Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers

Purpose

Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices–compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development.

Safety,Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous Siponimod: A Randomized,Open-label Study in Healthy Subjects

PurposeThe goal of this study was to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of intravenous (IV) siponimod in healthy subjects.MethodsThis randomized, open-label study was conducted in 2 parts. In Part 1, a total of 16 eligible subjects received either a single oral dose of siponimod (0.25 mg) followed by a single IV infusion (0.25 mg/3 h) in Sequence 1, or vice versa in Sequence 2. In Part 2, a total of 17 eligible subjects received single IV infusions of siponimod (1 mg/24 h).FindingsNo clinically relevant effect on mean 5-minute or hourly average heart rate was observed following the siponimod IV dosing regimens and both remained above 50 beats/min. Observed atrioventricular blocks and sinus pauses were asymptomatic. The mean change in absolute lymphocyte count from baseline was comparable for the siponimod 0.25 mg oral regimen and the two IV siponimod regimens. Oral siponimod displayed a good absolute bioavailability of 84%. The mean peak exposure of oral siponimod was approximately 48% lower than that of IV siponimod. The M17 metabolite was found to be the most prominent systemic metabolite of siponimod in humans.ImplicationsSiponimod IV infusions were well tolerated, with safety and PD (absolute lymphocyte count) profiles similar to those of oral siponimod. The PD/PK findings supported the development of an innovative rapid IV titration regimen for patients with intracerebral hemorrhage.     

An Open-label,Single-dose Study to Evaluate the Pharmacokinetic Variables of Edaravone in Subjects with Mild,Moderate, or No Renal Impairment

PurposeThe goal of this study was to compare edaravone pharmacokinetic (PK) variables and tolerability after a single intravenous (IV) infusion of 30 mg over 60 min in subjects with mild renal impairment (estimated glomerular filtration rate 60–89 mL/min/1.73 m²), moderate renal impairment (30–59 mL/min/1.73 m²), or normal renal function (≥90 mL/min/1.73 m²).MethodsThis open-label, single-dose study was conducted in Japan. After a screening period of up to 3 weeks, all subjects received a single IV dose of edaravone 30 mg/h on day 1. Blood samples were collected for PK analysis of edaravone and its sulfate conjugate for up to 48 h postdose.FindingsEdaravone was administered to 30 subjects: 11 with mild (Group 1), 8 with moderate (Group 2), and 11 with no (Group 3) renal impairment. Although geometric least-squares mean values for C_max and AUC_0–∞ for unchanged edaravone were 1.15- and 1.20-fold greater in Group 1 than in Group 3, and were 1.25- and 1.30-fold greater in Group 2 than in Group 3, no statistically significant differences in exposure (C_max and AUC) to edaravone were noted between the 3 groups (P > 0.05). The geometric least-squares mean values for C_max and AUC_0–∞ for the sulfate conjugate were 1.41- and 1.50-fold greater in Group 1 than in Group 3, and 1.41- and 1.97-fold greater in Group 2 than in Group 3. Differences in exposure (C_max and AUC) to the sulfate conjugate of edaravone were statistically significant between the 3 study groups (P < 0.0001). A total of 5 treatment-emergent adverse events in 3 subjects in Group 1 were considered by the investigator to be reasonably related to edaravone: headache (2 events/2 subjects), vomiting (2 events/1 subjects), and increased blood bilirubin level (n = 1). These treatment-emergent adverse events were mild and recovered without sequelae.ImplicationsMild to moderate renal impairment had no clinically significant effects on the PK profile of edaravone in Japanese subjects, relative to individuals with normal renal function, and there were no significant safety concerns. Thus, edaravone dosage adjustments are unlikely to be needed in patients with mild to moderate renal impairment. Clinicaltrials.gov identifier: NCT03289208.     

Identification of factors affecting meropenem pharmacokinetics in critically ill patients: Impact of inflammation on clearance

IntroductionThe purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy.MethodsThis prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software.ResultsMeropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients’ CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively.ConclusionThe findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.     

