Terminal Half-life Research Articles

Safety, Tolerability, and Pharmacokinetics of Long-Acting Broadly Neutralizing HIV-1 Monoclonal Antibody VRC07-523LS in Newborn Infants Exposed to HIV-1.

Vertical HIV-1 transmission despite antiretroviral therapy may be mitigated by the use of long-acting, broadly neutralizing, monoclonal antibodies (bNAb) such as VRC07-523LS. The present study was designed to determine the safety and pharmacokinetics of VRC07-523LS. VRC07-523LS, 80mg/dose, was administered subcutaneously after birth to non-breastfed (cohort 1; N = 11, enrolled in USA) and breastfed (cohort 2; N = 11, enrolled in South Africa and Zimbabwe) infants exposed to HIV-1. Breastfed infants (cohort 2) received a second 100-mg dose at 12 weeks if still receiving breastmilk. All infants received antiretroviral prophylaxis in addition to VRC07-523LS. VRC07-523LS levels were compared to VRC01 levels, as determined previously in this study. Local reactions (all grade ≤ 2) occurred after dose 1 in 18% of infants in cohort 1 and after doses 1 and 2 in 100% of infants in cohort 2. The VRC07-523LS dose at birth (mean 26mg/kg) achieved a mean ± SD plasma level of 222.3 ± 71.6 mcg/mL by 24 hours and 18.4 ± 7.2 mcg/mL at week 12, prior to dose 2. The pre-established target of ≥ 10 mcg/mL at week 12 was met in 94% of infants. The terminal half-life of VRC07-523LS was observed to be 39.2 ± 5.0 days. At week 4 and week 8, bNAb levels were significantly higher (P ≤ .002) after one dose of VRC07-523LS, compared to one dose of VRC01 (20mg/kg). No infant included in the study acquired HIV-1. VRC07-523LS was well tolerated with pharmacokinetics that support further studies of potent long-acting bNAbs together with antiretrovirals to prevent HIV-1 acquisition in infants.

Distribution, lipophilicity and tissue half-life as key factors in sulphonamide clearance from porcine tissues

Abstract Introduction Sulphonamides are some of the most widely used antimicrobial drugs in the treatment of bacterial diseases in pigs. The study was conducted to compare the total exposure of tissue to a group of active substances in a single formulation and evaluate the impact of the volume of distribution, lipophilicity and tissue half-life of sulfadimethoxine, sulphathiazole, sulphamethazine and sulphacetamide in two different veterinary drug formulations – Polisulfalent, which was preparation A, and Polisulfamid, which was preparation B. Material and Methods Each tested therapeutic preparation was administered to 15 piglets of the Polish Landrace breed. To assume general exposure expressed as the sum of all observed concentrations of all active substances, semi-log regression analyses were performed for both formulations. Results The estimated tissue half-life was 21.19 h for preparation A and 17.36 h for preparation B. The comparison of the semi-log regression parameters shows that formulation B’s Y-intercept and slope values were higher than formulation A’s. The upper-bound CI for the Y-intercept and slope value of formulation B was higher than those of formulation A, at 38.7 and 20.8%, respectively. The lower-bound CI for the Y-intercept and slope value of formulation B was also higher than those of formulation A, at 20.6 and 42.9%, respectively. Conclusion Current observations lead to the conclusion that in late-stage drug elimination, it is not the blood half-life, but rather a drug’s volume of distribution which is key in determining the clearance period, this volume being dependent on the physicochemical characteristics of the drug.

P-744. Admission Avoidance: A Protocol for Using Dalbavancin in the Emergency Department for Acute Bacterial Skin and Skin Structure Infections

