Pharmacokinetic Exposure Research Articles

Design, Biological Characterization, and Discovery of Capromorelin Derivatives as Oral Growth Hormone Secretagogue Receptor Type 1a Agonist for the Treatment of Growth Hormone Deficiency.

Recombinant human growth hormone (rhGH) is a well-established treatment for children with growth deficiencies worldwide. However, its requirement for subcutaneous administration limits convenience compared to that of oral therapies. Starting from capromorelin, we designed, synthesized, and characterized a novel orally active GHSR-1a agonist, compound 4b (hGHSR-1a EC50 = 0.49 nM), which effectively stimulates endogenous GH release in rats at oral doses as low as 0.1 mg/kg─100-fold more potent than ibutamoren (10 mg/kg). Notably, 10 day oral administration of 4b increased body weight and length in 4-week-old rats. To date, comprehensive preclinical studies on oral agents for short stature remain limited, and existing GHSR-1a agonists lack approval for this indication. Compound 4b exhibited superior pharmacokinetic exposure in dogs (oral bioavailability: 43.6%; half-life: 1.2 h) relative to other species. This study details the optimization of 4b, which demonstrates a promising pharmacological profile for clinical translation as a growth hormone replacement therapy.

Using Pharmacokinetic and Pharmacodynamic Analysis to Optimize the Dosing Regimens of Fanastomig (EMB-02) in Patients With Advanced Solid Tumors.

Fanastomig (also known as EMB-02)is a bispecific antibody targeting programmed cell death protein-1(PD-1) and lymphocyte activation gene-3 (LAG-3), developed for the treatment of advanced solid tumors. A first-in-human (FIH) Phase I study (NCT04618393) evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and clinical efficacy of Fanastomig in patients with advanced solid tumors. To determine the recommended Phase II dose (RP2D), population pharmacokinetics (PopPK), and exposure and response analysis (E-R) were conducted. The PopPK model, demonstrating good performance, showed no clinically meaningful relationship between areas under the concentration-time curve (AUC) or maximum concentration (Cmax) of Fanastomig and selected covariates of interest. A nonlinear Emax model was fitted to Fanastomig PD-1 receptor occupancy (RO) in the peripheral blood compartment. The estimated half-maximal effective concentration (EC50) was 0.084 μg/mL (95% confidence interval [CI]: 0.0369-0.131). Assuming a threefold lower exposure in tumor tissue compared to that in serum, a target trough concentration of Fanastomig at ~2.27 μg/mL would be needed for 90% PD-1 RO in the tumor. Modeling and simulation indicated that a weekly dosing (QW) of 360 mg would achieve full peripheral blood RO in approximately 90% of patients. The incidence of anti-drug antibodies (ADAs) for Fanastomig was high (95.7%, 44/46), with a negative correlation between the ADA titer and dose levels; meanwhile, ADA minimally impacted PK exposure and efficacy. An inverse trend was observed between anaphylaxis and PK exposure. Fanastomig was well tolerated and had acceptable safety profiles up to 900 mg QW. Based on these findings, two dosing regimens have been selected for further clinical development. Trial Registration: ClinicalTrials.gov identifier: NCT04618393.

Evaluation of Innate Immune System, Body Habitus, and Sex on the Pharmacokinetics and Pharmacodynamics of Anetumab Ravtansine in Patients With Cancer.

Anetumab ravtansine, like other ADC drugs, has high inter-patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0-inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.

Rezafungin in special populations with candidaemia and/or invasive candidiasis.

Achieving and maintaining therapeutic drug exposures with antifungals can be challenging in special patient populations, such as those with organ dysfunction (liver or kidney) or obesity, or elderly patients, due to dose-exposure relationships and potential drug-drug interactions. Dose adjustments may be needed in these populations to maintain therapeutic efficacy and/or prevent toxicity. We reviewed specific dosing considerations for antifungals in special populations with candidaemia and/or invasive candidiasis, focusing on those relating to echinocandins (based on prescribing information), and then explored the utility of the second-generation echinocandin rezafungin in treating these populations (based on currently available data identified from a PubMed and congress abstract search). Available data showed that echinocandins may sometimes require dosing modifications for special populations with candidaemia/invasive candidiasis, primarily due to decreases in pharmacokinetic exposures. Rezafungin appears to be suitable for use in a variety of special populations without the need for dose modifications based on available data, including patients with organ dysfunction or obesity, and elderly and critically ill patients. Further research is needed in populations where rezafungin data are not available including children, people living with HIV, patients receiving ECMO and those with underlying neurological conditions.

Assessment of ethnic differences in pharmacokinetics and clinical responses of acalabrutinib between Chinese and White patients with B-cell malignancies.

