scholarly journals Pharmacokinetics of Telavancin at Fixed Doses in Normal-Body-Weight and Obese (Classes I, II, and III) Adult Subjects

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Kristen L. Bunnell ◽  
Manjunath P. Pai ◽  
Monica Sikka ◽  
Susan C. Bleasdale ◽  
Eric Wenzler ◽  
...  
Keyword(s):  
Body Weight ◽  
Time Profile ◽  
Primary Objective ◽  
Fixed Dose ◽  
Target Area ◽  
Obese Patients ◽  
Time Curve ◽  
Content Type ◽  
Time Zero ◽  
Concentration Time

ABSTRACT A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects ( n = 32) received a single, weight-stratified, fixed dose of 500 mg ( n = 4), 750 mg ( n = 8), or 1,000 mg ( n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m 2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m 2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC 0–∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.)

scholarly journals Pharmacodynamics of Isavuconazole in a DynamicIn VitroModel of Invasive Pulmonary Aspergillosis

2015 ◽  
Vol 60 (1) ◽  
pp. 278-287 ◽  
Author(s):  
Helen Box ◽  
Joanne Livermore ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Timothy W. Felton ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pathogenic Fungi ◽  
Time Profile ◽  
Wild Type ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Target Values ◽  
Maximal Suppression

ABSTRACTIsavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamicin vitromodel of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates ofAspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

Obesity is not strongly associated with increased risk for febrile neutropenia during levofloxacin prophylaxis in patients with hematological malignancies receiving intermediate-risk myelosuppressive chemotherapy

2019 ◽  
Vol 26 (6) ◽  
pp. 1301-1305
Author(s):  
Amanda Kurtti ◽  
Kelly Fritz ◽  
Kathryn Elofson-Disney ◽  
Russell Benefield
Keyword(s):  
Body Weight ◽  
Febrile Neutropenia ◽  
Creatinine Clearance ◽  
Antibacterial Prophylaxis ◽  
Intermediate Risk ◽  
Obese Patients ◽  
Time Curve ◽  
Myelosuppressive Chemotherapy ◽  
Concentration Time ◽  
Increased Risk

Levofloxacin given at a standard dose of 500 mg daily is recommended for antibacterial prophylaxis in patients receiving myelosuppressive chemotherapy. Obese patients have been shown to exhibit enhanced clearance of levofloxacin and may be at risk for prophylactic failure. This single center, retrospective cohort study from June 2014 to May 2017 evaluated adult patients with estimated creatinine clearance ≥50 mL/min receiving their first cycle of a National Comprehensive Cancer Network defined intermediate-risk regimen. Primary endpoint was incidence of febrile neutropenia. Secondary endpoints included 30-day mortality and the correlation between estimated levofloxacin area under the concentration–time curve and rates of febrile neutropenia. Febrile neutropenia occurred in 26 patients: 12 (35.3%) obese and 14 (21.9%) non-obese ( P =  0.16). Six (23.1%) of these patients required intensive care, but there were no deaths within 30 days of a febrile neutropenia event. Estimated creatinine clearance was similar between obese and non-obese patients (median 97.5 vs. 91.8 mL/min, P =  0.39), as was estimated levofloxacin area under the concentration–time curve (median 85.6 vs. 90.8 mg×h/L, P =  0.39). There were no significant associations between body weight-related variables – total body weight (median 83.4 vs. 80.6 kg, P =  0.51), body mass index (mean 29.6 vs. 26.8 kg/m2, P =  0.35), or body surface area (1.98 vs. 1.99 m2, P =  0.68) – and febrile neutropenia in this cohort of patients with similar renal function. Obesity should not be a justification for more aggressive levofloxacin dosing schemes when used for febrile neutropenia prophylaxis.

scholarly journals Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
Tomefa E. Asempa ◽  
Romney M. Humphries ◽  
David P. Nicolau
Keyword(s):  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Hill Equation ◽  
Infection Model ◽  
Free Drug Concentration ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
The Hill ◽  
Susceptibility Breakpoint

ABSTRACT The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium. We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0–24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0–24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0–24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0–24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

scholarly journals Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Elizabeth A. Lakota ◽  
Justin C. Bader ◽  
Voon Ong ◽  
Ken Bartizal ◽  
Lynn Miesel ◽  
...  
Keyword(s):  
Time Course ◽  
Fungicidal Activity ◽  
Control Group ◽  
Time Curve ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Treatment Control Group ◽  
Pharmacological Basis

ABSTRACT CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.

