Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection.

Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gram-negative bacteria, including carbapenem-resistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 ml/min, and it is adjusted for patients with <60 ml/min or ≥120 ml/min CrCL. A population pharmacokinetic (PK) model was constructed using 3,427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors, including infection sites and mechanical ventilation, were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was >90% against MICs of ≤4 µg/ml for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients, including the patients with augmented renal function, ventilation, and/or severe illness.

Intrapulmonary pharmacokinetic profile of cefiderocol in mechanically ventilated patients with pneumonia.

OBJECTIVES: Lung penetration of cefiderocol, a novel siderophore cephalosporin approved for treatment of nosocomial pneumonia, has previously been evaluated in healthy subjects. This study assessed the intrapulmonary pharmacokinetic profile of cefiderocol at steady state in hospitalized, mechanically ventilated pneumonia patients. METHODS: Patients received cefiderocol 2 g (or ≤1.5 g if renally impaired), administered IV q8h as a 3 h infusion, or 2 g q6h if patients had augmented renal function (estimated CLCR > 120 mL/min). After multiple doses, each patient underwent a single bronchoalveolar lavage (BAL) procedure either at the end of the infusion or at 2 h after the end of infusion. Plasma samples were collected at 1, 3, 5 and 7 h after the start of infusion. After correcting for BAL dilution, cefiderocol concentrations in epithelial lining fluid (ELF) for each patient and the ELF/unbound plasma concentration ratio (RC, E/P) were calculated. Safety was assessed up to 7 days after the last cefiderocol dose. RESULTS: Seven patients received cefiderocol. Geometric mean ELF concentration of cefiderocol was 7.63 mg/L at the end of infusion and 10.40 mg/L at 2 h after the end of infusion. RC, E/P was 0.212 at the end of infusion and 0.547 at 2 h after the end of infusion, suggesting delayed lung distribution. There were no adverse drug reactions. CONCLUSIONS: The results suggest that cefiderocol penetrates the ELF in critically ill pneumonia patients with concentrations that are sufficient to treat Gram-negative bacteria with an MIC of ≤4 mg/L.

Human mass balance, metabolism, and cytochrome P450 phenotyping of lusutrombopag.

The human mass balance of lusutrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, was characterised in seven healthy male subjects after a single oral dose of [14C]-lusutrombopag (2 mg, 100 µCi) in solution. Lusutrombopag was the main component in plasma, accounting for 56% of plasma radioactivity AUC0-∞. In plasma, the half-life of radioactivity (70.7 h) was longer than that of lusutrombopag (25.7 h), suggesting the presence of long circulating metabolites. The main excretion pathway of lusutorombopag was feces, with a radioactivity recovery of approximately 83% within 336 h post-dose. M6 (lusutrombopag-O-propanol or lusutrombopag-O-acetic acid) and M7 (lusutrombopag-O-ethane-1,2-diol) were also identified as main components in feces, accounting for at most 17.9%, and 16.9% of the dose, respectively, and were ß-oxidation related metabolites. Our in vitro metabolism study of lusutrombopag indicated that ß-oxidation was a subsequent metabolism of ω-oxidation and CYP4 enzymes, including CYP4A11, were the major isozymes contributing to ω-oxidation. In conclusion, lusutrombopag is primarily eliminated via ω-oxidation and excreted in the feces, where CYP4 enzymes play an important role.

Evaluation of covariate effects using variance-based global sensitivity analysis in pharmacometrics.

In pharmacometrics, understanding a covariate effect on an interested outcome is essential for assessing the importance of the covariate. Variance-based global sensitivity analysis (GSA) can simultaneously quantify contribution of each covariate effect to the variability for the interested outcome considering with random effects. The aim of this study was to apply GSA to pharmacometric models to assess covariate effects. Simulations were conducted with pharmacokinetic models to characterize the GSA for assessment of covariate effects and with an example of quantitative systems pharmacology (QSP) models to apply the GSA to a complex model. In the simulations, covariate and random variables were generated to simulate the outcomes using the models. Ratios of variance explained by each factor (each covariate and random effect) over the overall variance of the outcome were used as sensitivity indices. The sensitivity indices were consistent with the effect size of covariate. The sensitivity indices identified the importance of creatinine clearance on the pharmacokinetic exposure for a renally-excreted drug. These sensitivity indices could be applied to plasma concentrations over time (repeated measurable outcomes over time) as interested outcomes. Using the GSA, each contribution of all of the covariate effects could be efficiently identified even in the complex QSP model. Variance-based GSA can provide insight when considering the importance of covariate effects by simultaneously and quantitatively assessing all covariate and random effects on interested outcomes in pharmacometrics.

