Geometric Mean Peak Research Articles

A loading dose of clofazimine to rapidly achieve steady-state-like concentrations in patients with nontuberculous mycobacterial disease.

Clofazimine is a promising drug for the treatment of nontuberculous mycobacterial (NTM) diseases. Accumulation of clofazimine to reach steady-state plasma concentrations takes months. A loading dose may reduce the time to steady-state-like concentrations. We evaluated the pharmacokinetics (PK), safety and tolerability of a loading dose regimen in patients with NTM disease. Adult participants received a 4-week loading dose regimen of 300 mg clofazimine once daily, followed by a maintenance dose of 100 mg once daily (combined with other antimycobacterial drugs). Blood samples for PK analysis were collected on three occasions. A population PK model for clofazimine was developed and simulations were performed to assess the time to reach steady-state-like (target) concentrations for different dosing regimens. Twelve participants were included. The geometric mean peak and trough clofazimine concentrations after the 4-week loading phase were 0.87 and 0.50 mg/L, respectively. Adverse events were common, but mostly mild and none led to discontinuation of clofazimine. Our loading dose regimen reduced the predicted median time to target concentrations by 1.5 months compared to no loading dose (3.8 versus 5.3 months). Further time benefit was predicted with a 6-week loading dose regimen (1.4 versus 5.3 months). A 4-week loading dose regimen of 300 mg once daily reduced the time to target clofazimine concentrations and was safe and well-tolerated. Extending the loading phase to 6 weeks could further decrease the time to target concentrations. Using a loading dose of clofazimine is a feasible strategy to optimize treatment of NTM disease. NCT05294146.

Geospatial Mapping and Seasonal Profiling of Urinary Schistosomiasis in Ase-Niger River Settlements: A Data-Driven Population-Base Study in Delta State, Nigeria.

This study is aimed to determine the geospatial, seasonal, age and gender prevalence and intensity of UgS; and to establish disease maps in the Ase-Niger River communities for effective drug administration. This study employed a 24 months longitudinal study design for parasitological investigations in 11 riparian communities of the Ase-Niger River basin, taking into cognizance their GPS locations imported into QGIS software for schistosomiasis mapping. A total of 7,219 urine samples with WHO structured questionnaires were retrieved and subjected to parasitological evaluation using swinnex urine filtration techniques. An overall prevalence of 48.10% was established. Geospatially, prevalence ranges from 34.27% (Ivrogbo) to 52.29% (Ase) with seasonal significant difference (p < 0.05) accounting for 76.19% of the total variance. Ashaka had the highest prevalence for both males (55.73%) and females (53.32%) with significant difference in the study sites (p < 0.05) accounting for 96.47% of the total variance. Age-group 11-20 years consistently maintain a high prevalence at all sites. The peak geometric mean intensity of 105.69 was obtained in the dry season at Lagos Iyede. Ashaka, Igbuku, Iyede-Ame, and Onogboko had heavy-intensity levels in both seasons. Overall, the intensity was lower during the wet season than the dry season, with significant variations (p < 0.05) at Awah and Itobi-Ige. Geospatial prevalence and intensity have a robust and strong positive correlation (r = 0.7178; p = 0.0129), with 51.53% of intensity variability being influenced by prevalence (R2 = 0.5153). UgS is a significant public health issue in the Ase-Niger River basin, with prevalences surpassing the national average of 29.0% which calls for MDA in these settlements.

Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 μg/mL (25.2, 33.4), 58.5 μg/mL (49.4, 69.3), and 257.2 μg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 μg/mL (8.8, 13.3) and 22.8 μg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 μg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 μg/mL (2.5, 4.6), 6.5 μg/mL (5.6, 7.5), and 27.2 μg/mL (23.9, 31.0) with IV dosing; 0.97 μg/mL (0.65, 1.4) and 3.1 μg/mL (2.2, 4.3) with SC dosing, and 2.6 μg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

#2547 Humoral response to COVID vaccine and infection is intact during sibeprenlimab treatment of IgAN: data from the ENVISION trial

