Median Peak Concentrations Research Articles

Preclinical and Clinical Pharmacokinetics of JNJ-75220795, an siRNA Therapeutic Targeting PNPLA3, for Metabolic Dysfunction-Associated Steatohepatitis.

JNJ-75220795 or ARO-PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N-acetyl-d-galactosamine that targets the PNPLA3 gene, currently being developed for metabolic dysfunction-associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ-75220795 in preclinical species as well as in human subjects with homozygous or heterozygous PNPLA3 I148M mutation in two phase 1 studies-a first-in-human study in the United States and a first-in-Japanese study in Japan. Preclinical PK in rats and non-human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses. JNJ-75220795 was predominantly distributed to the liver with peak liver concentrations reached at 4 h and still detectable at 672 and 336 h in rats and NHPs, respectively, with an apparent liver-to-plasma area under the curve (AUC) ratio of 2800 in rats. Consistent with the preclinical findings, clinical PK showed rapid systemic absorption and clearance in humans with median peak concentrations at 3.0-9.0 h and mean short half-life of 3.4-6.2 h. Plasma PK exposure parameters including Cmax and AUC increased approximately dose proportionally. Kidney had the second highest tissue exposure following the liver in rats. Renal excretion was a significant but minor elimination pathway as approximately 15%-25% of the administered dose was recovered in urine. Based on the overall data, JNJ-75220795 was primarily localized to the liver and exhibited sustained hepatic exposures, which confer prolonged pharmacodynamic effects in the target organ. The favorable PK profiles of single subcutaneous doses observed in the phase 1 studies support continued clinical development of JNJ-75220795 for the treatment of MASH.

Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037)

Background: On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005. Methods: HIV-uninfected adults received a series of 3 rectal PC-1005 doses—4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours. Results: Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1–2 h after dosing with a median peak concentrations range of 0.07–0.23 ng/mL and median half-life range of 4.9–7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5–1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity. Conclusions: MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate. Clinical Trials: NCT03408899.

High-dose colistin pharmacokinetics in critically ill patients receiving continuous renal replacement therapy

BackgroundColistin, administered as intravenous colistimethate (CMS), is still used in the critical care setting and current guidelines recommend high dosage CMS in patients undergoing continuous renal replacement therapy (CRRT). Due to the paucity of real-life data, we aimed to describe colistin pharmacokinetic/pharmacodynamic (PK/PD) profile in a cohort of critically ill patients with infections due to carbapenem-resistant (CR) bacteria undergoing CRRT.ResultsAll consecutive patients admitted to three Intensive Care Units (ICUs) of a large metropolitan University Hospital, treated with colistin for at least 48 h at the dosage of 6.75 MUI q12, after 9 MIU loading dose, and undergoing CRRT were included. After the seventh dose, patients underwent blood serial sampling during a time frame of 24 h. We included 20 patients, who had CR-Acinetobacter baumannii ventilator-associated pneumonia and were characterized by a median SAPS II and SOFA score of 41 [34.5–59.3] and 9 [6.7–11], respectively. Fifteen patients died during ICU stay and six recovered renal function. Median peak and trough colistin concentrations were 16.6 mcg/mL [14.8–20.6] and 3.9 mcg/mL [3.3–4.4], respectively. Median area under the time–concentration curve (AUC0 − 24) and average steady-state concentration (Css, avg) were 193.9 mcg h/mL [170.6–208.6] and 8.07 mcg/mL [7.1–8.7]. Probability of target attainment of colistin pharmacodynamics according to the fAUC0 − 24/MIC target ≥ 12 was 100% for MIC ≤ 2 mcg/mL and 85% for MIC = 4 mcg/ML, although exceeding the toxicity limit of Css, avg 3–4 mcg/mL.ConclusionsIn critically ill patients with CR infections undergoing CRRT, recommended CMS dosage resulted in colistin plasmatic levels above bacterial MIC90, but exceeding the safety Css, avg. limit.Trial registrationThis trial was registered in ClinicalTrials.gov on 23/07/2021 with the ID NCT04995133 (https//clinicaltrials.gov/study/NCT04995133).

Effects of Cannabidiol Ingestion on Thermoregulatory and Inflammatory Responses to Treadmill Exercise in the Heat in Recreationally Active Males.

