuticals, Inc. (Consultant) Barry HAFKIN, MD, MicuRx Pharmaceuticals Inc. (Consultant)

scholarly journals Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Elizabeth A. Lakota ◽  
Voon Ong ◽  
Shawn Flanagan ◽  
Christopher M. Rubino
Keyword(s):  
Body Weight ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Visual Predictive Check ◽  
Population Pharmacokinetic ◽  
Final Model ◽  
Content Type ◽  
Population Pk ◽  
Dose Study

ABSTRACT Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent in vitro activity against Candida albicans and Candida glabrata, including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (i.v.) administration. Data from two phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via i.v. infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles and can provide dose selection decision support for future clinical studies.

scholarly journals Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Patrick Vizeli ◽  
Isabelle Straumann ◽  
Friederike Holze ◽  
Yasmin Schmid ◽  
Patrick C. Dolder ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Subjective Effects ◽  
Plasma Concentrations ◽  
Psychiatric Research ◽  
Acute Effects ◽  
Double Blind ◽  
Common Genetic Variants

AbstractLysergic acid diethylamide (LSD) is a classic psychedelic substance that is used recreationally and investigated in psychiatric research. There are no pharmacogenetic studies on LSD. In vitro metabolic studies indicate that several cytochrome P450 (CYP) isoforms (e.g., CYP2D6, CYP1A2, and CYP2C9) are involved in LSD metabolism, but in vivo data are scarce. The present study examined the influence of genetic polymorphisms of CYP genes on the pharmacokinetics and acute effects of LSD in healthy subjects. We identified common genetic variants of CYPs (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6) in 81 healthy subjects who were pooled from four randomized, placebo-controlled, double-blind Phase 1 studies. We found that genetically determined CYP2D6 functionality significantly influenced the pharmacokinetics of LSD. Individuals with no functional CYP2D6 (i.e., poor metabolizers) had longer LSD half-lives and approximately 75% higher parent drug and main metabolite 2-oxo-3-hydroxy LSD area-under-the-curve blood plasma concentrations compared with carriers of functional CYP2D6. Non-functional CYP2D6 metabolizers also exhibited greater alterations of mind and longer subjective effect durations in response to LSD compared with functional CYP2D6 metabolizers. No effect on the pharmacokinetics or acute effects of LSD were observed with other CYPs. These findings indicate that genetic polymorphisms of CYP2D6 significantly influence the pharmacokinetic and subjective effects of LSD. Given the potential therapeutic use of psychedelics, including LSD, the role of pharmacogenetic tests prior to LSD-assisted psychotherapy needs to be further investigated.

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