Abstract Background and Aims In the Phase 2 placebo-controlled ENVISION trial, the APRIL (A Proliferation Inducing Ligand) inhibitor sibeprenlimab significantly decreased proteinuria and stabilized estimated glomerular filtration rate decline in patients with immunoglobulin A nephropathy (IgAN) [1]. A substudy was conducted to evaluate the humoral response to SARS-CoV-2 mRNA vaccination and infection. Here, we report the unblinded analysis of COVID outcomes in the overall and substudy populations of ENVISION. Method Patients enrolled in ENVISION (NCT04287985) received 12 monthly intravenous infusions of sibeprenlimab (2, 4, or 8 mg/kg) or placebo and were followed for 16 months after the first dose of study drug. Recognized COVID infection (reported as an adverse event [AE]) and vaccination data were recorded for all patients. For patients in the substudy, serum antibody responses to SARS-CoV-2 spike and nucleocapsid proteins were measured monthly using a validated Meso Scale Discovery V-PLEX SARS-CoV-2 Panel 24 multiplex assay. Vaccine responses among those who received a primary two-dose mRNA COVID vaccine series, with no recent or concurrent COVID infection, were evaluated. Peak post-vaccine serum SARS-CoV-2 receptor-binding domain (RBD) immunoglobulin G (IgG) titers were reported in World Health Organization binding antibody units (BAU)/mL. Slopes of RBD IgG decline curves were used to generate estimates of time above a protective threshold of 300 BAU/mL. Welch's two-sample t-test was applied to log-transformed peak RBD titers for significance testing. COVID infection–induced antibody responses and severity of COVID symptoms were also assessed. In substudy patients, retrospective serologic diagnosis of COVID infection was established when simultaneous elevation of nucleocapsid and spike antibody titers, unexplained by vaccine history, was observed. Results Among 155 patients who received sibeprenlimab (n = 117) or placebo (n = 38), 56 (36.1%) had COVID infection reported as an AE during the study (Table 1). Overall, proportionally fewer sibeprenlimab recipients (33.3%) had a reported COVID AE compared with placebo recipients (44.7%). Two patients (one each in the sibeprenlimab and placebo groups) were hospitalized with serious COVID AEs in accordance with local management protocols; none were admitted to intensive care or mechanically ventilated and there were no COVID-related deaths. The majority of COVID AEs were of mild severity, regardless of treatment/dosing arm. In the serology substudy (n = 74), symptomatic COVID (reported as an AE) occurred in 47.3% of all patients. With the addition of serologic diagnoses (in the absence of AEs), the overall rate of COVID infection increased to 68.9%. Asymptomatic COVID was identified in 1 of 15 (6.7%) placebo recipients versus 15 of 36 (41.7%) sibeprenlimab recipients, raising the possibility that patients treated with sibeprenlimab may have had attenuated symptom presentation compared with patients who received placebo. COVID seroconversion rates were 100% and peak RBD IgG antibody titers following primary mRNA vaccination exceeded the protective threshold of 300 BAU/mL in all patients (Fig. 1a), with higher geometric mean peak titers in placebo (4670 BAU/mL) compared with sibeprenlimab (1700 BAU/mL) recipients (p = 0.005). The rate of decline of peak RBD IgG titers after mRNA vaccination (in patients with ≥1 dose without confounding subsequent vaccination or infection) was similar between groups (Fig. 1b), with modeled time above the 300 BAU/mL threshold of 192 and 174 days in the sibeprenlimab and placebo groups, respectively. Conclusion COVID-specific antibody responses to vaccination or infection were preserved in patients with IgAN treated with sibeprenlimab. The possibility that COVID symptom presentation may have been modulated by sibeprenlimab warrants further investigation.

Long-term immunogenicity and safety of heterologous boosting with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants who had received two or three doses of inactivated vaccine.

The emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs booster vaccination. We evaluated the long-term safety and immunogenicity of heterologous boosting with a SARS-CoV-2 messenger RNA vaccine SYS6006. A total of 1000 participants aged 18 years or more who had received two (Group A) or three (Group B) doses of SARS-CoV-2 inactivated vaccine were enrolled and vaccinated with one dose of SYS6006 which was designed based on the prototype spike protein and introduced mutation sites. Adverse events (AEs) through 30 days and serious AEs during the study were collected. Live-virus and pseudovirus neutralizing antibody (Nab), binding antibody (immunoglobulin G [IgG]) and cellular immunity were tested through 180 days. Solicited all, injection-site and systemic AEs were reported by 618 (61.8%), 498 (49.8%), and 386 (38.6%) participants, respectively. Most AEs were grade 1. The two groups had similar safety profile. No vaccination-related SAEs were reported. Robust wild-type (WT) live-virus Nab response was elicited with peak geometric mean titers (GMTs) of 3769.5 (Group A) and 5994.7 (Group B) on day 14, corresponding to 1602.5- and 290.8-fold increase versus baseline, respectively. The BA.5 live-virus Nab GMTs were 87.7 (Group A) and 93.2 (Group B) on day 14. All participants seroconverted for WT live-virus Nab. Robust pseudovirus Nab and IgG responses to wild type and BA.5 were also elicited. ELISpot assay showed robust cellular immune response, which was not obviously affected by virus variation. In conclusion, SYS6006 heterologous boosting demonstrated long-term good safety and immunogenicity in participants who had received two or three doses of SARS-CoV-2 inactivated vaccine.