Exertional heat stress can induce systemic endotoxin exposure and a pro-inflammatory cascade, likely impairing thermoregulation. Cannabidiol (CBD) is protective in pre-clinical models of tissue ischaemia and inflammation. Therefore, this study examined the effects of CBD ingestion on exercise-induced thermoregulatory and inflammatory responses. In a randomised, double-blinded study, thirteen active males (age 25 ± 5 y; peak oxygen uptake [V̇O2peak] 50.4 ± 3.2 mL/kg/min) ingested 298 mg CBD or placebo 105 minutes before 1 h treadmill exercise (60-65% V̇O2peak) in 32 °C and 50% relative humidity. Core temperature, skin temperature, heart rate, subjective outcomes and sweat loss were assessed during/after exercise. Plasma osmolality, plasma volume changes and plasma markers of intestinal damage (I-FABP), monocyte activation (CD14) and inflammatory cytokine responses (IL-6, IL-8 and TNF-α) were assessed at baseline, pre-exercise, 20- and 90-min post-exercise. Core temperature (∆ 1.69 ± 0.48 °C [CBD] and 1.79 ± 0.53 °C [Placebo]) and I-FABP increased during exercise, with no differences between conditions (p > 0.050). Mean (95% CI) CD14 was 1776 (463 to 3090) pg/mL greater 90 min post-exercise in placebo (p = 0.049). Median (interquartile range) peak IL-6 concentration was -0.8 (-1.1, -0.3) pg/mL less in CBD (p = 0.050), whilst the between-conditions difference in IL-6 area under curve was -113 (-172, 27) pg/mL·270 min (p = 0.054). CBD did not affect thermoregulation during exertional heat stress but appeared to elicit minor immunosuppressive effects, reducing CD14 and IL-6 responses, warranting investigation in humans under more severe heat strain and other pro-inflammatory scenarios.

PHARMACOKINETIC PROFILES OF ORAL PHENYLBUTAZONE, MELOXICAM, AND FIROCOXIB IN SOUTHERN BLACK RHINOCEROS (DICEROS BICORNIS MINOR).

The pharmacokinetic profile of selected NSAIDs in southern black rhinoceros (Diceros bicornis minor) were studied. Phenylbutazone (PBZ), meloxicam (MEL), and firocoxib (FIR) were administered orally to five captive, black rhinoceros, and blood was collected at predetermined time points for NSAID quantification and noncompartmental pharmacokinetic (PK) analysis. Phenylbutazone 4.0 mg/kg PO q12h for three doses, MEL 0.3 mg/kg PO q24h administered twice, and a single oral dose of FIR 0.1 mg/kg, were tested with a minimum washout time of 2 wk. PBZ reached a median (range) peak concentration (Cmax) of 9.42 (2.74-11.5) g/ml at a mean (range) time (Tmax) of 6.00 (4.00 to >12.00) h, and the median (range) elimination half-life (T1/2) was 6.07 (3.95-6.49) h. Phenylbutazone pharmacokinetic parameters for black rhinoceros in this study were similar to domestic horses. Meloxicam reached a median (range) Cmax of 0.576 (0.357-0.655) µg/ml at a median (range) time (Tmax) of 6.00 (4.00-12.00) h; the median (range) T1/2 of MEL was 14.0 (12.4-17.9) h. These results demonstrate that once-daily administration of MEL at 0.3 mg/kg resulted in a serum concentration of greater than 0.200 µg/ml from 2 to 24 h in four animals, which is within the analgesic range (0.200-0.400 µg/ml) for this drug in other species postulated by other studies. A single dose of firocoxib (0.1 mg/kg) reached a median (range) peak concentration (Cmax) of 15.7 (9.65-17.3) ng/ml at a median (range) Tmax of 4.00 (4.00-6.00) h. The median (range) elimination T1/2 of FIR was 4.96 (4.47-6.51) h, which is faster than in the horse. The data suggest that extrapolation from equine FIR dosage recommendations is inappropriate for black rhinoceros.

A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.

On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally. MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively). Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420.

Evaluation of doxorubicin administrations in hepatocellular carcinoma in terms of genetic polymorphism, case study: Egypt

PurposeThis scientific article aims to evaluate the efficacy of the drug Doxorubicin for treating hepatocellular carcinoma (HCC) in Egypt. The study analyzes data from patients referred to a multi-disciplinary consultation at the National Cancer Institute, Cairo University. The study includes 40 intermediate-stage HCC patients who underwent treatment with either Doxorubicin-Lipiodol or Doxorubicin-loaded drug-eluting beads-trans-arterial chemoembolization (DEB-TACE).Design/methodology/approachPatients referred to a multi-disciplinary consultation at the National Cancer Institute, Cairo University with a possible diagnosis of HCC in the intermediate stage were eligible for the study.FindingsThe study finds that the plasma peak concentration of Doxorubicin is significantly higher in patients treated with Lipiodol compared to those treated with DEB-TACE. The median plasma peak concentration of patients treated with Lipiodol was significantly higher 424 (202.5–731) than the peak level of patients treated with beads 84.95 (26.6–156.5) with p-value = 0.036. However, there is no significant difference in other pharmacokinetic parameters between the two treatment groups. The research article also investigates the genetic polymorphisms in HCC patients treated with Doxorubicin-Lipiodol and Doxorubicin-loaded DEB-TACE. It identifies a significant association between the ABCB1 gene (C3435T) and the concentration of Doxorubicin in plasma. Patients with the CCand computed tomography (CT) genotypes of ABCB1 have higher concentrations of Doxorubicin compared to those with the TT genotype. Furthermore, the study examines the progression-free survival rates and tumour response in the two treatment groups. It demonstrates that DEB-TACE patients have a higher progression-free survival rate compared to cTACE patients. DEB-TACE also leads to better tumour regression.Originality/valueThe current study helps to increase the understanding of the genetic factors that may contribute to HCC susceptibility in the Egyptian population. However, it is essential to consider that genetic polymorphism is just one aspect of HCC risk, and other factors such as environment, lifestyle and viral infections also play crucial roles. Further research is needed to elucidate the complex interactions between genetic and environmental factors in HCC development among Egyptians.