Pharmacokinetic-pharmacodynamic modeling for hepatic delivery and efficacy of antisense oligonucleotides with lipophilic ligands in mice.

Conjugation with lipophilic ligands such as cholesterol and α-tocopherol dramatically improves the delivery and efficacy of antisense oligonucleotides (ASOs) in the liver. To estimate the hepatic ASO concentration and the efficacy of ASOs conjugated with lipophilic ligands in mice, we constructed a pharmacokinetic-pharmacodynamic (PK-PD) model that consisted of a two-linear compartment model for the plasma and the hepatic ASO concentration, and two indirect response models for the hepatic apolipoprotein B (Apo-B) mRNA and plasma total cholesterol. The model provided a good fit of the hepatic ASO concentration although it showed an overprediction of Apo-B mRNA and an underprediction of the plasma total cholesterol within 2-fold at a later time after single intravenous administration of ASOs conjugated with lipophilic ligands. In addition, the model simulations indicated that the efficacy at a dose regimen of ASOs conjugated with lipophilic ligands (0.2 mg/kg, once a week) in mice was comparable to that at an effective dose of unchanged ASO (2.5 mg/kg, once a week). Although further studies are required to refine the parameters of the PK-PD model, this approach could be used to guide dose-ranging pharmacological studies for ASOs conjugated with lipophilic ligands in mice.

Is platelet monitoring during 7-day lusutrombopag treatment necessary in chronic liver disease patients with thrombocytopenia undergoing planned invasive procedures? A phase IIIb open-label study.

AIM: Lusutrombopag is approved for thrombocytopenia in chronic liver disease patients planned to undergo invasive procedures. In previous clinical studies, lusutrombopag treatment was stopped in patients with an increase in platelet count (PC) of ≥20 × 109 /L from baseline and whose PC was ≥50 × 109 /L (discontinuation criteria). We assessed the influence of platelet monitoring during lusutrombopag treatment in lusutrombopag-naïve patients. METHODS: In this open-label study, Child-Pugh class A and B (A/B) patients were enrolled and treated with lusutrombopag (3 mg/day) for 7 days. In the treatment-naïve A/B-1 group, the discontinuation criteria were applied on day 6. In the treatment-naïve A/B-2 group, the criteria were not applied. In a non-naïve A/B group, the criteria were applied on days 3 and 5-7. The main efficacy end-point was the proportion of patients without platelet transfusion (PT) before the primary invasive procedure. RESULTS: In the A/B-1, A/B-2, and non-naïve A/B groups, the proportions of patients without PT were 80.9% (38/47), 83.0% (39/47), and 75.0% (6/8), respectively. The mean durations of PC ≥ 50 × 109 /L without PT were 20.7, 20.3, and 22.8 days, respectively. Excessive PC increases (≥200 × 109 /L) were not detected in any group. Treatment-related adverse events occurred in 4.3%, 6.4%, and 0% of A/B-1, A/B-2, and non-naïve A/B patients, respectively. Severe portal vein thrombosis occurred in one A/B-2 patient (PC 75 × 109 /L at onset). CONCLUSIONS: No meaningful efficacy and safety differences were observed among the groups with or without discontinuation criteria and the non-naïve group. These findings support lusutrombopag treatment without platelet monitoring and retreatment with lusutrombopag.

Evaluation of drug-drug interaction of lusutrombopag, a thrombopoietin receptor agonist, via metabolic enzymes and transporters.

PURPOSE: Drug-drug interaction (DDI) potentials of lusutrombopag, a thrombopoietin receptor agonist, on the activity of cytochrome P450 (CYP) 3A and of cyclosporine, which inhibits P-glycoprotein and breast cancer resistance protein, on lusutrombopag pharmacokinetics were assessed via clinical studies and physiologically based pharmacokinetic (PBPK) modeling. METHODS: The effect of lusutrombopag on midazolam (a CYP3A probe substrate) pharmacokinetics was assessed in 15 healthy subjects receiving a single midazolam 5-mg dose with or without coadministration of lusutrombopag 0.75 mg for 6 days (first dose: 1.5-mg dose). The effect of cyclosporine on lusutrombopag pharmacokinetics was assessed in 16 healthy subjects receiving a single lusutrombopag 3-mg dose with or without a single cyclosporine 400- to 600-mg dose. PBPK modeling was employed to extrapolate the effect of lusutrombopag at the clinical dose (3 mg once daily) on midazolam pharmacokinetics. RESULTS: In the clinical study, mean ratios (90% confidence intervals [CIs]) of with/without lusutrombopag for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of midazolam were 1.01 (0.908-1.13) and 1.04 (0.967-1.11), respectively, indicating no effect of lusutrombopag on midazolam pharmacokinetics. PBPK modeling suggested no effect of lusutrombopag at the clinical dose on midazolam pharmacokinetics. Mean ratios (90% CIs) of with/without cyclosporine for lusutrombopag Cmax and AUC were 1.18 (1.11-1.24) and 1.19 (1.13-1.25), respectively, indicating a slight increase in lusutrombopag exposure. CONCLUSIONS: In consideration with in vitro data, the in vivo and in silico results suggested no clinically significant DDI potential of lusutrombopag with other medical products via metabolic enzymes and transporters.

Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin.

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent in vitro activity and in vivo efficacy against most gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In phase 1 studies, cefiderocol demonstrated linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2-3 hours, and a protein binding of 58% in human plasma. Cefiderocol is a time-dependent cephalosporin; the probability of a target attainment at ≥75% of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 µg/mL is likely to be achieved at the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients. As expected, renal function markers were the most influential covariates for the pharmacokinetics of cefiderocol for patients with renal impairment or augmented renal clearance (ARC). Dose adjustment is recommended for patients with impaired renal function, and additionally, in ARC patients with creatinine clearance >120 mL/minute, a more frequent dosing regimen (ie, 2 g every 6 hours) was predicted to achieve the target fT > MIC. The single and multiple doses of cefiderocol tested were well tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT interval prolongation nor drug-drug interaction via organic anion transporters was demonstrated in healthy subjects. Cefiderocol is being investigated in phase 3 clinical studies for the treatment of infections caused by carbapenem-resistant bacteria.

Lusutrombopag Reduces Need for Platelet Transfusion in Patients With Thrombocytopenia Undergoing Invasive Procedures.

BACKGROUND & AIMS: Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. METHODS: We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/µL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/µL or more with an increase of 20,000/µL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded. RESULTS: The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P < .0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P < .0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/µL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/µL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/µL or more). CONCLUSION: In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323.

Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects.

BACKGROUND: Cefiderocol, a novel siderophore cephalosporin, has shown potent activity against Gram-negative bacteria, including MDR pathogens. Cefiderocol is under clinical investigation for the treatment of serious Gram-negative infections including nosocomial pneumonia. OBJECTIVES: This study assessed intrapulmonary penetration after a single intravenous dose of cefiderocol (2000 mg infused over 60 min) in healthy adult males. MATERIALS AND METHODS: Each subject underwent one bronchoscopy with bronchoalveolar lavage (BAL) to collect BAL fluid (BALF). Fifteen subjects were assigned to one of three collection timepoints (1, 2 or 4 h from start of infusion). Five additional subjects were assigned to a collection timepoint at 6 h, which was added based on concentration data between 1 and 4 h predicting measurable BALF cefiderocol concentrations at 6 h. RESULTS: Cefiderocol concentrations in plasma, epithelial lining fluid (ELF) and alveolar macrophages (AMs) were calculated for each subject. The ELF concentration of cefiderocol was 13.8, 6.69, 2.78 and 1.38 mg/L at 1, 2, 4 and 6 h after single intravenous dosing, respectively. Over 6 h, geometric mean concentration ratios ranged from 0.0927 to 0.116 for ELF to total plasma and from 0.00496 to 0.104 for AMs to total plasma. AUC ratios of ELF and AMs to plasma were 0.101 and 0.0177 based on total drug in plasma, respectively, and 0.239 and 0.0419 based on free drug in plasma, respectively. There were no major drug-related adverse events. CONCLUSIONS: Results of this study indicate that cefiderocol penetrates into ELF, and ELF and plasma concentrations appear to be parallel.

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

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 (Cmax), 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 Cmax 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.

Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Various Degrees of Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis.

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.

Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters.

PURPOSE: Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters. METHODS: DDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co-administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates. RESULTS: Ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71-1.42) and 0.92 (0.73-1.16) for furosemide, 1.09 (0.92-1.28) and 1.03 (0.93-1.15) for metformin, and 1.28 (1.12-1.46) and 1.21 (1.08-1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co-administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated. CONCLUSIONS: Cefiderocol has no clinically significant DDI potential via drug transporters.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function.

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (Tf>MIC) for an MIC range of 0.25 to 16 µg/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided >90% PTA for 75% Tf>MIC for an MIC of ≤4 µg/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect.