Safety and immunogenicity of primary vaccination with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants aged 18 years or more: Two randomized, observer-blinded, placebo-controlled and dose-escalation phase 1 clinical trials

ABSTRACT Vaccination plays a key role in preventing morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the safety and immunogenicity of a SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine SYS6006. In the two randomized, observer-blinded, placebo-controlled phase 1 trials, 40 adult participants aged 18–59 years and 40 elderly participants aged 60 years or more were randomized to receive two doses of SYS6006 or placebo (saline). Adverse events (AEs) were collected through 30 days post the second vaccination. Immunogenicity was assessed by live-virus neutralizing antibody (Nab), spike protein (S1) binding antibody (S1-IgG), and cellular immunity. The result showed that 7/15, 9/15 and 4/10 adult participants, and 9/15, 8/15 and 4/10 elderly participants reported at least one AE in the 20-µg, 30-µg and placebo groups, respectively. Most AEs were grade 1. Injection-site pain was the most common AE. Two adults and one elder reported fever. No vaccination-related serious AE was reported. SYS6006 elicited wild-type Nab response with a peak geometric mean titer of 232.1 and 130.6 (adults), and 48.7 and 66.7 (elders), in the 20-µg and 30-µg groups, respectively. SYS6006 induced moderate-to-robust Nab response against Delta, and slight Nab response against Omicron BA.2 and BA.5. Robust IgG response against wild type and BA.2 was observed. Cellular immune response was induced. In conclusion, two-dose primary vaccination with SYS6006 demonstrated good safety and immunogenicity during a follow-up period of 51 days in immunologically naive population aged 18 years or more. (Trial registry: Chictr.org.cn ChiCTR2200059103 and ChiCTR2200059104)

Chikungunya virus virus-like particle vaccine is well tolerated and immunogenic in chikungunya seropositive individuals

In a phase 2 safety and immunogenicity study of a chikungunya virus virus-like particle (CHIKV VLP) vaccine in an endemic region, of 400 total participants, 78 were found to be focus reduction neutralizing antibody seropositive at vaccination despite being ELISA seronegative at screening, of which 39 received vaccine. This post hoc analysis compared safety and immunogenicity of CHIKV VLP vaccine in seropositive (n = 39) versus seronegative (n = 155) vaccine recipients for 72 weeks post-vaccination. There were no differences in solicited adverse events, except injection site swelling in 10.3% of seropositive versus 0.6% of seronegative recipients (p = 0.006). Baseline seropositive vaccine recipients had stronger post-vaccination luciferase neutralizing antibody responses versus seronegative recipients (peak geometric mean titer of 3594 and 1728, respectively) persisting for 72 weeks, with geometric mean fold increases of 3.1 and 13.2, respectively. In this small study, CHIKV VLP vaccine was well-tolerated and immunogenic in individuals with pre-existing immunity.ClinicalTrials.gov Identifier: NCT02562482.

#3347 COVID VACCINE RESPONSES DURING SIBEPRENLIMAB TREATMENT OF IGA NEPHROPATHY (IGAN): AN INTERIM ANALYSIS

Abstract Background and Aims ENVISION, an ongoing global P2 trial of sibeprenlimab, a mAb that neutralizes A Proliferation Inducing Ligand (APRIL) for the treatment of IgAN, previously reported an interim 43% placebo (pbo)-adjusted reduction from baseline in 24-hour uPCR at 9 months. The trial has been conducted through the ongoing COVID pandemic. To assess the effect of sibeprenlimab on COVID-risk, infection and vaccination (vac) data were recorded for all subjects. For consenting substudy subjects (SS) (n = 72), serologic responses to SARS-CoV2 proteins were measured monthly. Method Serum IgG antibodies specific for SARS-CoV-2 antigens were quantified using Meso Scale Discovery (MSD) V-PLEX SARS-CoV-2 Panel 24, a validated multiplexed assay. IgG levels were reported in WHO binding antibody units (BAU)/mL. Peak Receptor Binding Domain (RBD) IgG antibody titers were evaluated for SS following primary (2-dose) mRNA vaccination. Slopes of IgG RBD decline were utilized to generate preliminary estimates of time above protective threshold. A Welch two-sample t-test was applied to the log-transformed peak RBD titer values for significance testing. Results Among 155 IgAN patients enrolled and followed for 16 months (with 12 monthly sibeprenlimab or pbo infusions) between August 2020 and the present, COVID infection was reported in 55 overall. Two patients were hospitalized in accordance with standard local COVID protocols; none were admitted to ICU or mechanically ventilated and there were no fatalities. All other episodes of COVID infection were considered to be of mild or moderate severity (treatment status remains blinded for AE evaluation). COVID vaccination was administered to 46 SS; including 34 recipients of mRNA vaccines only (1, 2, 3 or 4 doses). There were no identified IgAN disease flares following vaccinations. Parameters characterizing IgG RBD titer were obtained from subjects receiving a 2-dose mRNA primary vaccination with sufficient data, excluding subjects with confounding COVID infection at the time of vaccination (n = 22). All subjects achieved a peak titer of &amp;gt;935 BAU/mL, with similar kinetics between arms. Geometric mean peak RBD IgG antibody level (Fig. 1) following vaccination was higher in pbo recipients (5600 BAU/mL) vs Sibeprenlimab (2410 BAU/mL) (p = 0.033). RBD IgG decline post mRNA vaccination (in any patient with at least one mRNA dose without confounding subsequent vac or infection) was evaluable in 28 SS. Rates of decline were similar between groups (Fig. 2), with comparable modeled time above an arbitrary protective threshold of 300 BAU/mL (∼ 5-6 months, data not shown). In addition, there was no evidence that sibeprenlimab impeded robust humoral immune responses to actual infection. Conclusion Sibeprenlimab is a promising immunomodulatory therapy for treatment of IgAN. COVID-specific vaccine and infection-induced humoral immune responses were preserved during Sibeprenlimab therapy.