Abstract Background Dalbavancin is a glycopeptide with a 14.4 day terminal half-life that has been used previously in our institution to facilitate early discharge for acute bacterial skin and skin structure infections (ABSSSI). We have expanded this program with a pharmacist-driven protocol for use in the emergency department (ED) to avoid admission in ABSSSI for selected patients. The goal of this study was to evaluate the protocol for dalbavancin use in the ED for patient selection and financial impact. Dalbavancin Emergency Department Protocol Inclusion/Exclusion criteria for assessment to receive dalbavancin Methods This was a retrospective, multi-center, study performed in a community health system from June 2022 through March 2024 of patients who presented to the ED with ABSSSI, evaluated by pharmacist and physician, and discharged directly after receiving dalbavancin. Inclusion and exclusion criteria were based on the patient's symptoms, type of infection, and comorbidities (Figure 1). Data collected included clinical signs/symptoms of infection, previous antibiotic use, history of substance abuse or methicillin-resistant Staphylococcus aureus (MRSA), renal function, and readmissions. Direct costs and reimbursement, as well as if they received patient assistance, were also tracked. The primary objective was to evaluate adherence to the protocol for use of dalbavancin in the ED. The secondary objective was to analyze the financial impact to the health system. Table 1 & Table 2 Patient Demographics & Clinical Signs/Symptoms Results A total of 57 patients met inclusion/exclusion criteria and were evaluated. Patient demographics associated with adherence to protocol are summarized in Table 1. A majority of patients had failed oral therapy and were expected to be admitted for > 3 days. Six patients (10.5%) were re-admitted within 30 days, similar to national averages. Only 2 patients self-reported as persons who inject drugs (PWID). Table 2 summarizes clinical signs/symptoms associated with diagnosis of ABSSSI for the included population. Most patients met multiple diagnostic criteria, with erythema, tenderness, & swelling all reported >75%. For the secondary objective, patients as part of the ED visit had ∼$3800 average reimbursement per patient not including direct and indirect costs of care. Conclusion Pharmacists can help identify and facilitate appropriate patients to receive dalbavancin within a structured protocol to help prevent admissions for ABSSSI. Disclosures Christopher M. Bland, PharmD, FCCP, FIDSA, BCPS, Merck: Honoraria|Nestle/Seres: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria Bruce M. Jones, Pharm.D., FIDSA, BCPS, AbbVie: Advisor/Consultant|AbbVie: Honoraria|Ferring: Honoraria|Innoviva: Honoraria|Paratek: Honoraria

P-1262. Safety and Pharmacokinetics of Ainuovirine, a Novel Non-NucleosideReverse Transcriptase Inhibitor, in Healthy Chinese Adults

Abstract Background Ainuovirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. The safety profile and pharmacokinetics of ainuovirine was characterized in healthy adults administered with single ascending dose.Table 1.Summary statistics of pharmacokinetic parameters of ainuovirine after single oral doses in healthy participants. Data are expressed in median ± standard deviation (min, max); AUC0–t, area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration; AUC0–∞, AUC from time zero to infinity; AUC_%Extrap, percentage of extrapolated AUC; Cmax, maximum plasma concentration; C24h, concentrations at 24 hours postdose; CLz/F, apparent clearance; MRT0-t, mean retention time from time zero to time of the last quantifiable concentration; MRT0-∞, MRT from time zero to infinity; Vz/F, apparent volume of distribution; T1/2z, plasma terminal half-life; Tmax, time to maximum plasma concentration; λz, elimination rate constant. Methods A single-center, open-label, single-dose escalation study was conducted among healthy Chinese adults. Thirty participants, aged from 18 to 45 years, were randomly allocated to each cohort given a single-dose ainuovirine 75, 150 or 300 mg (10 participants per cohort), respectively. Inhibitory quotient (IQ) was defined as the ratio of the clinical trough concentration (C24h) to the protein-binding adjusted 50% effective concentration (pa-EC50). Results Across all dosage groups, most adverse events were rated as mild in severity. Major reported adverse events were abnormal serum lipids and elevated liver transaminase. No rash was reported and only one participant experienced central nervous system events (150 mg dose group). Pharmacokinetic parameters are shown in Table 1 for single-dose ainuovirine. Ainuovirine was readily absorbed, with a median Tmax of approximately 3 hours. Ainuovirine exposure (Cmax and AUC) increased to a lesser extent than the dose proportionality. Median apparent terminal half-life (T1/2z) remained similar across three dose cohorts, slightly longer than 24 hours. The IQs for wild type (pa-EC50=4.78 ng/mL) were 16.8, 23.8, and 28.1 folds, respectively. Those were 2.0, 2.9, and 3.4 folds for K103N (pa-EC50=39.17 ng/mL), respectively, and 1.1, 1.5, and 1.8 folds for Y181C (pa-EC50=232.2 ng/mL), respectively. All the IQs were above 1 fold. Conclusion Ainuovirine was well tolerated and showed a dose-dependent,nonlinear pharmacokinetics. The pharmacikinetics supported once daily oral dosing regimen of ainuovirine, with candidate doses of 75 to 300 mg in subsequent dose-ranging, proof-of-concept study. Disclosures Juan Yang, M.S., Jiangsu Aidea Pharmaceutical Co., Ltd.: Honoraria Xinming Yun, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd.: Honoraria Hong Qin, MD, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd: Honoraria