Tolerability and Pharmacokinetics of Contezolid at Therapeutic and Supratherapeutic Doses in Healthy Chinese Subjects,and Assessment of Contezolid Dosing Regimens Based on Pharmacokinetic/Pharmacodynamic Analysis

PurposeThis study assessed the tolerability and pharmacokinetic (PK) properties of a new-generation oxazolidinone, contezolid (MRX-I), and its major inactive metabolite, M2, after single oral administrations of 800, 1200, and 1600 mg in the fed state, and compared the efficacy of 3 dosing regimens in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection based on PK/pharmacodynamic (PD) analysis.MethodsA Phase I study at a single study center was conducted with 2 parts. In the first part, 20 healthy subjects received a single oral dose of 1200 or 1600 mg of contezolid or placebo in the fed state in a double-blind, placebo-controlled, dose-escalation tolerance study. In the second part of the study, 52 subjects received a single oral dose of 800 mg of contezolid in the fed state in a single-center, randomized, blinded, 4-period, crossover, thorough QT study. Noncompartmental analyses were used to evaluate the PK properties of contezolid and M2. Steady-state concentrations of contezolid following the 3 dosing regimens (800, 1200, and 1600 mg q12h) were simulated by employing a newly developed 2-compartmental PK model. The minimum inhibitory concentration (MIC) distributions of contezolid were analyzed in 178 Staphylococcus, Enterococcus, and Streptococcus clinical isolates. Monte Carlo simulations were conducted to predict the efficacy of the 3 dosing regimens to obtain probability of target attainment and cumulative fraction of response.FindingsSingle-dose oral administrations of 800, 1200, and 1600 mg of contezolid were well tolerated in healthy subjects in the fed state, and nonlinear PK was observed. The mean plasma exposures to M2 exceeded 17.3% of contezolid exposure in the 3 groups. Both MIC₅₀ and MIC₉₀ (MICs that inhibit the growth of 50% and 90% of microorganisms, respectively) of contezolid against MRSA were 1 mg/L with clinical isolates from China. PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12h of oral contezolid would be efficacious against MRSA infection, with a MIC of ≤4 mg/L (probability of target attainment, >90%; cumulative fraction of response, >90%).ImplicationsContezolid is a well-tolerated treatment option for MRSA infection, including at supratherapeutic doses up to 1600 mg. The regimen of 800 mg q12h could achieve efficacy in treating bacterial infection with MRSA. To our knowledge, this is the first PK study to predict that a dosing regimen of 800 mg q12h of oral contezolid is sufficient for treating MRSA infection, with a MIC of ≤4 mg/L. A Phase III study of this suggested dosing regimen is being conducted. Chinadrugtrials.org.cn identifier: CTR20161074.     

Population Pharmacokinetics Study of Contezolid (MRX-I), a Novel Oxazolidinone Antibacterial Agent,in Chinese Patients

PurposeContezolid (MRX-I) is a novel oxazolidinone with potent in vitro activity against gram-positive pathogens. The aim of this study was to establish the dose-pharmacokinetic (PK) exposure-pharmacodynamic (PD)–response relationship and to quantitatively evaluate the variability of MRX-I after continuous oral administration of 600 mg BID and 800 mg BID for 14 days under fed conditions in patients with skin and skin structure infections. Another goal was to evaluate the 2 dosing regimens against methicillin-resistant Staphylococcus aureus infections based on PK/PD analysis.MethodsPK data from healthy volunteers and patients were pooled to develop a population PK model using a nonlinear mixed effect modeling method. Monte Carlo simulations were used to predict probability of target attainment (PTA) and cumulative fraction of response after single oral administration of 600 and 800 mg of MRX-I under fed conditions.FindingsThe PK profile of oral administration of MRX-I was described by using a 2-compartment model with first-order elimination. Absorption of MRX-I may be affected by food intake. Type of volunteers could affect absorption constant rate and volume of distribution in the peripheral compartment, and weight could affect volume of distribution in the central department. No obvious effect on PK parameters was identified for other factors such as age, sex, creatinine clearance, concomitant medicine, and baseline diseases. Based on Monte Carlo simulation, MRX-I 600 or 800 mg BID up to 14 days on ordinary fed status could produce satisfactory efficacy against methicillin-resistant S aureus, with cumulative fraction of response >90% for fAUC_0–24/MIC targeted at 2.3. At MIC ≤2.0 μg/mL for MRX-I 600 mg BID, or at MIC ≤4.0 μg/mL for MRX-I 800 mg BID, with continuous administration for 14 days at fed status, both regimens could obtain satisfactory clinical and antibacterial efficacy, with PTA >90%. Hence, the MRX-I regimen of 800 mg BID for 7–14 days can be recommended for confirmative clinical trials in patients with skin and skin structure infections.ImplicationsPK profiles of MRX-I were well captured by using a 2-compartment PK model, and disease status, food intake, and weight were found to significantly affect PK profiles. A dosing regimen of 800 mg BID for 7–14 days with ordinary food intake was recommended for pivotal study based on simulated fAUC_0–24/MIC and PTA values. Results suggest that dose adjustments are not necessary for patient sex in confirmatory studies. Chinese Clinical Trial Registration identifier: CTR20140056.     