P748 Pharmacokinetics, relative bioavailability, and dose proportionality of a tablet formulation of the sphingosine 1-phosphate-1 receptor modulator VTX002 (formerly OPL-002)

Abstract Background VTX002 is an oral selective sphingosine 1-phosphate-1 receptor (S1P1R) modulator in clinical development for treatment of ulcerative colitis (UC). Single and multiple doses of a spray-dried dispersion (SDD) oral suspension of VTX002 were well-tolerated up to 45 mg in a phase 1 study in healthy participants and were accompanied by dose proportional reductions in lymphocyte counts, an expected pharmacodynamic outcome of treatment.1 A separate phase 1 study compared the pharmacokinetics (PK) and pharmacodynamics of the SDD oral suspension and a tablet formulation of VTX002. Methods Healthy adult participants (N=12) were randomised (4 per dose group) in an open-label 3-way crossover study to receive single oral doses of 5 mg or 20 mg VTX002 tablets, or 20 mg VTX002 SDD suspension followed by at least a 1-week washout between each dose as shown in Fig. 1. Study assessments included: VTX002 plasma concentrations, PK parameters, change from baseline in absolute lymphocyte count (ALC), and adverse events (AE). Results A total of 10 participants completed the study. Mean plasma VTX002 concentrations were greatest with a single oral dose of 20 mg VTX002 SDD suspension (Fig. 2). The geometric mean peak (Cmax) and total (AUCinf) exposure to VTX002 were lower with the 5 mg (dose normalized to 20 mg tablet) and 20 mg VTX002 tablets compared to the 20 mg VTX002 SDD suspension (Table 1). Geometric mean ratios for the tablet and SDD formulations of VTX002 are shown in Table 2. Maximum percent (SD) reduction in ALC from baseline was greatest for the 20 mg VTX002 SDD suspension and was observed at 6 hours post-dose both for the SDD suspension and the 20 mg VTX002 tablet (59.9% [11.0%] and 51.6% [9.4%], respectively). The maximum percent reduction in ALC from baseline for the 5 mg VTX002 tablet was 22.4% (9.2%) which occurred 2 hours post-dose. A total of 23 AEs were reported; of which 19 were considered mild, and 4 were moderate. Conclusion All doses and formulations of VTX002 were well-tolerated and associated with ALC reductions. Data from this relative bioavailability study was used to convert the results from the prior phase 1 multiple ascending dose study performed with VTX002 SDD suspension to AUC equivalent tablet doses and enable tablet dose selection for phase 2. A phase 2 study of VTX002 tablets for treatment of UC is underway (ClinicalTrials.gov Identifier:NCT05156125). 1Luo A, et al. 2020 Gastroenterology. 2020;158(6):S1188.

Pharmacokinetics and Pharmacodynamics of Nipocalimab Administered at Different Rates of Intravenous Infusion in Healthy Participants: Results of a Phase 1 Placebo-Controlled Single-Dose Study

Background: Warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune condition driven by autoantibodies that can significantly impact a patient's quality of life. wAIHA is characterized by the premature destruction of red blood cells (RBCs) in the presence of autoantibodies which preferentially bind to RBCs at 37°C. There is currently no approved treatment for wAIHA. Patients with severely symptomatic anemia are typically managed with corticosteroids and rituximab, both of which are associated with potential relapse and adverse events. Nipocalimab, which is in clinical development for the treatment of wAIHA (NCT04119050), is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity to lower circulating IgG levels. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of single doses of nipocalimab administered at different IV infusion rates in healthy adults to support the potential use of shortened infusions in future studies. Nipocalimab was generally safe and well-tolerated at all doses and infusion rates; detailed safety results have been presented separately [Leu JH, et al. EHA 2022. Presentation P1534]. Methods: The trial was a single dose, sequential, randomized, double-blind, placebo-controlled, escalating dose and infusion rate study. Eligible participants were males or females aged 18-55 years with no clinically significant medical or physical conditions. Participants were randomized to 1 of 5 cohorts (n=8 per cohort [6 nipocalimab, 2 placebo]) to receive nipocalimab 30 mg/kg IV infused over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min), nipocalimab 60 mg/kg IV infused over 15 min (4 mg/kg/min) or matching placebo. Escalation to the next dose level was permitted following review by a safety monitoring committee. Pharmacokinetic sampling of nipocalimab was conducted predose, midpoint of infusion (MOI), end of infusion (EOI), EOI + 0.083h, EOI + 0.25h, EOI + 1h, start of infusion + 24h, Day 8, and Day 15 postdose; MOI and EOI varied for each dose. In terms of PD, total serum IgG was assessed. Results: A total of 40 participants (70% female, 93% white) received study drug, of which 30 were included in the PK analysis; 39 completed the study. Mean serum nipocalimab concentration-time profiles were similar following all 30 mg/kg doses regardless of infusion rate; mean serum concentrations were ~2 times higher following a 60 mg/kg infusion. Nipocalimab remained detectable up to ~169 hours postdose for 30 mg/kg groups and ~337 hours postdose for the 60 mg/kg group. Geometric mean peak (Cmax) and overall exposure (AUC) to nipocalimab were unaffected by infusion rate when administered at 30 mg/kg. Following a 60 mg/kg infusion, AUCs were 2.4-2.8 times higher and Cmax was 2.0-2.2 times higher than with 30 mg/kg infusions. Median Tmax was approximately at EOI following the 60 mg/kg infusion. Mean half-life (t½) values were similar in all treatment groups. In terms of total serum IgG, changes from baseline were decreased among all nipocalimab cohorts at all postdose time points. The maximum decrease in mean serum IgG levels was 79% at day 15 with nipocalimab 60 mg/kg. Conclusion: Nipocalimab Cmax and AUC were not affected by infusion rates when given at a dose of 30 mg/kg, but Tmax was delayed at the fastest infusion rates. Following the 60 mg/kg infusion, peak and overall nipocalimab exposures were 2-2.8 times higher than following 30 mg/kg infusions.