P-1243. Evaluation of Single and Multiple Dose Safety and Pharmacokinetics of Ledaborbactam Etzadroxil and Ceftibuten-Ledaborbactam Etzadroxil in Healthy Volunteers

Abstract Background Ledaborbactam etzadroxil (LED-E), a novel oral prodrug that converts to the active β-lactamase inhibitor ledaborbactam (LED), is being developed in combination with ceftibuten (CTB) to address the urgent need for new oral (PO) treatments against drug-resistant gram-negative infections. Methods In part 1, healthy participants (PT) received single (100mg to 1000mg) or multiple (75mg to 500mg q8h for 10 days) PO doses of LED-E or matching placebo (PBO); PTs in Part 2 received single doses of LED-E 500mg, CBT 400mg, and LED-E+CTB 500mg+400mg; Part 3 PT received LED-E+CTB 300mg+400mg, LED-E+CTB 500mg+400mg or PBO q8h for 10 days. Serial blood and urine samples were obtained to determine single dose and steady-state plasma PK of CTB, LED-E, and LED. Safety was assessed by recording adverse events (AE), and changes in laboratory, vital signs, and ECGs. Results AUC of LED-E was ≤ 2% of exposures of LED across the dose range tested, suggesting extensive conversion of the prodrug to the active drug. LED exposures increased in a generally dose proportional manner across single LED-E doses from 100mg to 1000mg and multiple doses from 75mg to 500mg q8h. The terminal half-life of LED in plasma is approximately 11-12 h, with 30-35% accumulation of LED following q8h dosing of LED-E. Excretion in urine of LED-E derived material was 84.4% over the 8-hour dosing interval at steady state. No clinically relevant changes in the pharmacokinetics of CTB, LED, or LED-E occurred when CTB and LED-E were co-administered compared to each administered alone (Table 1). The number of participants with treatment-emergent AEs (TEAE) was similar in the LED-E (+/- CTB) (81.7%) and PBO (77.8%) groups. Headache and nausea were the most frequently reported TEAEs in LED-E dosed PTs (Table 2). Most events were mild and only 1 TEAE led to drug discontinuation. No serious adverse events or deaths occurred. No clinical relevant changes were noted in clinical labs, ECGs, or vital signs Conclusion LED exposure increased in a dose proportional manner. No clinically relevant drug-drug interaction was observed between LED and CTB When LED-E and CTB are co-administered. LED-E was safe and well tolerated when given with CTB at multiple doses up to 1500mg daily for 10 days. Disclosures Carlos Fernando de Oliveira, MD, PhD, MS, Venatorx Pharmaceuticals: Stocks/Bonds (Private Company) Mary Beth Dorr, PhD, Merck: Stocks/Bonds (Public Company)|Pfizer: Stocks/Bonds (Public Company)|Venatorx: Stocks/Bonds (Private Company) Kathryn Lowe, MS, Venatorx Pharmaceuticals: Stocks/Bonds (Private Company) Gregory A. Winchell, PhD, Certara: Advisor/Consultant|Merck: Advisor/Consultant|Venatorx: Advisor/Consultant Paul McGovern, MD, Venatorx Pharmaceuticals, Inc.: employee|Venatorx Pharmaceuticals, Inc.: Stocks/Bonds (Private Company)

P-1892. Dabbling with Dalbavancin: Implementation and Cost-savings of an Inpatient-to-Outpatient Dalbavancin Pathway