Tolerability,Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin,a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration

BackgroundHenagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus.PurposeTo evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers.MethodsTwo clinical studies were conducted. One was a single ascending dose (SAD) study (2.5–200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25–100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies.FindingsNo serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a T_max of 1.5–3 h, and then eliminated from plasma with a half-life of 11–15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5–200 mg (SAD) and 1.25–100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%–5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration.ImplicationsHenagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.     

Tolerability and Pharmacokinetics of Single Escalating and Repeated Doses of CN-105 in Healthy Participants

PurposeCN-105 is an IV, apolipoprotein E–mimetic pentapeptide. Preclinical studies have reported that CN-105 effectively down-regulates neuroinflammatory responses in microglia and mitigates neuronal excitotoxicity following acute brain injury. The CN-105 Phase I and II trials that have been done in the United States have demonstrated that CN-105 was well tolerated in US participants. Thus, the main objective of the present Phase I study was to investigate the tolerability and pharmacokinetic (PK) profiles of CN-105 in healthy Chinese participants.MethodsThis randomized, double-blind, placebo-controlled, dose-escalation study was performed in healthy participants using sequential 30-minute IV administration of single and multiple doses of CN-105 (four times daily for 13 doses). Forty volunteers were randomly assigned, in an 8:2 ratio, to one of four dosing groups, receiving either CN-105 (0.03, 0.1, 0.3, or 1 mg/kg), or placebo. Serial blood samples were collected for the measurement of plasma concentrations of CN-105. Tolerability was also assessed.FindingsAfter single-dose administration, the plasma CN-105 concentration rapidly reached the peak by the end of infusion. The mean elimination half-life of CN-105 ranged from 2.3 to 3.6 hours. During single- and multiple-dosing paradigms, exposure to CN-105 (AUC) exhibited linear dependency on dose. Steady state was reached by the fourth dose, with minimal accumulation. The PK properties of CN-105 with single and multiple dosing were comparable to those observed in US participants. CN-105 was generally well tolerated in Chinese participants. A total of 13 adverse events were reported in 30% of subjects (12/40) at the 0.03 mg/kg (6/8), 0.1 mg/kg (1/8), 0.3 mg/kg (2/8), 1 mg/kg (0/8) doses and with placebo (3/8). All adverse events were mild or moderate in severity and self-limited, with no dose relationship observed.ImplicationsCN-105 was well tolerated in these healthy Chinese participants at doses of 0.1 to 1 mg/kg with single and multiple IV administrations. The PK characteristics of CN-105 were comparable among Chinese and Western subjects. A Phase II study in patients with intracranial hemorrhage is being planned in China. ClinicalTrials.gov identifiers: NCT02670824 and NCT03168581; Chinese Clinical Trial Registration identifier: CTR20202397.     