Physiologically-based pharmacokinetic modeling to predict CYP3A4-mediated drug-drug interactions of finerenone.

Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist that recently demonstrated its efficacy to delay chronic kidney disease (CKD) progression and reduce cardiovascular events in patients with CKD and type 2 diabetes. Here, we report the development of a physiologically‐based pharmacokinetic (PBPK) model for finerenone and its application as a victim drug of cytochrome P450 3A4 (CYP3A4)‐mediated drug‐drug interactions (DDIs) using the open‐source PBPK platform PK‐Sim, which has recently been qualified for this application purpose. First, the PBPK model for finerenone was developed using physicochemical, in vitro, and clinical (including mass balance) data. Subsequently, the finerenone model was validated regarding the contribution of CYP3A4 metabolism to total clearance by comparing to observed data from dedicated clinical interaction studies with erythromycin (simulated geometric mean ratios of the area under the plasma concentration‐time curve [AUCR] of 3.46 and geometric mean peak plasma concentration ratios [CmaxRs] of 2.00 vs. observed of 3.48 and 1.88, respectively) and verapamil (simulated AUCR of 2.91 and CmaxR of 1.86 vs. observed of 2.70 and 2.22, respectively). Finally, the finerenone model was applied to predict clinically untested DDI studies with various CYP3A4 modulators. An AUCR of 6.31 and a CmaxR of 2.37 was predicted with itraconazole, of 5.28 and 2.25 with clarithromycin, 1.59 and 1.40 with cimetidine, 1.57 and 1.38 with fluvoxamine, 0.19 and 0.32 with efavirenz, and 0.07 and 0.14 with rifampicin. This PBPK analysis provides a quantitative basis to guide the label and clinical use of finerenone with concomitant CYP3A4 modulators.

CTNI-16. TROTABRESIB (CC-90010, BMS-986378), A REVERSIBLE, POTENT ORAL BROMODOMAIN AND EXTRATERMINAL INHIBITOR (BETi) IN PATIENTS WITH HIGH-GRADE GLIOMAS: A PHASE 1 OPEN-LABEL ‘WINDOW OF OPPORTUNITY’ STUDY

Abstract Trotabresib is a potent, reversible oral BETi with antitumor activity in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270). The CC-90010-GBM-001 study (NCT04047303) enrolled patients with progressive or recurrent astrocytoma or recurrent glioblastoma scheduled for salvage resection. Patients were treated with trotabresib 30 mg daily for 4 days before surgery, then trotabresib 45 mg daily 4 days on/24 days off after recovery. Primary objectives were trotabresib tumor tissue concentration and plasma pharmacokinetics (PK). Secondary and exploratory objectives included safety, antitumor activity, cerebrospinal fluid concentration, and pharmacodynamics (PD). Twenty patients were enrolled; blood PK, blood PD, and tumor PD data were available for 14, 12, and 11 patients, respectively. Geometric mean peak trotabresib plasma concentration on day 4 was 1.92 μM; median time to peak concentration was 1.5 hours. At the time of resection, geometric mean trotabresib concentrations in plasma and brain tumor tissue were 1.01 and 0.68 μM, respectively. Blood CCR1 mRNA was reduced ≥ 50% from baseline after dose 4. Blood HEXIM1 mRNA increased at 72–96 hours following first dose, and at the time of surgery the percentage increase was related to plasma trotabresib concentration. Tumor HEXIM1 RNA increased in 10 of 11 patients. Eighteen patients (90%) had ≥ 1 treatment-related adverse event (TRAE). Nine patients (45%) had grade 3/4 TRAEs, most frequently thrombocytopenia (5 patients [25%]). Only 1 patient had serious TRAEs (hemiparesis and lethargy). Two patients died of intracranial hemorrhage unrelated to study drug. Of 16 patients evaluable for antitumor response, 7 had stable disease per RANO criteria, with 3 ongoing beyond data cutoff at cycles 4–11. Median progression-free survival was 1.9 months (95% CI, 1.4–3.3). Overall, trotabresib showed good tumor tissue penetration, with PD signals of response, and was well tolerated. A study of trotabresib + temozolomide in first-line glioblastoma is ongoing (NCT04324840).