Effect of Renal Impairment on Pharmacokinetics and Safety of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor.

INTRODUCTION: Ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2, shows efficacy and safety in participants with mild to moderate COVID-19. Since urinary recovery of ensitrelvir ranged from 12.9% to 21.8% across dose groups given 20-1000 mg in a single-ascending dose study, renal excretion contributes to the elimination of ensitrelvir. Therefore, the effect of renal impairment on the pharmacokinetics and safety of ensitrelvir needed to be evaluated. METHODS: This study (NCT05363215) was a phase 1, open-label, nonrandomized, parallel-group study. The effect of renal function on the pharmacokinetics of ensitrelvir was investigated. Ensitrelvir was administered as a single dose of 375 mg to participants with normal renal function and those with mild, moderate, and severe renal impairment. The participants with normal renal function were matched to each participant with moderate renal impairment with respect to sex, age, and body mass index. The unbound fractions in plasma after administration of ensitrelvir were also evaluated. For the safety assessment, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The plasma concentrations of participants with renal impairment were higher than those of participants with normal renal function. The ratios (90% confidence intervals) of the area under the plasma concentration-time curve from 0 to infinity (AUC0-inf) in participants with mild, moderate, and severe renal impairment compared to normal renal function were 1.4374 (1.1716-1.7636), 1.4885 (1.1883-1.8646), and 1.6021 (1.2782-2.0080), respectively. The plasma protein-unbound fraction was similar regardless of the plasma ensitrelvir concentration or renal function. Ensitrelvir was well tolerated in participants with mild to severe renal impairment and normal renal function. CONCLUSION: Ensitrelvir was well tolerated by participants with renal impairment. There was no clinically meaningful increase on exposure to ensitrelvir in participants with renal impairment, indicating that no dose adjustment would be required due to renal function.

Intrapulmonary Pharmacokinetic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients With Pneumonia and Healthy Subjects.

Cefiderocol is a siderophore cephalosporin for the treatment of infections caused by gram-negative bacteria including carbapenem-resistant strains. The aim of this study was to develop an intrapulmonary pharmacokinetic (PK) model of cefiderocol and assess the PK profile in lungs. An intrapulmonary PK model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 patients with pneumonia requiring mechanical ventilation and 20 healthy subjects. Subsequently, the model was applied to assess the ELF exposure of 125 patients with nosocomial pneumonia. Monte Carlo simulations were performed to calculate the probability of target attainment for the percentage of time for which free ELF concentrations exceed the minimum inhibitory concentration (MIC) over the dosing interval (%fT>MIC,ELF ). The developed model adequately described ELF concentrations and suggested the delayed distribution in ELF for patients with pneumonia compared to healthy subjects. Lung penetration ratio of cefiderocol in patients with pneumonia was calculated to be 34%, which was 1.4-fold that in healthy subjects. The estimated %fT>MIC,ELF was 100% in most of patients with nosocomial pneumonia, and no PK/pharmacodynamic relationship with %fT>MIC,ELF was found for microbiological or clinical outcome. The probability of target attainment for 100% fT>MIC,ELF was ≥ 99.5% against MICs ≤2 µg/mL and ≥87.0% against MICs ≤4 µg/mL regardless of renal function. The median of simulated ELF trough concentrations at steady state was >4 µg/mL regardless of renal function. These results reveal the adequacy of cefiderocol exposure in plasma and ELF at the recommended dosing regimens adjusted on the basis of renal function in critically ill patients with pneumonia.

Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy.