Abstract Background Dalbavancin is a lipoglycopeptide antibiotic with in vitro activity against gram-positive organisms and a terminal half-life of 14.4 days. One dose provides 7 days of therapy whereas a novel 2-dose regimen provides up to 4-6 weeks. These strategies are attractive alternatives to standard of care for patients in whom daily IV antibiotics are not feasible. There also may be a financial benefit as the dosing schedule allows for completion of therapy in the outpatient setting and can reduce hospitalization costs. Methods This study is a retrospective chart review of all patients who received dalbavancin at Tampa General Hospital. Our institution approved the use of dalbavancin at no cost to patients for vancomycin-susceptible gram-positive infections who remain hospitalized only to receive IV antibiotics. All patients received at least one 1500mg dose inpatient to save 7 days of hospitalization; some patients planned to follow up a week later in an outpatient clinic for a second 1500mg dose to save at least 4 weeks of hospitalization. Cost estimates are based on the patient’s hospitalization cost prior to receiving dalbavancin and do not include avoided implicit costs. Results From 12/13/22 to 3/31/24, 28 patients received dalbavancin; 14 (50%) planned to receive a second dose and 11 (78.6%) successfully received their dose in clinic. The majority of patients (60.7%) reported a history of injection drug use. Most infections were monomicrobial (85.7%) with S. aureus being the most common pathogen. An estimated 527 days of hospitalization were avoided, representing a cost savings of $684,712.44. The institutional drug cost for dalbavancin was $104,772, leading to an estimated net hospital cost savings of $579,940.44. The all-cause 30-day readmission or revisit rate was 28.6%, similar to reported readmission rates in this population, however the 30-day infection-related readmission or revisit rate was favorable (10.7%). Conclusion The use of dalbavancin to facilitate discharge resulted in significant cost savings without increasing infection-related readmissions. Further cost-benefit analysis on true economic impact including the reduction in nosocomial infections and avoidance of toxicities is warranted. Disclosures All Authors: No reported disclosures

Pharmacokinetic analysis on compatibility of Atractylodes macrocephala and Paeoniae radix herb pair ameliorates functional constipation model rats using microdialysis with ultra-performance liquid chromatography.

In a previous study, we found that Atractylodes macrocephala and Paeoniae radix (AM-PR) was useful for the alleviation of functional constipation (FC). However, the precise mechanism underlying the compatibility between AM and PR in the treatment of FC remains uncertain. This study aims to analyze the pharmacokinetic differences in the active ingredients in the blood of rat models with FC when applied individually and in combination with AM-PR. It also seeks to compare the changes in the content of the active ingredient when applied individually and in combination with invitro AM-PR, further in-depth investigation into its material foundation in terms of pharmacokinetics, as well as the composition of the substance. Blood microdialysis samples were collected using microdialysis technology. These samples from rats with FC were compared after administration of AM, PR, and AM-PR. The concentration of the main active ingredients was determined using the Ultra Performance Liquid Chromatography-Tunable Ultraviolet (UPLC-TUV) method. The concentration of the main active ingredients of the decoction compatibility before and after combining AM-PR was also determined using the UPLC-TUV method. Our findings reveal that upon combination, the time to maximum concentration (Tmax) of isochlorogenic acid A (ICA-A) and ataridolide II (ATR-II) Tmax was prolonged, terminal elimination half-life (T1/2) was reduced, and maximum plasma concentrations (Cmax) increased. The Tmax of ataridolide III (ATR-III) remained consistent, whereas its T1/2 and Cmax were significantly reduced. Conversely, for peoniflorin (PAE), Tmax occurred sooner, T1/2 was shortened, and Cmax increased. The Tmax for albiflorin (ALB) remained consistent, whereas T1/2 and Cmax witnessed significant increases. The area under the moment curve (AUMC) (0-t) and AUMC (0-∞) of PAE, ALB, ICA-A, ATR-II experienced an increase after AM-PR administration in rats, attributable to the heightened Cmax. In comparison to individual herb administration, the Tmax of ALB was advanced in combination, the Tmax of PAE remained unchanged, and the Tmax of ICA-A and ART-II was delayed, with an increased area under the concentration-time curve (AUC) (0-t), indicating enhanced Cmax and bioavailability. Furthermore, the dissolution rates of PAE, ICA-A, and ATR-II significantly improved after compatibility. This study partially clarifies the rationale and compatibility of AM-PR in treating FC and offers a new perspective on the pharmacokinetic interactions of AM-PR in FC treatment.

Inhibition of cap-dependent endonuclease in influenza virus with ADC189: a pre-clinical analysis and phase I trial.

ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.

Homotypic membrane-camouflaged camptothecin nanorods combining photothermal and chemotherapy for synergistic antitumor therapy.