Pharmacokinetics and Safety of Extended-release Ranolazine in Korean and White Healthy Subjects

PurposeRanolazine, an inhibitor of late inward sodium current, is an antianginal agent. In this study, the pharmacokinetic (PK) properties and tolerability of single- and multiple-dose ranolazine were compared between healthy Korean and white subjects.MethodsAn open-label, ascending single- and multiple-dose study was conducted with healthy male Korean and white subjects. Subjects were administered 375–750 mg of ranolazine once in a single-dose and twice daily in multiple-dose based on their dose groups. Blood samples for the PK assessment were collected up to 48 h after dosing. The geometric mean ratio and its 90% confidence interval in Korean to white subjects for C_max, C_max,ss, AUC_last, and AUC_0–12h,ss of ranolazine were calculated. A population PK analysis was also performed. Safety profiles were assessed throughout the study.FindingsA total of 70 Korean and 48 white subjects completed the study. Ranolazine exposure was similar between Korean and white subjects in all dose groups; however, ranolazine exposure at 750 mg was observed to increase by up to 29% in Korean subjects compared with that in white subjects. On the basis of previous studies, these differences in ranolazine exposure between the 2 ethnic groups may not result in any clinically significant difference. Furthermore, ethnicity was not significantly correlated with the PK properties of ranolazine in the ranolazine PK model. In addition, no significant difference was found in the safety profile of ranolazine between the 2 ethnic groups.ImplicationsThe PK properties of ranolazine had no clinically significant difference, and no difference was found in the safety profiles of ranolazine between Korean and white subjects. It is anticipated that ranolazine can be administered in Korean subjects without dose adjustment. ClinicalTrials.gov identifier: NCT02817932.     

Open-label,Single-dose Studies of the Pharmacokinetics of Edaravone in Subjects with Mild,Moderate, or Severe Hepatic Impairment Compared to Subjects with Normal Hepatic Functioning

PurposeTwo studies were conducted to assess the pharmacokinetic (PK) properties and tolerability of edaravone in Japanese subjects with mild to moderate hepatic impairment or normal hepatic functioning (study 1), and in white subjects with severe hepatic impairment compared to subjects with normal hepatic functioning (study 2).MethodsStudies 1 and 2 were multicenter, open-label, single-dose studies that included subjects aged 18–75 years. In study 1, subjects were stratified into 3 different groups of hepatic functioning according to Child-Pugh score: mild hepatic impairment, score 5 or 6 (n = 8); moderate hepatic impairment, score 7–9 (n = 6); or normal hepatic functioning (n = 8). In study 2, subjects had severe hepatic impairment (Child-Pugh score 10–14; n = 6) or normal hepatic functioning (n = 6). In both studies, all subjects were given edaravone 30 mg IV infused over 60 min on the morning of day 1. Blood samples for use in PK analyses were collected from days 1–3. The PK properties (C_max, AUC_0–last, and AUC_0–∞) of edaravone and its sulfate conjugate metabolite were measured.FindingsIn study 1, the geometric least-squares mean (GLSM) C_max and AUC_0–∞ of unchanged edaravone were 1.203- and 1.065-fold greater, respectively, in subjects with mild hepatic impairment versus normal hepatic functioning, and were 1.235- and 1.142-fold greater, respectively, in subjects with moderate hepatic impairment versus normal hepatic functioning. In study 2, GLSM C_max and AUC_0–∞ of unchanged edaravone were 1.203- and 1.190-fold greater, respectively, in subjects with severe hepatic impairment versus normal hepatic functioning. In both studies the AUC_0–last, AUC_0–∞, unbound AUC from time zero to infinity, and C_max of unchanged edaravone were increased slightly with increases in Child-Pugh classification. No adverse events considered related to edaravone were reported, except for 1 case of sinus bradycardia in a subject with normal hepatic functioning in study 2. The event was moderate in severity, considered as possibly related to edaravone, and resolved during the study.ImplicationsMild to moderate and severe hepatic impairment had no apparent clinically significant effects on the PK profile of edaravone in Japanese and white subjects, respectively, relative to individuals with normal hepatic functioning, and there were no notable tolerability concerns. Thus, edaravone dosage adjustments are unlikely to be needed in edaravone-treated patients with mild to moderate and severe hepatic impairment. ClinicalTrials.gov identifiers: NCT03289234 (mild to moderate hepatic impairment) and NCT03664544 (severe hepatic impairment).     