An alternative fully human anti-BCMA CAR-T shows response for relapsed or refractory multiple myeloma with anti-BCMA CAR-T exposures previously

Chimeric antigen receptor T (CAR-T) cells therapy has made remarkable progress in relapsed/refractory multiple myeloma (R/R MM) treatment. Unfortunately, patients still eventually experience disease progression or relapse even after receiving anti-BCMA CAR-T therapy. At present, there are limited data on available treatment options for patients who have progressed on anti-BCMA CAR-T therapy. In this study, we evaluated the safety and efficacy of fully human anti-BCMA CAR-T (HRC0202) in seven R/R MM patients who were previously exposed to anti-BCMA CAR-T therapy. Three patients received 6.0 × 106 CAR+T cells/kg, one patient received 10.0 × 106 CAR+T cells/kg and three patients received 15.0 × 106 CAR+T cells/kg. Cytokine release syndrome (CRS) of grades 1–2 occurred in three patients (42.9%) and grade ≥3 in two patients (28.6%). Immune effector cell-associated neurotoxic syndrome (ICANS) was not observed in any of the patients. The best overall response rate (ORR) was 71.4% (5/7), with a stringent complete response/complete response (sCR/CR) achieved in three patients. The median progression-free survival (PFS) was 269 days, and median overall survival (OS) for all patients was not reached. The median peak concentration (Cmax) of HRC0202 was 30117.70 (range, 6084.35–147415.10) copies/μg DNA. This study indicated that fully human anti-BCMA CAR-T (HRC0202) is a promising treatment for R/R MM patients who relapsed or refractory from prior anti-BCMA CAR-T infusion.

Comparative Pharmacokinetic Studies of One‐Month Donepezil IM Depot and Once Daily Oral Tablet in Healthy Male Volunteers

AbstractBackgroundThis study is to evaluate the safety and tolerability of single dose of one‐month donepezil IM depot (GB‐5001) in healthy male volunteers and to compare pharmacokinetic parameters of 70mg donepezil IM depot and 10mg once daily oral tablet (Aricept®) in human.MethodIn this phase 1, a randomized, double‐blind, placebo‐controlled, dose‐escalation study, 48 healthy subjects were randomized to single dose of Aricept tablet or placebo or GB‐5001 (70mg or 140mg or 280mg) for 64 days. In this study, safety and tolerability of 70mg donepezil IM depot were examined by monitoring adverse events and vital signs. PK parameters such as AUCt, AUCinf, Cmax and Tmax were compared by measuring donepezil concentration after a single dose of 70mg IM depot and 10mg oral tablet.ResultA single dose of 70mg donepezil IM depot showed no significant adverse events and was well tolerated in healthy male volunteers. In 70mg GB‐5001, all the subjects had measurable concentrations up to 1512 h post dose. The geometric mean of PK exposure parameters are 6482.82 h*ng/mL, 6604.01 h*ng/mL and 11.40 ng/mL for AUCt(0‐1512h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 432h post dose. In 10mg oral Aricept, all the subjects had measurable concentrations up to 240 h post dose. The geometric mean of PK exposure parameters are 656.84 h*ng/mL, 751.34 h*ng/mL and 17.68 ng/mL for AUCt(0‐240h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 2.25 h post dose.ConclusionA single dose of 70mg donepezil IM depot was found to be safe and well tolerated in healthy male volunteers. The pharmacokinetic results of 70mg donepezil IM depot showed stable donepezil blood concentration for more than one month without burst drug release, and showed comparable unit dose drug exposure not lower than that of once daily 10mg oral formulation. Through the PK results for additional higher doses and multiple PK simulations, optimal once monthly dose of donepezil IM depot could be suggested which will be bioequivalent to 10mg once daily tablet.