Chemotherapy hardly achieves satisfactory therapeutic efficacy owing to the widely occurred adverse effects and drug tolerance, and the extensively investigated delivery systems suffer from complicated synthesis, low drug loading and less efficient tumor accumulation. Herein, we developed rod-shape nanocrystals to address challenges in the circulation stability, tumor targeting and therapeutic efficacy of camptothecin (CPT), a mainstay of treatments for various cancers. CPT nanorods (CNR) were coated with polydopamine (PDA) to achieve combinational chemo- and photothermal therapies (PTT) and then wrapped with cell membrane (CM) from homotypic tumor cells to obtain CNR@PDA-CM. CNR@PDA-CM retained the membrane proteins presented on 4T1 cell surface, holding the potential to decrease phagocytic uptake and selectively accumulate in tumor cells. The integration of rod shape and CM wrapping prolongs blood circulation, and CNR@PDA-CM achieves 73-fold longer terminal half-life and nearly 5-fold higher tumor accumulation than free CPT after intravenous injection. When reaching tumor sites, PDA-mediated photothermal effect accelerates CPT release and enhances drug permeability in tumors. The combination of PTT and CPT-based chemotherapy produce robust and synergistic therapeutic outcome in metastatic breast cancer, with almost compete inhibition of tumor growth and 100% mouse survival at the end of experiment. Thus, this study demonstrates a concise design of CNRs with high drug loading, desirable homotypic targeting, synergistic antitumor efficacy to potentially provide new insight for effective treatment of metastatic cancers.

Clinical Pharmacokinetics of Psilocin After Psilocybin Administration: A Systematic Review and Post-Hoc Analysis.

Psilocybin is currently being extensively studied as a potential therapeutic agent for multiple psychiatric disorders. Here, a systematic literature review of all published pharmacokinetic data on the pharmacologically active metabolite of psilocybin, psilocin, is presented. The review includes clinical studies that reported pharmacokinetic data and/or parameters after psilocybin administration in humans. In addition, raw pharmacokinetic data from these studies was requested and/or extracted to further compare results across studies. In total, 309 publications were identified, of which 19 publications were ultimately included, which covered 12 unique clinical datasets. Except for one study that investigated intravenous psilocybin, all included studies administered psilocybin orally. Psilocybin acts as a pro-drug and is rapidly absorbed and transformed to psilocin after oral administration. In the majority of studies, unconjugated psilocin was measured while some also measured conjugated and total concentrations. Psilocin's biphasic concentration-time profiles demonstrates fast and extensive disposition with an apparent distribution volume of 505-1267 L and a terminal half-life of 1.23-4.72 h. Only 1.5-3.4% of the dose is excreted as psilocin in urine. Psilocin is mainly transformed to 4-hydroxyindole-3-acetic acid and in less amounts to conjugated psilocin, where 4-hydroxyindole-3-acetic acid formation may occur prior to systemic psilocin absorption. Information on the absolute bioavailability of psilocin was limited, and estimated at 55% in one study. No covariates nor food effects have been reported, based on four studies with known fasting status. Overall, we found the pharmacokinetic parameters of psilocin to be consistent between studies. This review may guide the further clinical development of psilocybin-based therapies.

Impact of Sotorasib, a KRAS G12C Inhibitor, on the Pharmacokinetics and Therapeutic Window of Digoxin, a P-Glycoprotein Substrate.

Sotorasib is a small-molecule Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C inhibitor indicated for the treatment of KRAS G12C-driven cancers. KRAS G12C is a common mutation in solid tumors, including non-small cell lung cancer. In vitro studies suggested that sotorasib is a weak inhibitor of P-glycoprotein transporter. Digoxin is a known substrate for P-glycoprotein. The primary objective of this study was to assess the impact of sotorasib on digoxin pharmacokinetics in healthy subjects. This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 0.5mg of digoxin on Day 1 and 960mg of sotorasib followed by 0.5mg of digoxin on Day 7. Blood samples for digoxin pharmacokinetics were collected before dosing and up to 144hours after the digoxin dose. Digoxin median time to maximum observed plasma concentration and mean terminal half-life were similar following coadministration of digoxin with sotorasib compared with those of digoxin alone. Geometric mean digoxin area under the concentration-time curve from time 0 extrapolated to infinity following coadministration of digoxin with sotorasib (40.3h•ng/mL) was similar to that of digoxin alone (33.2h•ng/mL). Geometric mean digoxin maximum observed plasma concentration following coadministration of digoxin with sotorasib (3.64ng/mL) was higher compared with that of digoxin alone (1.90ng/mL). Coadministration of digoxin and sotorasib did not impact sotorasib exposure. Single doses of 0.5mg of digoxin were safe and well tolerated when administered alone or coadministered with 960mg of sotorasib. Coadministration of digoxin with a single dose of sotorasib increased digoxin area under the concentration-time curve from time 0 extrapolated to infinity and maximum observed plasma concentration by factors of 1.21 and 1.91, respectively, compared with digoxin alone.