Food Effect Study to Assess the Impact on Edaravone Pharmacokinetic Profiles in Healthy Participants

PurposeThe safety and efficacy of intravenous edaravone, a neuroprotectant used for the treatment of amyotrophic lateral sclerosis (ALS), have been shown in clinical trials. An oral suspension of edaravone has been developed, but the food effect on its pharmacokinetic profile has not been evaluated. This study aimed to assess the food effect on the pharmacokinetic profile of edaravone after oral administration and to investigate dosing regimens and administration instructions with different meal intake and timing.MethodsData from 3 Phase I clinical studies were used to evaluate the effect of food on the pharmacokinetic profiles of a single dose of edaravone oral suspension. In all 3 studies, participants received a single dose of edaravone with various meal conditions. Healthy Japanese adult male participants (Studies 1, 2, and 3) or female participants (Study 3) aged 20 to 45 years at the time of informed consent were included.FindingsIn Study 1, 6 participants were enrolled and 5 completed the study. Nine and 16 participants were treated in Studies 2 and 3, respectively, and all completed the study. The C_max and AUC_0–∞ of edaravone were lower when administered 30 minutes after a high-fat meal compared with those in a fasted condition (Study 1). Lower plasma edaravone concentrations (approximately within the first hour) and subsequent lower C_max and AUC_0–∞ were observed after administration of edaravone 4 hours after a high-fat meal (Study 2) or 2 hours after a low-fat meal (Study 3). The C_max and AUC_0–∞ of oral edaravone were generally similar and not affected when administered 8 hours after a high-fat meal, 4 hours after a low-fat meal, or 2 hours after a light meal relative to the fasted condition. Administration of edaravone 1 hour before a high-fat meal resulted in no effect on C_max or AUC_0–∞ relative to the fasted condition. Administration of edaravone in the fed or fasted conditions resulted in a similar urine pharmacokinetic profile.ImplicationsOral administration of edaravone with a meal decreased the plasma concentration of edaravone. Oral administration of edaravone 8 hours after a high-fat meal, 4 hours after a low-fat meal, 2 hours after a light meal, and 1 hour before a high-fat meal showed no effect of food on the PK profile of unchanged edaravone compared with that observed under a fasted condition. ClinicalTrials.gov identifiers: NCT04481750, NCT04481789, and NCT05342597.     

Optimal levofloxacin dosing regimens in critically ill patients with acute kidney injury receiving continuous renal replacement therapy

PurposesTo determine appropriate dosing of levofloxacin in critically ill patients receiving continuous renal replacement therapy (CRRT).MethodsAll necessary pharmacokinetic and pharmacodynamic parameters from critically ill patients were obtained to develop mathematical models with first order elimination. Levofloxacin concentration-time profiles were calculated to determine the efficacy based on the probability of target attainment (PTA) of AUC_24h/MIC ≥50 for Gram-positive and AUC_24h/MIC ≥125 for Gram-negative infections. A group of 5000 virtual patients was simulated and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the dose achieved target PTA at least 90% of the virtual patients.ResultsNo conventional, FDA approved regimens achieved at least 90% of PTA for Gram-negative infection with Pseudomonas aeruginosa at MIC of 2 mg/L. The successful dose (1750 mg on day 1, then 1500 mg q 24 h) was far exceeded the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg q 24 h was sufficient to attain PTA target of ~90% at the MIC of 2 mg/L for Streptococcus pneumoniae.ConclusionsLevofloxacin cannot be recommended as an empiric monotherapy for serious Gram-negative infections in patients receiving CRRT due to suboptimal efficacy.     