Abstract 257: VIGAB-STAT- A Phase IIa Feasibility Trial of Irreversible GABA-Transaminase Inhibition as Adjunct Treatment of Status Epilepticus After Cardiac Arrest

Background: Effective therapeutic interventions for post-anoxic status epilepticus (PASE) are lacking. Vigabatrin (VGB) could be an attractive adjunct drug in PASE by increasing GABA availability in inhibitory synapses; however, enteral malabsorption in the post-cardiac arrest (CA) period and difficulty enrolling in the FDA mandatory registry could hinder its use in this setting. We hypothesize that CA survivors absorb VGB despite vasopressor use, concurrent enteral feeding, and regardless of gastric or post-pyloric drug delivery. Goals: Prove feasibility and study pharmacokinetics of a single enteric VGB load within 48 hours of PASE onset. Methods: We administered a single load 1125-4500 mg VGB (based on creatinine clearance; CrCl) in adults with non-traumatic CA, with electrographic SE and gastric or duodenal access. Plasma samples were collected at 0, 0.5, 1, 2, 3, 6, 12, 24, 48, 72 and 168 hours. Results: Interim results from a cohort of 6 subjects comprised of 67% male (4 of 6), 83% White (5 of 6), with a median age 62 years 22-68), median BMI 30 Kg/m 2 (20-53), and median CrCl 44cc/min (22-186) are presented. All subjects received VGB within 48h window; median VGB dose was 2250 mg (1125-4500). The median time to peak (Tmax) was 2 h (1-3); median peak concentration (Cmax) was 38.1 mcg/ml (16.7 -91.8). Median 24h VGB concentration (C24) was 9.4 mcg/ml (3.4-14.2) and half-life (T1/2) was 16 h (10-24). The AUC 0-24 value was 318 mcg*h/ml (262-1012). No significant association was found between sex or BMI and Cmax. Three out of six patients achieved EEG response following VGB load; no association with dose or concentration was noted. Conclusions: All patients achieved detectable VGB levels with peak occurring between 1-3 hours post-administration. Enteric administration of VGB does not preclude phase IIb clinical trials of VGB in PASE. Registration: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT04772547

Biomarker Correlates of Response to Ciltacabtagene Autoleucel in Patients with Relapsed or Refractory Multiple Myeloma from CARTITUDE-1, a Phase 1b/2 Open-Label Study, at the ~3 Year Follow-up

Ciltacabtagene autoleucel (cilta-cel) consists of autologous T cells genetically modified to express a two-binding domain chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells (PC) from multiple myeloma subjects. In the Phase 1b/2 CARTITUDE-1 study, cilta-cel led to early, deep, and durable responses and was approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy by FDA. Despite cilta-cel's outstanding overall response rate (97.9%) and duration of response (DOR) in RRMM patients, relapse still occurs. Biomarkers associated with this durable response and acquired resistance remain to be elucidated. We present updated correlative data from the CARTITUDE-1 study. At the ~3 year follow-up (October 2022 data cutoff), 97 patients had received a single infusion of cilta-cel (median 0.71 x10 6 cells/kg [range 0.52 x10 6-0.94 x10 6]); the median follow up was 33.4 months (range 1.5-45.2), median DOR was 33.9 months (95% CI, 25.5-not estimable [NE]) and median PFS was 34.9 months (95% CI, 25.2-NE) (Lin Y et al, ASCO 2023). Drug product (DP), baseline and on-treatment whole blood and bone marrow samples from enrolled patients were analyzed by methods including flow cytometry, MSD immunoassays, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and TCR sequencing. In CARTITUDE-1, the DP contained a mixture of transduced and non-transduced T cells; the median transduction efficiency was 16% (range 5-32%), with a balanced distribution of CAR+CD4+ and CAR+CD8+ cells, median frequency 12% (range 2-28%) and 6% (range 2-20%), respectively. Further, the DP T cell subset composition was variable but balanced between central (Tcm) and effector memory (Tem) phenotypes. CAR+ T cells expanded reaching a median peak concentration (C max of 730 cells/µL; range 3-13805 cells/µL) in blood between days 12-14 post-infusion and persisted in circulation for a median of 100 days (range 20-912 days). High efficacy (best response) and DOR were achieved despite variable CAR-T cell expansion and lack of detectable CAR-T cell persistence over time. At C max, the CD4:CD8 ratio (based on % of CAR+ cells) was 0.29, demonstrating a CAR+CD8+ T cell preferential expansion, and both CAR+CD4+ and CAR+CD8+ T cells were predominantly of a Tcm phenotype, median 95% (range 62-99.5%) and 96% (range 33-99.7%), respectively. Higher frequency of early-memory T cell phenotypes has been associated with clinical responses to CAR-T therapies in MM (Dancy et al., Blood 2018). CITE-seq analyses showed that DP characteristics such as a high CD8+ stem-like phenotype and a low CD4+ Treg-like phenotype in the CAR+ T cell compartment associated with longer DOR. Some of the most abundant clones in the DP single cell TCR data were CAR+CD8+ T cells expressing granzyme B, suggesting high cytotoxic potential. Additional bulk TCR sequencing data suggest both diversity and individual clonal expansion longitudinally after cilta-cel infusion. We also evaluated tumor and patient intrinsic characteristics at baseline. BCMA expression on bone marrow PC was prevalent and highly variable among RRMM patients; however, expression did not associate with best response or DOR. Further, high ORR was observed in patients with high-risk cytogenetics, high tumor burden (&amp;gt;= 60% bone marrow PC), or baseline plasmacytomas, although with a non-statistically significant shorter PFS. Sustained MRD negativity strongly associated with longer DOR. Conversely, patient-intrinsic characteristics associated with inflammation (CRP, ferritin, neutrophils, pro-inflammatory cytokines) correlated with shorter DOR. Treatment benefit of the magnitude seen with cilta-cel had not been reported with any other approved therapy in this setting. Correlative analyses suggest an emerging profile to help understand such outstanding clinical activity: a balanced CD4/CD8 ratio and Tcm/Tem phenotype of the manufactured DP and preferential expansion of CAR+CD8+ Tcm cells. Further, certain baseline patient-intrinsic and tumor characteristics may explain the longer DOR in the RRMM setting. These investigations help identify markers of response to cilta-cel and may lead to CAR-T cell design or manufacturing strategies that enhance drug product characteristics and thus clinical efficacy.

Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study

Nonintravenous inotropic-delivery options are needed for patients with inotropic-dependent heart failure (HF) to reduce the costs, infections and thrombotic risks associated with chronic central venous catheters and home infusion services. We developed a novel, concentrated formulation of nebulized milrinone for inhalation and evaluated the feasibility, safety and pharmacokinetic profile in a prospective, single-arm, phase I clinical trial. We enrolled 10 patients with stage D HF requiring inotropic therapy during a hospital admission for acute HF. Milrinone 60 mg/4 mL was inhaled via nebulization 3 times daily for 48 hours. The coprimary outcomes were adverse events and pharmacokinetic profiles of inhaled milrinone. Acute changes in hemodynamic parameters were secondary outcomes. A concentrated nebulized milrinone formulation was well tolerated, without hypotensive events, arrhythmias or inhalation-related adverse events requiring discontinuation. Nebulized milrinone produced serum concentrations in the goal therapeutic range with a median plasma milrinone trough concentration of 39 (17-66) ng/mL and a median peak concentration of 207 (134-293) ng/mL. There were no serious adverse events. From baseline to 24 hours, mean pulmonary artery saturation increased (60% ± 7%-65 ± 5%; P = 0.001), and mean cardiac index increased (2.0 ± 0.5 mL/min/1.73m2-2.5 ± 0.1 mL/min/1.73m2; P = 0.001) with nebulized milrinone. In a proof-of-concept study, a concentrated, nebulized milrinone formulation for inhalation was safe and produced therapeutic serum milrinone concentrations. Nebulized milrinone was associated with improved hemodynamic parameters of cardiac output in a population with advanced HF. These promising results require further investigation in a longer-term trial in patients with inotrope-dependent advanced HF.

Preliminary pharmacokinetics and patient experience of jet-injected dexmedetomidine in healthy adults.

Jet injection is a drug delivery system without a needle. A compressed liquid drug formulation pierces the skin, depositing the drug into the subcutaneous or intramuscular tissues. We investigated the pharmacokinetics and patient experience of dexmedetomidine administered using jet injection in six healthy adult study participants. This needleless jet injection device was used to administer dexmedetomidine 0.5 μg/kg to the subcutaneous tissues overlying the deltoid muscle. Serum concentrations of dexmedetomidine were assayed at approximately 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours after administration. Pharmacokinetic interrogation of concentration time profiles estimated an absorption half time for jet-injected dexmedetomidine of 21 minutes (coefficient of variation 69.4%) with a relative bioavailability assumed unity. In our samples the measured median peak (range) concentration was 0.164 μg/l (0.011-0.325 μg/l), observed in the sample taken at a median (range) of 13.5 minutes (11-30 minutes). The Richmond agitation sedation scale was used to assess the sedative effect, and scored 0 (alert and calm) or -1 (drowsy) in all participants. Five of the six participants stated they would prefer jet injection to needle injection in the future and one had no preference. The findings suggest that the use of a larger dose (>2 μg/kg) would be required to achieve the clinically relevant target concentration of 1 μg/l necessary to achieve deeper sedation (Richmond agitation sedation scale ≤3).

