Safety and pharmacokinetics of antifungal agent VT-1598 and its primary metabolite, VT-11134, in healthy adult subjects: phase 1, first-in-human, randomized, double-blind, placebo-controlled study of single-ascending oral doses of VT-1598.

VT-1598 is a novel fungal CYP51 inhibitor and 1-tetrazole-based antifungal drug candidate with improved selectivity minimizing off-target binding to and inhibition of human CYP450 enzymes. Data are presented from this first clinical study in the evaluation of the safety and pharmacokinetic (PK) of single ascending doses of 40, 80, 160, 320, and 640 mg VT-1598, comprising a 160 mg cohort in both fasting and fed states. Eight healthy adults per dose were randomized to receive either oral VT-1598 or placebo (3:1). Over the dose range, exposures were with relatively high variation. The maximum plasma concentrations (Cmax) for VT-1598 were 31.00-279.4 ng/ml and for its primary metabolite, VT-11134, were 27.80-108.8 ng/ml. The plasma area under the concentration-time curve to the last measurable concentration (AUC0-last) for VT-1598 were 116.1-4507 ng*h/ml, and for VT-11134 were 1140-7156 ng*h/ml. The dose proportionality was inconclusive based on the results of the power model. The peak concentration time (Tmax) was 4-5 h for VT-1598 and for VT-11134. Half-life was 103-126 h for VT-11134. After food intake, Cmax of VT-1598 increased by 44% (geometric mean ratio (GMR), 1.44; 90%CI [0.691, 2.19]) and AUC0-last by 126% (GMR, 2.26; 90%CI [1.09, 3.44]), while exposure of VT-11134 was decreased 23% for Cmax (GMR, 0.77; 90%CI [0.239, 1.31]) and unchanged for AUC0-last (GMR, 1.02; 90%CI [0.701, 1.33]). Neither VT-1598 nor VT-11134 were detected in urine. No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development.

VT-1598 is a tetrazole antifungal with improved selectivity and demonstrated a high survival rate when murine infected with invasive aspergillosis, coccidiodomycosis, cryptococcosis, and candidiasis. We report a first-in-human study to evaluate safety and pharmacokinetics after an oral dose of VT-1598.

Population pharmacokinetics and target attainment analyses to identify a rational empirical dosing strategy for cefepime in critically ill patients.

OBJECTIVES: We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis. PATIENTS AND METHODS: A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method. All cefepime PK data were analysed simultaneously using the non-linear mixed-effects modelling approach. Monte Carlo simulations were performed to evaluate the PTA of cefepime at different MIC values following different dose regimens in subjects with different renal functions. RESULTS: The PK of cefepime in critically ill patients was best characterized by a two-compartment model with zero-order input and first-order elimination. Creatinine clearance and body weight were identified to be significant covariates. Our simulation results showed that prolonged 3 h infusion does not provide significant improvement on target attainment compared with the traditional intermittent 0.5 h infusion. In contrast, for a given daily dose continuous infusion provided much higher breakpoint coverage than either 0.5 h or 3 h intermittent infusions. To balance the target attainment and potential neurotoxicity, cefepime 3 g/day continuous infusion appears to be a better dosing regimen than 6 g/day continuous infusion. CONCLUSIONS: Continuous infusion may represent a promising strategy for cefepime treatment in critically ill patients. With the availability of institution- and/or unit-specific cefepime susceptibility patterns as well as individual patients' renal function, our PTA results may represent useful references for physicians to make dosing decisions.

Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan.

BACKGROUND AND OBJECTIVE: Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults. METHODS: A total of 121 adult patients were included. The population pharmacokinetic models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination. RESULTS: Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the pharmacokinetics of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥ 65 years of age. CONCLUSIONS: The simulations suggested that adults ≤ 50 years of age infected with organisms with higher minimum inhibitory concentrations may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT + minimum inhibitory concentration, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥ 120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher minimum inhibitory concentrations.

Evaluation of Empirical Dosing Regimens for Meropenem in Intensive Care Unit Patients Using Population Pharmacokinetic Modeling and Target Attainment Analysis.

In the present study, population pharmacokinetic (PK) analysis was performed based on meropenem data from a prospective study conducted in 114 critically ill patients with a wide range of renal functions and various disease conditions. The final model was a one-compartment model with linear elimination, with creatinine clearance and continuous renal replacement therapy affecting clearance, and total bodyweight impacting the volume of distribution. Our model is a valuable addition to the existing meropenem population PK models, and it could be particularly useful during implementation of a therapeutic drug monitoring program combined with Bayesian forecasting. Based on the final model developed, comprehensive Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of 16 different dosing regimens. Simulation results showed that 2 g administered every 8 h with 3-h prolonged infusion (PI) and 4 g/day by continuous infusion (CI) appear to be two empirical dosing regimens that are superior to many other regimens when both target attainment and potential toxicity are considered and renal function information is not available. Following a daily CI dose of 6 g or higher, more than 30% of the population with a creatinine clearance of <60 mL/min is predicted to have neurotoxicity. With the availability of institution- and/or unit-specific meropenem susceptibility patterns, as well as an individual patient's renal function, our PTA results may represent useful references for physicians to make dosing decisions.

Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

A phase I randomized, double-blind, single subcutaneous dose escalation study to determine the safety, tolerability, and pharmacokinetics of rezafungin in healthy adult subjects.

Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double-blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.) administration. The study design consisted of six sequential cohorts of eight subjects, except for the first cohort with four subjects. The subjects were randomized in a 3:1 ratio of rezafungin to placebo and were to receive a single dose of 1, 10, 30, 60, 100, or 200 mg. The most common adverse events (AEs) were increased alanine aminotransferase and sinus bradycardia (unsolicited) and erythema at the injection site (solicited). Unsolicited AEs were generally mild to moderate and not rezafungin-related. Although the study was terminated after the 10 mg dose cohort due to concerns of potential increased severity of injection site reactions, no predetermined dose escalation halting criteria were met. Following the 10 mg single s.c. dose of rezafungin (n = 6), the geometric mean (GM) maximum concentration (Cmax ) was 105.0 ng/ml and the median time to Cmax was 144 h. The GM area under the concentration-time curve was 32,770 ng*h/ml. The median estimated terminal half-life was 193 h. The GM apparent oral clearance was 0.255 L/h and the GM apparent volume of distribution was 68.5 L. This study demonstrates that a single s.c. dose of rezafungin in healthy adult subjects: (1) did not result in serious AEs, death, or withdrawal from the study due to an AE; and (2) produced a pharmacokinetic profile with long exposure period postadministration. In an effort to reduce the occurrence of injection site reactions, a re-evaluation of the rezafungin s.c. formulation could be considered in the future.

Population Pharmacokinetics of Moxifloxacin in Children.

BACKGROUND/OBJECTIVE: Moxifloxacin is a fluoroquinolone that is commonly used in adults, but not children. Certain clinical situations compel pediatric clinicians to use moxifloxacin, despite its potential for toxicity and limited pharmacokinetics (PK) data. Our objective was to further characterize the pharmacokinetics of moxifloxacin in children. METHODS: We performed an opportunistic, open-label population PK study of moxifloxacin in children < 18 years of age who received moxifloxacin as part of standard care. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling. Covariates with known biological relationships were investigated for their influence on PK parameters. RESULTS: We obtained 43 moxifloxacin concentrations from 14 participants who received moxifloxacin intravenously (n = 8) or orally (n = 6). The dose of moxifloxacin was 10 mg/kg daily in participants ≤ 40 kg and 400 mg daily in participants > 40 kg. The population mean clearance and mean volume of distribution were 18.2 L/h and 167 L, respectively. The oral absorption was described by a first-order process. The estimated extent of oral bioavailability was highly variable (range 20-91%). Total body weight was identified as a covariate on clearance and volume of distribution, and substantially reduced the random unexplained inter-individual variability for both parameters. No participants experienced suspected serious adverse reactions related to moxifloxacin. CONCLUSION: These data add to the existing literature to support use of moxifloxacin in children in certain situations; however, further prospective studies on the safety and efficacy of moxifloxacin are needed.

Thorough QT Study To Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults.

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae. To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin at 2 g (therapeutic), zoliflodacin at 4 g (supratherapeutic), placebo, and moxifloxacin at 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia's formula (QTcF). At each time point up to 24 h after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1 to 4 h after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, electrocardiogram (ECG) morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well tolerated. These findings suggest that zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT03613649.).

Hypothermic storage of isolated human hepatocytes: a comparison between University of Wisconsin solution and a hypothermosol platform.

Until now little is known about the functional integrity of human hepatocytes after hypothermic storage. In order to address this limitation, we evaluated several commercially available hypothermic preservation media for their abilities to protect freshly isolated hepatocytes during prolonged cold storage. Human hepatocytes were isolated from non-transplantable/rejected donor livers and resuspended in ice-cold University of Wisconsin solution (UW), HypoThermosol-Base (HTS-Base), or HypoThermosol-FRS (HTS-FRS) with or without the addition of fetal bovine serum. Cells were stored at 4 degrees C for 24-72 h, and evaluated for hepatocyte viability (trypan blue exclusion, or labeling with fluorochromes), cell attachment, and function. The energy status of hepatocytes was evaluated by measurement of intracellular adenosine 5'-triphosphate. To determine whether the test cells expressed metabolic functions of freshly isolated cells, the activities of major phase I (cytochromes P450, FMO) and phase II (UGT, ST) drug-metabolizing enzymes were examined. Although hepatocytes are shown to be satisfactory after 24 h storage in all of the tested solutions, the cell viability, energy status, and xenobiotic metabolism following cold preservation in HTS-FRS was consistently and, in some cases, markedly higher when compared with other systems. The same metabolites for each of the tested substrates were detected in all groups of cells. Moreover, the use of HTS-FRS eliminates the need for serum in preservation solutions. HTS-FRS represents an improved solution compared to HTS-Base and UW for extending the shipping/storage time of human hepatocytes.