Population pharmacokinetic model and dosing optimization of vancomycin in hematologic malignancies with neutropenia and augmented renal clearance

AimData on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies.MethodsA retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC_0-24 of 400–600 mg h/L at the steady-state.ResultsThe VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients.ConclusionAML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended.     

Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC_48–72) that were <50% of the SAB-IE AUC_48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC_48–72 values, while maintaining acceptable trough concentration (C_min) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C_min reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of C_min being ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.     

Pharmacokinetics of levetiracetam in neurosurgical ICU patients

Background/objectivesThe pharmacokinetics (PK) of drugs is dramatically altered in critical illness. Augmented renal clearance (ARC), a phenomenon characterized by creatinine clearance (CrCl) greater than 130 ml/min/1.73m², is commonly described in critically ill patients. Levetiracetam, an antiepileptic drug commonly prescribed for seizure prophylaxis in the neurosurgical ICU, undergoes predominant elimination via the kidneys. Hence, we hypothesize that current dosing practice of intravenous (IV) levetiracetam 500 mg twice daily is inadequate for critically ill patients due to enhanced drug elimination. The objectives of our study were to describe the population PK of levetiractam using a nonparametric approach to design an optimal dosing regimen for critically ill neurosurgical patients.MethodsThis was a prospective, observational, population PK study. Serial blood samples were obtained from neurosurgical ICU patients who received at least one dose of IV levetiracetam. We used uHPLC to analyze these samples and Pmetrics™ software to perform PK analysis.ResultsTwenty subjects were included, with a median age of 54 years and CrCl of 104 ml/min. A two-compartmental model with linear elimination adequately described the profile of levetiracetam. Mean clearance (CL) was 3.55 L/h and volume of distribution (V) was 18.8 L. No covariates were included in the final model. Monte Carlo simulations showed a low probability of target attainment (PTA, trough at steady state of ≥6 mg/L) with a standard dose of 500 mg twice daily. A dose of at least 1000 mg twice daily was required to achieve 80% PTA. Two subjects, both with subtherapeutic trough levels, developed early onset seizures.ConclusionOur study examined the population PK of levetiracetam in a critically ill neurosurgical population. We found that this population displayed higher clearance and required higher doses to achieve target levels.     

Weight-based versus non-weight-based diltiazem dosing in the setting of atrial fibrillation with rapid ventricular response

PurposeThere is conflicting evidence to support the superiority of weight-based (WB) dosing of intravenous (IV) diltiazem over non-weight-based (NWB) dosing strategies in the management of atrial fibrillation (AFib) with rapid ventricular response (RVR).MethodsA retrospective review evaluated patients presenting to the emergency department (ED) in AFib with RVR and receiving IV diltiazem from 2015 to 2018. Those receiving a NWB dose were compared with those receiving a WB dose based on actual body weight (ABW). Secondary analyses evaluated safety profiles of the regimens and compared response in groups defined by ABW or ideal body weight (IBW).ResultsA total of 371 patients were included in the analysis. No significant difference was observed in achieving a therapeutic response (66.5% vs. 73.1%, p = 0.18) or adverse events between the groups. Patients receiving a WB dose were significantly more likely to have a HR < 100 bpm than those receiving a NWB dose (40.9% vs. 53.5%, p = 0.01). When groups were defined by IBW, WB dosing was associated with a significantly higher incidence of achieving a therapeutic response (62.7% vs. 74.3%, p = 0.02).ConclusionIn patients presenting with AF with RVR, there was no significant difference in achieving a therapeutic response between the two strategies. A WB dosing approach did result in a greater proportion of patients with a HR < 100 bpm. The utilization of IBW for WB dosing may result in an increased achievement of a therapeutic response.     