Pharmacokinetics of cisplatin in the systemic versus hyperthermic intrathoracic or intraperitoneal chemotherapy

ObjectiveTo compare the pharmacokinetics and adverse effects of cisplatin administered via intravenous infusion for systemic chemotherapy (SC) versus injection into the perfusate during hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC).MethodsTotal 60 patients who received SC, HITHOC, or HIPEC in the Department of Oncology, Tangdu Hospital, were enrolled into this study. After administering same dose of cisplatin (40 mg) via either intravenous infusion (SC group) or injection into the perfusate during the HITHOC or HIPEC procedure, concentration of cisplatin in the plasma as well as in the hyperthermic perfusate at various time points was quantified by HPLC analysis. The area under the plasma or perfusate concentration–time curve over the last 24h dosing interval (AUC0–24h), mean residence time over the 24 h (MRT0–24h), terminal elimination half-life (t1/2z), time to peak concentration (Tmax), apparent clearance (Clz/F), and peak concentration (Cmax) in the perfusate and plasma were compared.ResultsIn the perfusate, the AUC0–24h (64.32 ± 27.12 µg/mL·h) and Cmax (21.62 ± 5.88 µg/mL) were significantly higher in the HITHOC group compared to that in the HIPEC group (31.68 ± 13.29 µg/mL·h and 16.96 ± 5.54 µg/mL, respectively, p ≤ 0.01). In contrast, MRT0–∞, t1/2z, and Clz/F were significantly lower in the HITHOC group compared to that in the HIPEC group (p < 0.01). In the plasma, average AUC0–24h and Cmax of the HITHOC group were 2.57 ± 0.55 µg/mL·h and 0.26 ± 0.08 µg/mL, respectively, which were significantly lower than that of systemic chemotherapy (SC) group (3.26 ± 0.56 µg/mL·h and 0.69 ± 0.14 µg/mL, respectively, p < 0.01), but no difference compared to that of HIPEC group (3.02 ± 0.52 µg/mL·h and 0.40 ± 0.15 µg/mL, respectively, p > 0.05). In contrast, MRT0-24h and Tmax in the plasma of HITHOC group were significantly longer compared to that of SC group (p < 0.05), but no significant difference compared to that of HIPEC group (p > 0.05). Absolute bioavailability of cisplatin in the thoracic (HITHOC group) and abdominal (HIPEC group) cavities was 20 and 10 times higher than that in the blood administered intravenously (SC group), respectively. There was no significant difference in the incidence of adverse events among the three groups (p < 0.05).ConclusionThe current study demonstrated that, in the perfusate, AUC0–24h and Cmax of cisplatin was significantly higher in the group of HITHOC compared to that of HIPEC, and that, in the plasma, AUC0–24h and Cmax of cisplatin was lower in the group of HITHOC compared to that of HIPEC or SC group. This study provided pharmacokinetic evidence to further support the concept that topical application of chemotherapeutic drug through minimally invasive HITHOC or HIPEC may enhance local exposure compared to systemic chemotherapy for the patients with malignant pleural effusion or ascites.

Population Pharmacokinetics of Epcoritamab Following Subcutaneous Administration in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE® NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL. Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling. Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (tmax) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics. Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal impairment, or mild hepatic impairment. The risk of immunogenicity was low. These are the first published results of population pharmacokinetic modeling for epcoritamab.

Lack of Clinically Meaningful Effect of Cariprazine on the Pharmacokinetics of a Combined Oral Contraceptive.

Cariprazine (CAR) is a potent dopamine receptor partial agonist antipsychotic approved by the EMA and the FDA. To address the uncertainty regarding the effectiveness of hormonal contraceptives during CAR co-administration and whether a second barrier method is necessary, a drug-drug interaction study with an oral contraceptive was conducted post-approval. The phaseI, fixed-sequence multicenter study involved two periods with 24 patients with schizophrenia, aiming to evaluate the effect of CAR on the pharmacokinetics (PK) of a combined oral contraceptive (COC) containing 30μg ethinylestradiol (EE) and 150μg levonorgestrel (LNG). In periodA, a single dose of COC alone was administered on day1. In periodB, the highest therapeutic dose of 6mg CAR was administered once daily from day4, and a second dose of COC was given concomitantly on day31. Overall, CAR had no clinically meaningful effect on the PK of the COC. The terminal half-life and the time of maximum plasma concentration of EE and LNG were not altered by CAR co-administration. The highest difference observed was a decrease of 14% in the maximum plasma concentration of EE, with only slight deviation of the 90% confidence interval (CI) of the test/reference ratio (77.09-96.81) from the generally accepted bioequivalence range of 80-125%, which is not considered clinically relevant. Confidence intervals of all other exposure measures were within the 80-125% range for both EE and LNG. According to these results, hormonal contraceptives can be considered effective during CAR treatment. Trial registration number (EudraCT) 2018-003722-80.