scholarly journals Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

2013 ◽  
Vol 57 (11) ◽  
pp. 5714-5716 ◽  
Author(s):  
David R. Andes ◽  
Daniel K. Reynolds ◽  
Scott A. Van Wart ◽  
Alexander J. Lepak ◽  
Laura L. Kovanda ◽  
...  
Keyword(s):  
Dose Level ◽  
Randomized Trials ◽  
Clinical Investigation ◽  
Time Curve ◽  
Content Type ◽  
Dosing Interval ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Dosing Strategy ◽  
Current Report

ABSTRACTEchinocandins exhibit concentration-dependent effects onCandidaspecies, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P= 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.)

scholarly journals Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Vanessa E. Rees ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Jürgen B. Bulitta ◽  
Veronika Wirth ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Respiratory Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
Content Type ◽  
Concentration Time

ABSTRACT Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa. Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

scholarly journals Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

2020 ◽  
Author(s):  
Armin Sadighi ◽  
Lorenzo Leggio ◽  
Fatemeh Akhlaghi
Keyword(s):  
Pbpk Model ◽  
Organ Damage ◽  
Time Profile ◽  
Sensitivity Analyses ◽  
Pbpk Modeling ◽  
Time Curve ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

Abstract Aims A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

scholarly journals Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Yutaka Saisho ◽  
Takayuki Katsube ◽  
Scott White ◽  
Hiroyuki Fukase ◽  
Jingoro Shimada
Keyword(s):  
Healthy Subjects ◽  
Active Drug ◽  
Single Subject ◽  
Gram Negative Bacteria ◽  
Multiple Dosing ◽  
Time Curve ◽  
Gram Negative ◽  
Time Zero ◽  
Concentration Time ◽  
Dose Study

ABSTRACT Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection. The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects. A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). A multiple-ascending-dose study at doses of 1,000 (two groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). There were no serious or clinically significant adverse events (AEs) observed in either study. A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs. Dose-proportional increases in the maximum plasma concentration ( C max ), the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing, and the area under the concentration-time curve extrapolated from time zero to infinity were observed across the dose range of 100 to 2,000 mg. The mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was primarily excreted unchanged in the urine (61.5% to 68.4% of the dose). There was little accumulation of C max and AUC by dosing q8h, and the PK of cefiderocol did not change with multiple dosing. This study indicates that single and multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in healthy subjects and exhibit linear PK at doses up to 2,000 mg.

scholarly journals Determination of Pharmacodynamic Target Exposures for Rezafungin against Candida tropicalis and Candida dubliniensis in the Neutropenic Mouse Disseminated Candidiasis Model

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
David R. Andes
Keyword(s):  
Candida Tropicalis ◽  
Free Drug ◽  
Candida Dubliniensis ◽  
Time Curve ◽  
Content Type ◽  
Susceptibility Data ◽  
Concentration Time ◽  
Target Exposure ◽  
Human Dose

ABSTRACT Rezafungin (CD101) is a novel echinocandin under development for once-weekly intravenous (i.v.) dosing. We evaluated the pharmacodynamics (PD) of rezafungin against 4 Candida tropicalis and 4 Candida dubliniensis strains, using the neutropenic mouse invasive candidiasis model. The area under the concentration-time curve (AUC)/MIC was a robust predictor of efficacy (R2 = 0.93 and 0.72, respectively). The stasis free-drug 24-h AUC/MIC target exposure for the group ranged from 3 to 25, whereas the 1-log-kill free-drug 24-h AUC/MIC target exposure ranged from 4.3 to 62. These values are similar to those found in previous rezafungin PD studies with other Candida spp. Based on recent surveillance susceptibility data, AUC/MIC targets are likely to be exceeded for >99% of C. tropicalis and C. dubliniensis isolates with the previously studied human dose of 400 mg i.v. once weekly.

scholarly journals Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects

2014 ◽  
Vol 58 (12) ◽  
pp. 7340-7346 ◽  
Author(s):  
Borimas Hanboonkunupakarn ◽  
Elizabeth A. Ashley ◽  
Podjanee Jittamala ◽  
Joel Tarning ◽  
Sasithon Pukrittayakamee ◽  
...  
Keyword(s):  
Crossover Study ◽  
Hospital Admissions ◽  
Geometric Mean ◽  
Radical Cure ◽  
Open Label ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Pharmacokinetic Assessment ◽  
Adult Volunteers

ABSTRACTDihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicatedPlasmodium falciparummalaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduceP. falciparumtransmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (Cmax), area under the concentration-time curve from 0 h to the end of the study (AUC0–last), and area under the concentration-time curve from 0 h to infinity (AUC0–∞) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.)

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