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease

PurposeLevodopa (LD) is the most effective oral pharmacotherapy for the management of motor symptoms in Parkinson's disease. However, LD use is complicated by a progressive shortening of the duration of efficacy of a dose, resulting in episodes of inadequate responsiveness, or OFF periods. OFF periods may also occur unpredictably, partly due to the pharmacokinetic (PK) variability of oral LD, resulting from gastrointestinal dysfunction and from the effects of food on absorption. CVT-301 is a levodopa inhalation powder for the treatment of OFF period symptoms in patients on oral dopa-decarboxylase inhibitor/LD. PK and safety profiles of single dose CVT-301, administered with oral carbidopa (CD) and oral CD/LD, were examined in patients with Parkinson's disease in the fed state.MethodsEligible patients were aged 30–85 years, with a clinical diagnosis of Parkinson's disease and a body mass index of 18–32 kg/m², and were receiving treatment with a stable regimen that included oral CD/LD (25/100 mg) (total LD, ≤800 mg/d). A high-fat/protein meal was eaten 4–5 h after the administration of the morning oral CD/LD dose. Blood samples for predose PK analysis were obtained after the meal, followed by a single inhaled dose of CVT-301 84 mg (+25 mg of oral CD) or oral CD/LD (25/100 mg) or vice versa in 2 dosing periods in a crossover design. Blood was sampled at 0, 5, 10, 15, 30, and 45 min and at 1, 1.5, 2, 3, and 4 h postdose. Tolerability assessments included treatment-emergent adverse events.FindingsTwenty-three patients were enrolled (65.2% male; 87.0% white; mean age, 69.3 years; mean body mass index, 26.9 kg/m²; mean Parkinson's disease duration, 8.2 years; mean baseline LD dosage, 460.9 mg/d; 73.9% at Hoehn and Yahr stage <2.5). PK analyses were based on LD concentrations without baseline adjustment. Median T_max values with CVT-301 and oral CD/LD were 15 and 120 min (P < 0.001). C_max with CVT-301 was lower than with oral CD/LD (590.3 vs 844.3 ng/mL). C_10min and C_30min values with CVT-301 were approximately twice those with CD/LD (522.9 and 531.5 ng/mL vs 247.3 and 300.9 ng/mL, respectively). %CV for C_5min to C_max with CVT-301 was lower than that with oral CD/LD. The most common treatment-emergent adverse event was cough (CVT-301, 7 patients [30.4%]; oral CD/LD, 1 patient [4.5%]).ImplicationsPK properties showed that CVT-301 was more rapidly absorbed, with higher plasma LD concentrations in the first 45 min, and demonstrated lower interpatient variability, than was oral CD/LD in the fed condition. The study findings suggest that CVT-301 can be used without regard to food intake. ClinicalTrials.gov identifier: NCT03887884.     

Pharmacokinetics of cefmetazole in plasma,peritoneal fluid,peritoneum, and subcutaneous adipose tissue of patients scheduled for lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment

IntroductionCefmetazole (CMZ) has gained interest as a carbapenem-sparing alternative to the epidemic of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E). In this study, we investigated the pharmacokinetics (PK) of CMZ in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue to assess the dosing regimen needed to achieve pharmacodynamic (PD) goals at the target site.MethodsPatients scheduled for elective lower gastrointestinal surgery were intravenously administered CMZ. Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected after CMZ infusion and during the surgery, and CMZ concentrations were measured. The non-compartmental and compartmental PK parameters were estimated and used to evaluate site-specific PD target attainment.ResultsA total of 38 plasma, 27 peritoneal fluid, 36 peritoneum, and 38 subcutaneous adipose tissue samples were collected from 10 patients. The non-compartmental PK analysis revealed the ratios of the mean area under the drug concentration-time curve (AUC_0–3.5 h) of peritoneal fluid-to-plasma, peritoneum-to-plasma, and subcutaneous adipose tissue-to-plasma were 0.60, 0.36, and 0.11, respectively. The site-specific PD target attainment analyses based on the breakpoints for ESBL-E per the Japanese surgical site infection (SSI) surveillance (MIC₉₀ = 8 mg/L) revealed that 2 g CMZ every 3.5 h achieved desired bactericidal effect at all sites and 2 g CMZ every 6 h achieved PD goals at peritoneum and peritoneal fluid.ConclusionThese findings clarify the PK of CMZ in abdominal tissues and could help decide optimal dosing regimens to treat intra-abdominal infection and prophylaxis of SSI.