PHARMACOKINETICS OF CEFTAZIDIME IN SIGNAL CRAYFISH (PACIFASTACUS LENIUSCULUS) FOLLOWING A SINGLE DOSE.

Crustaceans are housed in zoos and aquariums and have also gained importance in the private sector and food industry. Shell lesions are common and often attributed to bacterial infections. However, few controlled studies have been performed evaluating antibiotics in crustaceans. This study assessed the pharmacokinetics of a single dose of ceftazidime (22 mg/kg) given by IM or IV injection in wild-caught signal crayfish (Pacifastacus leniusculus). Pharmacokinetic parameters were calculated by noncompartmental analysis of sparse data. Maximum ceftazidime hemolymph concentration following IM administration was 124.6 ± 14.7 µg/mL and Tmax was 5 min, with 80% bioavailability. Following IV administration, the extrapolated maximum concentration of ceftazidime, (C [0]), was 581.4 µg/mL. Ceftazidime was last detected at 72 hr and 120 hr post IM and IV administration, respectively. Terminal half-life was 8.03 hr and 10.3 hr after IM and IV administration, respectively. Results suggest that both routes have the capacity to reach a maximum hemolymph concentration quickly in signal crayfish. Moreover, ceftazidime was maintained above a concentration of 4 µg/mL, a published minimal inhibitory concentration for Vibrio spp., for 24 hr for both IM and IV routes. Therefore, ceftazidime may be useful for infections with susceptible Vibrio spp. in signal crayfish.

First-in-Human Study of 23ME-00610, an Antagonistic Antibody for Genetically Validated CD200R1 Immune Checkpoint, in Participants with Advanced Solid Malignancies.

In this phase 1 portion of a first-in-human phase 1/2a study (NCT05199272), 23ME-00610 was evaluated in participants with advanced solid malignancies to determine its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Exploratory biomarkers were evaluated to examine potential correlates of efficacy and safety. Eligible participants (≥18 years) were administered 23ME-00610 intravenously every 3 weeks (Q3W) using an accelerated titration design followed by a traditional 3 + 3 design, with an initial dose level of 2 mg. Twenty-eight participants were enrolled across seven cohorts and received a median of four cycles of 23ME-00610. No treatment-related serious adverse events (AE) were observed, and the maximum tolerated dose was not reached. Overall, the PK of 23ME-00610 was linear and dose proportional for doses ≥60 mg, with a median terminal half-life of 13 days at 1,400 mg. Peripheral saturation of CD200R1 was observed for doses ≥60 mg. Immune-related AEs, including rash, pruritus, and hypothyroidism, were predicted by phenome-wide association studies and observed for doses ≥60 mg. A confirmed partial response was observed in a participant with well-differentiated pancreatic neuroendocrine cancer whose tumor was among those with the highest tumor CD200 expression. 23ME-00610 has mild-to-moderate on-target AEs and PK/PD consistent with tumor target saturation and dosing every 3 weeks. The trend for clinical benefit in participants with tumor CD200 expression suggests that 23ME-00610 inhibits CD200R1 signaling and may reverse CD200-mediated immune evasion. Based on PK/PD, safety, and preliminary antitumor activity, 1,400 mg Q3W was selected as the dose for further study. Genome-wide association studies (GWAS) of the 23andMe genetic database identified CD200R1 as a promising therapeutic target for cancer. This phase 1 study of 23ME-00610, a CD200R1 antagonist IgG1, showed acceptable safety and tolerability, PK supporting Q3W dosing, and PD and preliminary clinical activity supporting an initial recommended phase 2 dose of 1,400 mg.

Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non-human primate studies and clinical trials.

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre-clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13-week recovery period. In healthy humans receiving 1-25 mg of obicetrapib, the mean terminal half-life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6-fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post-treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half-life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.