Association of High-Sensitivity Cardiac Troponin T With 30-Day and 5-Year Mortality After Cardiac Surgery

BackgroundThe relevance of perioperative myocardial injury (PMI) after cardiac surgery for 30-day mortality and long-term survival remains to be determined. ObjectivesThis study assessed the association of PMI after cardiac surgery, reflected by postoperative troponin release, with 30-day mortality and long-term survival after: 1) coronary artery bypass grafting (CABG); 2) isolated aortic valve replacement (AVR) surgery; and 3) all other cardiac surgeries. MethodsA consecutive cohort of 8,292 patients undergoing cardiac surgery with serial perioperative high-sensitivity cardiac troponin T (hs-cTnT) measurements was retrospectively analyzed. The relationship between postoperative hs-cTnT release and 30-day mortality or 5-year mortality was analyzed after adjustment with EuroSCORE II using a Cox proportional hazards model. hs-cTnT thresholds for 30-day and 5-year mortality were determined for isolated CABG (32.3%), AVR (14%), and other cardiac surgery (53.8%). ResultsHigh postoperative hs-cTnT levels were associated with higher 30-day mortality but not 5-year mortality. In CABG, median peak concentration of postoperative hs-cTnT was 1,044 ng/L, in AVR it was 502 ng/L, and in other cardiac surgery it was 1,110 ng/L. hs-cTnT thresholds defining mortality-associated PMI were as follows: for CABG, 2,385 ng/L (170× the upper reference limit of normal in a seemingly healthy population [URL]); for AVR, 568 ng/L (41× URL); and for other cardiac procedures, 1,873 ng/L (134× URL). hs-cTnT levels above the cutoffs resulted in an HR for 30-day mortality for CABG of 12.56 (P < 0.001), for AVR of 4.44 (P = 0.004), and for other cardiac surgery of 3.97 (P < 0.001). ConclusionsPMI reflected by perioperative hs-cTnT release is associated with the expected 30-day mortality but not 5-year mortality. Postoperative hs-cTnT cutoffs to identify survival-relevant PMI are higher than suggested in current definitions.

Population pharmacokinetics and model-based dosing optimization of teicoplanin in elderly critically ill patients with pneumonia

PurposeTo evaluate the population pharmacokinetics and pharmacodynamics of teicoplanin in elderly critically ill patients with pneumonia for optimal dosages. MethodsFifteen critically ill patients (9 men) ≥ 60 years received teicoplanin 6 mg/kg for three doses followed by standard maintenance doses (6 mg/kg q24h) with renal dosing adjustment. Serial plasma samples from all patients were analyzed simultaneously by population pharmacokinetic modeling using NONMEM. Probability of target attainment (PTA) was calculated through Monte Carlo simulations for various dosing regimens to achieve adequate systemic exposures. ResultsThe median (interquartile range, IQR) age, body mass index, and creatinine clearance (CrCl) was 75 (64–78) years, 22.5 (20.8–25.4) kg/m2, and 64 (47–106) mL/min, respectively. The median (IQR) peak and trough concentration was 46.5 (42.7–51.0) and 8.7 (7.2–9.5) mg/L. The population pharmacokinetic model showed slower clearance (CL) and larger peripheral volume of distribution (V2) in patients with reduced CrCl: CL (L/h) = 0.629 × (CrCl/64)0.656, V2 (L) = 55.7 × (CrCl/64)-0.665. Model-based simulations showed PTAs ≥85% only for higher-dose regimens (12 mg/kg) up to an MIC of 0.5 mg/L. ConclusionsStandard teicoplanin dosages for pneumonia may provide inadequate systemic exposures in elderly critically ill patients. High-dose regimens should be considered as empiric therapy or for less susceptible pathogens.

507: PLASMA BIOMARKERS AS PROGNOSTICATION IN PATIENTS RECEIVING EXTRACORPOREAL MEMBRANE OXYGENATION

Introduction: Neurological complications in VA-ECMO beget a 7-15% mortality rate; however, existing literature demonstrates that neuromonitoring reduces the rate of complications. There is an increasing need for easily measured, accurate markers that can predict neurological injury. We propose that plasma biomarkers such as Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NFL), and Tau can be utilized for prognostication of neurologic outcomes on ECMO. We hypothesised that patients with higher levels of inflammatory biomarkers will be at higher risk for neurologic complications. Methods: In this pilot prospective, cohort study, patients were consented within 24 hours of cannulation and followed over duration of VA-ECMO course. Peak concentrations of plasma biomarkers were used for analysis. Samples were taken daily for first 7 days and every other day afterwards as long as patient remained in the ICU. Outcomes were determined by the modified Rankin Scale (mRS) with a favorable outcome of mRS < 4. Statistical analyses used STATA v17 to calculate the Area Under ROC curves to determine sensitivity and specificity. Results: 20 patients were enrolled. Median age was 48.5 (41.5-62 IQR) yrs, and patients were 55% female. The median peak concentration values of GFAP, NFL, and Tau were 382.3 pg/ml (100.8-5,516.4), 8,306.7 pg/ml (2,338.9-13,577.2), and 1,278.4 pg/ml (318.7-3,447.4), respectively. There were 15 patients (75%) with unfavourable neurologic outcome at discharge, 17 patients had acute brain injury (85%), 10 patients had thromboembolic events (50%), and 14 patients had hemorrhagic events (70%). In prognostication of acute brain injury in patients, the plasma biomarkers GFAP, NFL and Tau achieved an AUC of 0.84, 0.73, and 0.73 respectively. Furthermore, GFAP, NFL and Tau achieved an AUC of 0.70, 0.81, and 0.70 for prediction of hemorrhagic events on ECMO. Conclusions: We identify three key plasma biomarkers, GFAP, NFL and Tau, that have the groundbreaking potential to assist prognostication of acute brain injury and hemorrhagic events on ECMO. We strongly recommend further research to identify feasibility and utility of novel biomarkers in the context of VA-ECMO and neurological complications to understand which combination of plasma biomarkers has the highest clinical yield.