A Phase I, Open-label, Randomized, 2-Way Crossover Study to Evaluate the Relative Bioavailability of Intranasal and Oral Varenicline

PurposeTo estimate the systemic bioavailability of OC-01 (varenicline) nasal spray, an investigational treatment for dry eye disease, relative to oral varenicline approved for smoking cessation. MethodsThe Study to Evaluate the Relative Bioavailability of Varenicline Administered as OC-01 (Varenicline) Nasal Spray as Compared to Varenicline Administered Orally as Chantix (ZEN study) was a Phase I, open-label, randomized, single-center, 2-way crossover study. On day 1, 22 healthy participants were randomized 1:1 to a single intranasal dose of varenicline 0.12 mg in OC-01 nasal spray or a single oral dose of varenicline 1 mg. On day 15, all participants crossed over to receive a single dose of the alternate treatment. Plasma samples were collected for 6 days after each dose, and pharmacokinetic parameters were estimated using noncompartmental analysis. Tolerability was monitored throughout. FindingsAfter a single dose of intranasal varenicline 0.12 mg in OC-01 nasal spray, peak systemic exposure (mean plasma Cmax) was 0.34 ng/mL, which occurred at a median Tmax of 2.0 hours. In comparison, mean plasma Cmax after oral varenicline 1 mg was 4.63 ng/mL at a median Tmax of 3.0 hours. On the basis of geometric mean ratio point estimates, peak exposure (Cmax) and total exposure (AUC0–∞) after intranasal varenicline 0.12 mg were 7.0% and 7.5%, respectively, of the systemic exposure associated with oral varenicline 1 mg. Dose-normalized Cmax and AUC0–∞ for intranasal varenicline remained 39% and 33% lower versus oral varenicline, respectively. No new or unexpected tolerability signals were detected. ImplicationsAt its highest intended single dose in OC-01 nasal spray, intranasal varenicline delivered less drug to the systemic circulation than oral varenicline at its highest approved single dose. ClinicalTrials.gov identifier: NCT04072146.

Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection

BackgroundA safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease.MethodsIn this phase 1–2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months.ResultsA total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, −53%; 95% CI, −255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, −66%; 95% CI, −250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups.ConclusionsIn this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.)

Rubella virus-specific humoral immune responses and their interrelationships before and after a third dose of measles-mumps-rubella vaccine in women of childbearing age

In the U.S., measles, mumps, and rubella vaccination is recommended as two vaccine doses. A third dose of measles-mumps-rubella (MMR) vaccine is being administered in certain situations (e.g., identified seronegativity and during outbreaks).We studied rubella-specific humoral immunity (neutralizing antibody, enzyme-linked immunosorbent assay/ELISA IgG titer and antibody avidity) and the frequencies of antigen-specific memory B cells before and after a third dose of MMR-II in 109 female participants of childbearing age (median age, 34.5 years old) from Olmsted County, MN, with two documented prior MMR vaccine doses. The participants were selected from a cohort of 1117 individuals if they represented the high and the low ends of the rubella-specific antibody response spectrum. Of the 109 participants, we identified four individuals (3.67% of all study participants; 7.14% of the low-responder group) that were seronegative at Baseline (rubella-specific ELISA IgG titers <10 IU/mL), suggesting a lack of protection against rubella before receipt of a third MMR vaccine dose. The peak geometric mean neutralizing antibody titer one month following the third dose of MMR vaccine for the cohort was 243 NT50 (CI; 241, 245), which is expected for a cohort with two doses of MMR, and the peak geometric mean IgG titer was 150 IU/mL (CI; 148, 152) with no seronegative individuals at Day 28. One-third of all subjects (31.8% for the neutralizing antibody; 30.8% for the IgG titer) experienced a significant boost (≥4-fold) of antibody titers one month following vaccination. Antibody titers and other tested immune-response variables were significantly higher in the high-responder group compared to the low-responder group. The frequencies of rubella-specific memory B cells were modestly associated with the antibody titers. Our study suggests the importance of yet unknown inherent biologic and immune factors for the generation and maintenance of rubella-vaccine-induced humoral immune responses.