The Effect of Extracorporeal Membrane Oxygenation on the Pharmacokinetics of Dexmedetomidine Hydrochloride.

Our objective was to explore the effects of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics of dexmedetomidine hydrochloride via vitro and in vivo experiments DESIGN: A single-center animal investigation. An experimental animal facility in a tertiary hospital. Eighteen male Landrace pigs. For the in vitro experiment, ECMO circuits were primed with whole blood solutions of dexmedetomidine at different concentrations and ran ex vivo. The adsorption rates of dexmedetomidine hydrochloride in ECMO circuits and control glass tubes were compared at 60 minutes, 5 hours, and 10 hours after the start of the in vitro experiment. In the in vivo experiment, 12 Landrace pigs were randomly allocated to the venovenous ECMO group or the control group. Dexmedetomidine hydrochloride (1 μg/kg) was administered to both groups. Blood samples were collected at 0 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 5 hours, 7 hours, and 10 hours after administration. The plasma concentrations of dexmedetomidine were measured, and pharmacokinetic analysis was conducted in both groups. The results revealed no significant difference in adsorption rates of dexmedetomidine hydrochloride in ECMO circuits at 60 minutes and 5 hours, but differences were observed at 10 hours. In vivo experiment, pharmacokinetic analysis revealed no significant difference in the area under the curve (AUC0-t), AUC0-∞, distribution half-life, elimination half-life, clearance, apparent volume of distribution, mean residence time or peak drug concentrations between the 2 groups (p > 0.05). The ECMO circuit had an adsorption effect on dexmedetomidine hydrochloride, but this effect was not sufficient to impact the in vivo pharmacokinetics of dexmedetomidine significantly. The effect of ECMO on the pharmacokinetics of dexmedetomidine hydrochloride was not significant.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral allosteric TYK2 inhibitorESK-001 using a randomized, double-blind, placebo-controlled study design.

ESK-001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune-mediated diseases. In 2 phase I studies, a first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple-dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK-001 in healthy participants using a randomized, double-blind, placebo-controlled study design. ESK-001 was rapidly absorbed with systemic exposures generally increasing dose-proportionally across all cohorts. The mean terminal half-life ranged from 8 to 13 h with no to minimal accumulation of ESK-001 following q.d. doses and ~2-fold accumulation following Q12 doses. Less than 1% of unchanged ESK-001 was eliminated in urine. ESK-001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose-dependent inhibition of Type I IFN-induced genes and SIGLEC1, a novel TYK2-responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK/PD relationship was demonstrated. There were no deaths, serious treatment-emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK-001 was generally safe and well-tolerated in healthy participants, showed linear dose-dependent PK characteristics, and maximally inhibited TYK2-dependent pathways with a predictable concentration-dependent PK/PD relationship. These findings were used to select the dose range of ESK-001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK-001 in other TYK2-mediated diseases.

Detection of levamisole and its metabolites in horses after oral levamisole administration over seven days.

Levamisole is a regulated substance sometimes administered to racehorses to treat equine protozoal myelitis. Metabolites include compound II, aminorex, and pemoline. Aminorex and pemoline are Horseracing Integrity and Safety Authority-banned substances. Previous studies have examined single doses of the drug. This study examined the disposition of levamisole after 7 days of dosing. 6 healthy Thoroughbred geldings. Horses were treated with 500 mg (approx 0.91 to 1 mg/kg) of compounded levamisole hydrochloride paste PO every 12 hours for a total of 13 doses over 7 days. Serum and urine samples were analyzed for levamisole and its metabolites over a 28-day period. The terminal half-life of levamisole in serum was variable between horses. Following the last dose of levamisole on day 7, serum levamisole levels took 3 to 14 days (days 10 to 21) to fall below the limit of detection (LOD) in 5 of 6 horses. Serum from 1 horse remained over LOD on the last testing day (day 28). In urine, following the final dose (day 7), levamisole was below LOD on day 13 (6 days after final dose) and aminorex was below LOD on day 10 (3 days after final dose). Compound II was above LOD in 4 of 5 horses sampled on the last sampling day (day 28). Levamisole and its metabolites can be detected for variable lengths of time in horses, with detection lasting for days to weeks following multiple doses. This study supports the Racing Medication and Testing Consortium Advisory on levamisole, which suggests that clearance sample testing should be conducted on treated horses to verify elimination of levamisole and its metabolites.