Increasing tourniquet number has no effect on amikacin concentration within the radiocarpal joint in horses undergoing intravenous regional limb perfusion.

To determine whether IV regional limb perfusion (IVRLP) performed in the cephalic vein with a wide rubber tourniquet (WRT) applied proximal and distal to the carpus results in a higher peak concentration (Cmax) of amikacin in the radiocarpal joint (RCJ), compared with the Cmax for IVRLP using a single WRT proximal to the carpus. 7 healthy adult horses. Horses underwent IVRLP using standing sedation with 2 g of amikacin sulfate diluted to 60 mL by use of saline (0.9% NaCl) solution in the cephalic vein with 2 different tourniquet techniques; proximal WRT (P) and proximal and distal WRT (PD). Synovial fluid was collected from the RCJ at 5, 10, 15, 20, 25, and 30 minutes after IVRLP. Tourniquets were removed after the 30-minute sample was collected. Blood samples from the jugular vein were collected at 5, 10, 15, 20, 25, 29, and 31 minutes after IVRLP. Amikacin concentration was quantified by a fluorescence polarization immunoassay. Median peak concentration (Cmax) of amikacin and time to maximum drug concentration (Tmax) within the RCJ were determined. Median peak concentration in the RCJ was 1331.4 μg/mL with technique P and 683.1 μg/mL with technique PD. Median Tmax occurred at 30 minutes with technique P and 25 minutes with technique PD. No significant (Cmax, P = 0.18; Tmax, P = 0.6) difference in amikacin Cmax or Tmax between techniques was detected. Placement of 2 WRTs offers no advantage to a single proximal WRT when performing IVRLP to deliver maximal amikacin concentrations to the RCJ using IVRLP.

Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers

BackgroundIn response to the World Health Organization call for research on alternative routes for tranexamic acid (TXA) administration in women with postpartum haemorrhage, we examined the pharmacokinetics of TXA after i.v., i.m., or oral administration. MethodsWe conducted a randomised, open-label, crossover trial in 15 healthy volunteers who received i.v. TXA 1 g, i.m. TXA 1 g, or oral TXA solution 2 g. Blood samples were drawn up to 24 h after administration. Tranexamic acid concentration was measured with liquid chromatography–mass spectrometry, and the parameters of the pharmacokinetic models were estimated using population pharmacokinetics. ResultsThe median time to reach a concentration of 10 mg L−1 was 3.5 min for the i.m. route and 66 min for the oral route, although with the oral route the target concentration was reached in only 11 patients. Median peak concentrations were 57.5, 34.4, and 12.8 mg L−1 for i.v., i.m., and oral routes, respectively. A two-compartment open model with body weight as the main covariate best fitted the data. For a 70 kg volunteer, the population estimates were 10.1 L h−1 for elimination clearance, 15.6 L h−1 for intercompartmental clearance, 7.7 L for the volume of central compartment, and 10.8 L for the volume of the peripheral compartment. Intramuscular and oral bioavailabilities were 1.0 and 0.47, respectively, showing that i.m. absorption is fast and complete. Adverse events were mild and transient, mainly local reactions and low-intensity pain. ConclusionsThe i.m. (but not oral) route appears to be an efficient alternative to i.v. tranexamic acid. Studies in pregnant women are needed to examine the impact of pregnancy on the pharmacokinetics. Clinical trial registrationEudraCT 2019-000285-38; NCT 03777488.

Sex-related pharmacokinetic differences with aging.