A live attenuated H5N2 prime- inactivated H5N1 boost vaccination induces influenza virus hemagglutinin stalk specific antibody responses

BackgroundThe emergence and spread of highly pathogenic avian influenza (H5N1) viruses have raised global concerns of a possible human pandemic, spurring efforts towards H5N1 influenza vaccine development and improvements in vaccine administration methods. We previously showed that a prime-boost vaccination strategy induces robust and broadly cross-reactive antibody responses against the hemagglutinin globular head domain. Here, we specifically measure antibodies against the conserved hemagglutinin stem region in serum samples obtained from the prior study to determine whether stalk-reactive antibodies can also be induced by the prime-boost regimen. MethodSerum samples collected from 60 participants before vaccination and on days 7, 28 and 90 following boosting vaccination were used in this study. 40 participants received two doses of live attenuated H5N2 vaccine (LAIV H5N2) followed by one dose of inactivated H5N1 vaccine a year later, while 20 participants received only the inactivated H5N1 vaccine. We tested these serum samples for stalk-reactive antibodies via enzyme-linked immunosorbent (ELISA) and microneutralization assays. ResultsStalk-specific antibody levels measured by both assays were found to be significantly higher in primed individuals than the unprimed group. ELISA results showed that 22.5, 70.5 and 57.5% of primed participants had a four-fold or more increase in stalk antibody titers on days 7, 28 and 90 following boosting vaccination, respectively; whereas the unprimed group had no increase. Peak geometric mean titers (GMT) for stalk antibodies in the LAIV H5N2 experienced group (24,675 [95% CI; 19,531–31,174]) were significantly higher than those who received only the inactivated H5N1 vaccine (8877 [7140–11,035]; p < 0·0001). Moreover, stalk antibodies displaying neutralizing activity also increased in primed participants, but not in the unprimed group. ConclusionOur finding emphasizes the importance of prime-boost vaccination for effectively inducing stalk antibodies, which is an attractive target for developing vaccines that induce stalk reactive antibodies.

Pharmacokinetics of pyrazinamide during the initial phase of tuberculous meningitis treatment

Tuberculous meningitis (TBM) is the most severe manifestation of tuberculosis. Pyrazinamide (PZA) is a pivotal antituberculous drug, but its dose has not been optimised for TBM. The aims of this study were to describe the pharmacokinetics of PZA during TBM treatment, to identify predictors of PZA exposure and to assess relationships between PZA dose and exposures in plasma and CSF. Plasma PZA pharmacokinetic data were assessed on Days 2 and 10 of treatment in 52 adult TBM patients. A CSF-to-plasma concentration ratio was determined on Day 2. Predictors of plasma PZA exposure, correlation between plasma and CSF exposures, and prediction of CSF concentrations based on dose and plasma exposure were evaluated. The geometric mean plasma PZA exposure (AUC0-24) and peak concentration (Cmax) on Day 2 were 709 h·mg/L and 59 mg/L following a median dose of 33.3 mg/kg/day; AUC0-24 on Day 10 (523 h·mg/L) was lower (P < 0.001). Dose and BMI correlated with AUC0-24 and Cmax. The CSF concentration at 3-6 h was 42 mg/L and the CSF-to-plasma ratio was 90%. AUC0-24, Cmax and CSF concentration were highly correlated. CSF concentration could be predicted based on dose and various plasma exposure measures with <5% bias and <21% imprecision. Exposure to PZA decreases during the first days of TBM treatment, possibly due to the evolving inductive effect of rifampicin. PZA penetrates well in CSF. The association between PZA dose and exposures in plasma and CSF provides a rationale to study higher PZA doses for TBM.

Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study.

IntroductionTo investigate the absolute bioavailability of esaxerenone and the effects of food on its pharmacokinetics (PK) after a single oral dose in healthy Japanese subjects.MethodsTwenty-four Japanese males aged 20–45 years were randomised to six groups (each n = 4) in this single-centre, open-label, three-way, three-period crossover study. Esaxerenone (5 mg) was administered in the fasting state as a single oral dose, single intravenous infusion over 1 h, or in the postprandial state as a single oral dose. Plasma samples were taken before and during the 96 h after drug administration. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry. PK parameters were calculated using noncompartmental analysis, and safety was assessed.ResultsAfter fasting intravenous administration, total body clearance was 3.69 L h−1 and volume of distribution was 92.7 L. The plasma concentration–time profile of esaxerenone was similar after fasting and postprandial administration. Absolute bioavailability of a single oral 5-mg dose of esaxerenone was 89.0% in the fasting state and 90.8% postprandially. Point estimates (1.010 and 1.019, respectively) and 90% confidence intervals for geometric least squares mean peak plasma concentrations and area under the plasma concentration–time curve ratios after postprandial versus fasting oral esaxerenone were within the prespecified range (0.80, 1.25). No severe adverse events occurred throughout the study.ConclusionsEsaxerenone has a high absolute bioavailability of approximately 90% and food has no effect on esaxerenone PK after a single oral dose of 5 mg in healthy Japanese subjects. Additionally, no safety concerns were identified.Clinical Trial RegistrationJapicCTI No. 163452.FundingDaiichi Sankyo Co., Ltd.

Apixaban Levels in Octogenarian Patients with Non-valvular Atrial Fibrillation.