BACKGROUND: The need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated with clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable in large part to subtherapeutic antimicrobial exposure and failure to achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol is a novel siderophore cephalosporin with broad in vitro activity against resistant pathogens and is often used to treat critically ill patients, including those receiving CRRT, despite the lack of data to guide dosing in this population. OBJECTIVE: The aim of this study was to evaluate the PK and PD of cefiderocol during in vitro and in vivo CRRT and provide optimal dosing recommendations. METHODS: The PK and dialytic clearance of cefiderocol was evaluated via an established in vitro CRRT model across various modes, filter types, and effluent flow rates. These data were combined with in vivo PK data from nine patients receiving cefiderocol while receiving CRRT from phase III clinical trials. Optimal dosing regimens and their respective probability of target attainment (PTA) were assessed via an established population PK model with Bayesian estimation and 1000-subject Monte Carlo simulations at each effluent flow rate. RESULTS: The overall mean sieving/saturation coefficient during in vitro CRRT was 0.90 across all modes, filter types, effluent flow rates, and points of replacement fluid dilution tested. Adsorption was negligible at 10.9%. Three-way analysis of variance (ANOVA) and multiple linear regression analyses demonstrated that effluent flow rate is the primary driver of clearance during CRRT and can be used to calculate optimal cefiderocol doses required to match the systemic exposure observed in patients with normal renal function. Bayesian estimation of these effluent flow rate-based optimal doses in nine patients receiving CRRT from the phase III clinical trials of cefiderocol revealed comparable mean (± standard deviation) area under the concentration-time curve values as patients with normal renal function (1709 ± 539 mg·h/L vs. 1494 ± 58.4 mg·h/L; p = 0.26). Monte Carlo simulations confirmed these doses achieved >90% PTA against minimum inhibitory concentrations ≤4 mg/L at effluent flow rates from 0.5 to 5 L/h. CONCLUSION: The optimal dosing regimens developed from this work have been incorporated into the prescribing information for cefiderocol, making it the first and only antimicrobial with labeled dosing for CRRT. Future clinical studies are warranted to confirm the efficacy and safety of these regimens.

Pharmacokinetic Assessment and Treatment Effect of Lusutrombopag in Child-Pugh Class C Patients: Review of Patient Data from Two Clinical Studies and Post-Marketing Surveillance.

INTRODUCTION: Patients with thrombocytopenia and chronic liver disease are at increased risk of bleeding during invasive procedures due to low platelet counts. Lusutrombopag, an orally active thrombopoietin receptor agonist, increases platelet count and reduces the need for platelet transfusion in chronic liver disease patients with thrombocytopenia undergoing a planned invasive procedure. The safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease is not known. The present analysis was performed to determine the pharmacokinetics, efficacy, and safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease. METHODS: Data for patients with Child-Pugh class C chronic liver disease were collected from three data sets: a phase 1/2 Child-Pugh class C study (n = 5) (JapicCTI-163289 [Japan Pharmaceutical Information Center]), a phase 3 pivotal study (L-PLUS 2, n = 3) (NCT02389621 [Clinicaltrials.gov]), and ongoing post-marketing surveillance (n = 27) (JapicCTI-163432 [Japan Pharmaceutical Information Center]). Patients received lusutrombopag at 3 mg for up to 7 days. Safety and efficacy assessments were collected from two clinical studies and the post-marketing surveillance; pharmacokinetic data were collected from the phase 1/2 study. RESULTS: Mean Cmax and AUC0-τ were lower in Child-Pugh class C patients than Child-Pugh class A and B; individual patients' Cmax and AUC0-τ values overlapped among Child-Pugh classes. In lusutrombopag patients who did not receive platelet transfusion (n = 4 in phase 1/2, n = 1 in phase 3, n = 24 in post-marketing surveillance), the median (range) maximum platelet count was 88.5 × 109/L (54-105 × 109/L), 80 × 109/L, and 91 × 109/L (41-186 × 109/L; n = 23), respectively. There were no treatment-related adverse events or treatment-related serious adverse events. One patient from the phase 1/2 study had a non-serious portal vein thrombosis, which was not considered treatment-related. CONCLUSIONS: The analysis presented in this study suggests that lusutrombopag increases platelet counts in Child-Pugh class C patients and is safe and well tolerated in this patient population. TRIAL REGISTRATION: L-PLUS 2: NCT02389621 (Clinicaltrials.gov). Phase 1/2: JapicCTI-163289 (Japan Pharmaceutical Information Center [JAPIC]). Post-marketing surveillance: JapicCTI-163432 (JAPIC).

Quantitative systems pharmacology model of thrombopoiesis and platelet life-cycle, and its application to thrombocytopenia based on chronic liver disease.

Platelets are produced by hematopoietic stem cells via megakaryocytes in the bone marrow and play a critical role in hemostasis. The aim of this study was to develop a new platelet model based on the thrombopoiesis and platelet life-cycle by a quantitative systems pharmacology modeling approach, which could describe changes in platelet count profiles in platelet-related diseases and drug intervention. The proposed platelet model consists of 44 components. The model was applied to thrombopoiesis of a thrombopoietin receptor agonist, lusutrombopag. It could well describe the observed platelet count profiles after administration of lusutrombopag for both healthy subjects and patients with chronic liver disease and thrombocytopenia. This model should be useful for understanding the disease progression of platelet-related conditions, such as thrombocytopenia and for predicting platelet count profiles in various disease situations related to platelets and drug administration in drug development.