The proportion of women increases with advanced age, but older women are often underrepresented in clinical trials. Therefore, little is known about the combined effect of sex- and age-related physiological changes on drug pharmacokinetics. We compiled clinical studies, which investigated sex-related pharmacokinetic differences both in older and young women and men. The ratio women/men was calculated for various pharmacokinetic parameters across adulthood to assess sex-related differences in drug pharmacokinetics with aging. The contribution of body weight and drug characteristics to sex-related pharmacokinetic differences were explored using analysis of variance. We found 67 studies reporting the pharmacokinetics for 56 drugs both in older and young women and men. Median peak concentration (Cmax) (interquartile range (IQR)) and drug exposure (AUC) (IQR) were 22% (8-41%) and 20% (0-39%) higher in women compared with men whereas time to peak concentration (tmax), apparent volume of distribution (VdF) and elimination half-life (t1/2) were not significantly different. Body weight and the drug main elimination pathway contributed to sex-related differences in Cmax and AUC. Relative to men, women had a modest increase in Cmax with increasing age (r = 0.19, p = 0.04). Conversely, sex-related differences in AUC remained constant with increasing age. The pharmacokinetic differences between women and men were modest and, with the exception of Cmax, remained constant with increasing age. The higher plasma concentration might be correlated to more adverse events in older women and thus, drug treatment should be started on the lower recommended dosage when appropriate particularly for drugs characterized by a narrow therapeutic index.

No Impact of Pharmacokinetics Profiles on the Clinical and Biological Response to Hydroxyurea in Children with Sickle Cell Disease

▪Hydroxyurea (HU) is an important drug for sickle cell disease (SCD) that improves clinical outcome and survival. However, its pharmacokinetics (PK) and pharmacodynamics (PD) are highly variable. HU has an excellent oral bioavailability, with half-life of 2-4 hours and renal elimination. Two oral absorption phenotypes have been identified: slow phenotype with a peak concentration reached after 60 to 120 minutes and rapid phenotype with a peak at 15 to 30 minutes. These phenotypes seem to be linked to the maximal tolerated dose of hydroxyurea and could affect the response to HU.The aim of this study was to explore the possible correlation between clinical and biological response to HU and PK and PD parameters.This study was conducted at Hôpital Universitaire des Enfants Reine Fabiola (Brussels, Belgium) and included SCD children older than 7 years, regularly followed for more than 3 years. PK samples (salivary and plasmatic) were collected at 0, 30, 60 and 180 minutes after oral HU intake. Patients have been classified as good (GR) or poor responders (PR) to HU according to the absence of recurrence of acute chest syndrome on HU and the number of vaso-occlusive crisis (VOC) and hospitalization days on HU. Changes in biological parameters were assessed after 1 year on HU. Chi square test was used for the comparison between good and poor responders on HU. Paired T test was used to compare biological effect of HU for each oral absorption phenotype and ANOVA to compare PK profile among them.Thirty-one patients have been included in this study. The characteristics of the patients are detailed in the Table 1. On HU, a significant decrease of the number of VOC and hospitalization days was observed with an improvement of biological parameters (Table 2). The numbers of VOC and hospitalization days were significantly lower in girls compared to boys on HU (0.33 vs. 0, P=0.02 and 3.17 vs. 1.33, P = 0.02 respectively). However except for reticulocyte count, biological data, age, dose of HU or PK parameters were similar in both sexes.Eighteen patients have been classified as GR (14 girls) and 13 as PR (5 girls). Their demographic characteristics and biological values (pre and on HU) were not significantly different, except a higher change of HbF level in GR compared to PR (+13% vs. +3.7% ; P=0.034). Girls had a non-significant trend to belong to the GR group (P = 0.059).The median plasmatic peak concentration (Cpmax) was 42.25mg/l (Range: 14.8-62), the median salivary peak concentration (Csmax) was 19.54 mg/l (Range: 5.03-124.43) and the median AUC was 4650mg.min/l (Range: 1197-8742). AUC was similar in both sexes (4650mg.min/l vs. 4666mg.min/l; P=0.79). Except for salivary concentration at 60 minutes, all PK parameters were not significantly different between the GR and PR (Table 3). No significant correlation was found between peak concentration (Cmax) and demographic parameters.We identified 3 absorption phenotypes with a Cpmax reached at 30, 60 and 180 minutes for rapid, intermediate and slow absorbers (Table 4). Biological changes on HU were similar among the 3 phenotypes, but did not reached statistical signification in slow absorbers (only 5 patients). 16/18 GR patients reach Cpmax at 30 and 60 minutes compared to 10/13 for PR (P=0.63). The AUC in the 3 absorption phenotypes was not significantly different (P=0.069). No correlation was found between salivary and plasmatic concentration at time-points studied.In conclusion, no correlation between the absorption phenotype and the clinical response to HU could be found. No correlation was found between AUC, Cpmax and clinical response. Nevertheless our study has limitation due to the limited sample size. Salivary measurement did not provide reliable information and cannot be used instead of plasmatic samples. The gender is the only factor identified that can predict the biological response to HU (with a trend to a better clinical response in girls) despite similar AUC and PK parameters. This finding may reflect the better adherence to treatment in girls compared to boys.The variability of the clinical response to HU remains to be elucidated. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.