There is a paucity of data on apixaban levels among octogenarians with non-valvular atrial fibrillation (NVAF). We aimed to compare apixaban levels between octogenarians (with and without dose reduction) and younger patients, to assess the frequency of high and above-range drug levels. A cross-sectional, prospective study of 80 patients treated with apixaban for NVAF was conducted. Apixaban levels were compared among octogenarians treated with 5 mg twice daily (bid), octogenarians with appropriately reduced dose (2.5mg bid), octogenarians with inappropriately reduced dose and younger patients (age < 70years). Trough and peak levels were measured by a chromogenic assay calibrated for apixaban and compared to predicted manufacturer levels. A significant proportion of the cohort had above-range trough [n = 11 (13.8%)] and peak [n = 16 (20%)] levels, especially octogenarians with the 5-mg bid dosage [n = 6 (30%) for trough and n = 8 (40%) for peak]. No significant differences were found in the trough or peak geometric mean (GM) levels among the groups, apart from the peak GM levels between the 5-mg octogenarian group and the other two 2.5-mg bid octogenarian groups (p = 0.0004). The frequency of apixaban peak levels within the upper quartile was significantly higher in the 5-mg octogenarian group compared to the other groups [n = 12 (60%) of measurements, p = 0.019), whereas trough levels were comparable between groups. High and above-range peak apixaban steady-state levels are highly prevalent in octogenarians receiving the appropriate dosage of 5mg bid for NVAF stroke prevention. Age above 80 strongly affects apixaban levels. ClinicalTrials.gov Identifier number NCT02623049.

Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults

Pfs25H-EPA is a protein-protein conjugate transmission-blocking vaccine against Plasmodium falciparum that is safe and induces functional antibodies in malaria-naive individuals. In this field trial, we assessed Pfs25H-EPA/Alhydrogel for safety and functional immunogenicity in Malian adults. This double-blind, randomised, comparator-controlled, dose-escalation trial in Bancoumana, Mali, was done in two staggered phases, an initial pilot safety assessment and a subsequent main phase. Healthy village residents aged 18-45 years were eligible if they had normal laboratory results (including HIV, hepatitis B, hepatitis C tests) and had not received a previous malaria vaccine or recent immunosuppressive drugs, vaccines, or blood products. Participants in the pilot safety cohort and the main cohort were assigned (1:1) by block randomisation to a study vaccine group. Participants in the pilot safety cohort received two doses of Pfs25H-EPA/Alhydrogel 16 μg or Euvax B (comparator vaccine), and participants in the main cohort received Pfs25H-EPA/Alhydrogel 47 μg or comparator vaccine (Euvax B for the first, second, and third vaccinations and Menactra for the fourth vaccination). Participants and investigators were masked to group assignment, and randomisation codes in sealed envelopes held by a site pharmacist. Vials with study drug for injection were covered by opaque tape and labelled with a study identification number. Group assignments were unmasked at final study visit. The primary outcomes were safety and tolerability for all vaccinees. The secondary outcome measure was immunogenicity 14 days after vaccination in the per-protocol population, as confirmed by the presence of antibodies against Pfs25H measured by ELISA IgG and antibody functionality assessed by standard membrane feeding assays and by direct skin feeding assays. This trial is registered with ClinicalTrials.gov, number NCT01867463. Between May 15, and Jun 16, 2013, 230 individuals were screened for eligibility. 20 individuals were enrolled in the pilot safety cohort; ten participants were assigned to receive Pfs25H-EPA/Alhydrogel 16 μg, and ten participants were assigned to receive comparator vaccine. 100 individuals were enrolled in the main cohort; 50 participants were assigned to receive Pfs25H-EPA/Alhydrogel 47 μg, and 50 participants were assigned to receive comparator vaccine. Compared with comparator vaccinees, Pfs25H vaccinees had more solicited adverse events (137 events vs 86 events; p=0·022) and treatment-related adverse events (191 events vs 126 events, p=0·034), but the number of other adverse events did not differ between study vaccine groups (792 vs 683). Pfs25H antibody titres increased with each dose, with a peak geometric mean of 422·3 ELISA units (95% CI 290-615) after the fourth dose, but decreased relatively rapidly thereafter, with a half-life of 42 days for anti-Pfs25H and 59 days for anti-EPA (median ratio of titres at day 600 to peak, 0·19 for anti-Pfs25H vs 0·29 for anti-EPA; p=0·009). Serum transmission-reducing activity was greater for Pfs25H than for comparator vaccine after the fourth vaccine dose (p<0·001) but not after the third dose (p=0·09). Repeated direct skin feeds were well tolerated, but the number of participants who infected at least one mosquito did not differ between Pfs25H and comparator vaccinees after the fourth dose (p=1, conditional exact). Pfs25H-EPA/Alhydrogel was well tolerated and induced significant serum activity by standard membrane feeding assays but transmission blocking activity was not confirmed by weekly direct skin feed. This activity required four doses, and titres decreased rapidly after the fourth dose. Alternative antigens or combinations should be assessed to improve activity. Division of Intramural Research, National Institute of Allergy and Infectious Diseases.