The aim of this study was to assess differences between Chinese and White patients in pharmacokinetics (PK) of, and clinical response to, acalabrutinib and its pharmacologically active major metabolite, ACP-5862, to support recommended dosing in Chinese patients with B-cell malignancies. A population pharmacokinetic (pop-PK) analysis was conducted to integrate data from a Chinese and a Japanese study into the existing model. The effect of race (East Asian vs. non-East Asian) on acalabrutinib and ACP-5862 PK parameters was assessed. The relationships between model-predicted exposures (e.g., acalabrutinib area under the plasma concentration-time curve for 24 h at steady-state [AUC24h,ss]) and best overall response and safety outcomes were investigated in Chinese patients and the overall population. The pop-PK analysis included 686 patients with B-cell malignancies (Chinese, n = 105; Japanese, n = 6). A two-compartment model adequately described the PK profiles of acalabrutinib and ACP-5862 for Chinese patients. East Asian race was a statistically significant covariate on relative bioavailability and apparent volume of the peripheral compartment of acalabrutinib, showing 28% higher PK exposures in Chinese patients. The exposure-efficacy analysis showed that efficacy plateaued in Chinese patients with 100 mg twice-daily dosing while the exposure-safety analysis indicated a flat relationship of acalabrutinib AUC24h,ss with grade ≥2 or ≥3 adverse events in both Chinese patients and the overall population with 100-400 mg daily doses. Higher PK exposure was observed in Chinese patients vs. White patients but did not indicate a safety concern based on exposure-response relationships. The results supported using the 100 mg twice-daily dosing regimen in Chinese patients.

Simulated exposures of oritavancin in in vitro pharmacodynamic models select for methicillin-resistant Staphylococcus aureus with reduced susceptibility to oritavancin but minimal cross-resistance or seesaw effect with other antimicrobials.

Dalbavancin exposures select for VAN and daptomycin cross-resistance in Staphylococcus aureus often by walK-related mutations. Oritavancin is another long-acting lipoglycopeptide, but its proclivity to select for cross-resistance is unknown. The objective of this study was to determine if post-distributional pharmacokinetic oritavancin exposures select for meaningful susceptibility changes in S. aureus. We simulated average post-distributional, free-drug exposures of oritavancin 1200 mg IV once (fCmax 11.2 µg/mL; β-elimination t1/2 13.4 h; γ-elimination t1/2 245 h) in an in vitro pharmacodynamic model for 28 days against five S. aureus including four MRSA. Samples were taken daily for colony enumeration and resistance screening. Susceptibility testing was repeated on isolates from resistance screening plates against oritavancin, vancomycin, daptomycin, dalbavancin and 6 beta-lactams with varying penicillin-binding protein affinities. Tested oritavancin exposures were bactericidal against 5/5 strains for 2-17 days before regrowth of less-susceptible subpopulations occurred. Isolates with reduced susceptibility to oritavancin were detected as early as 5 days, but the MIC increased above the susceptibility breakpoint (>0.125 mg/L) in 4/5 strains eventually. Vancomycin and daptomycin MICs increased by 2- to 8-fold but did not exceed the susceptibility breakpoints in most isolates. β-lactam MICs were largely unchanged among the recovered isolates with reduced oritavancin susceptibility. Mutations were diverse but often involved purR with 13 unique variants identified among 4/5 strains. Oritavancin-selected resistance was primarily associated with purR mutation and less frequently associated with cross-resistance and walK mutation than dalbavancin-selected resistance in similar strains and conditions. The reason for this is unclear but may stem from differences in the mechanism(s) and divergent mutational pathways.

Modulation of enhancer of zeste homolog 2 (EZH2) pharmacodynamic markers and tumor gene expression by mevrometostat (PF-06821497) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC).

146 Background: Mevrometostat (PF-06821497; M) is a potent and selective small molecule inhibitor of EZH2. Dose exploration of M in combination with enzalutamide (E) showed a manageable safety profile and promising activity in patients with mCRPC in a phase 1 study (NCT03460977). M exhibited dose-dependent pharmacokinetic (PK) exposure increases up to 1250 mg BID in combination with E (160 mg daily). We report the corresponding pharmacodynamic (PD) effects of EZH2 inhibition and tumor gene expression changes by M+E in patients with mCRPC. Methods: Serial whole blood and paired tumor biopsy samples were collected during dose escalation of M from 150 to 1250 mg BID in combination with E (160 mg QD) given on empty stomach in patients with mCRPC. Paired tumor biopsy samples were collected before the study and after 21 days of M+E or E. H3K27Me3 PD marker was evaluated in peripheral granulocytes by flow cytometry and in paired tumor biopsy samples by an immunohistochemistry assay. Tumor gene expression was profiled by whole transcriptomic RNA sequencing. Pre- and post-treatment sample gene expression levels and gene signature Gene Set Variation Analysis (GSVA) enrichment scores were analyzed by a simple linear model with transformation, if appropriate. Results: Dose-dependent H3K27Me3 PD marker reduction was observed in peripheral granulocytes and paired tumor biopsies by M+E in patients with mCRPC. Strong H3K27Me3 reduction (≥75%) in granulocytes was achieved at ≥375 mg of M+E. Tumor H3K27Me3 levels were effectively reduced from baseline in 6 patients receiving M at 1250 mg +E with a group mean change of –67% determined by H scores (95% CI: –86%, –23%; P =0.020) and –75% determined by H3K27Me3 staining (positive cells with high and medium intensity in tumor area) (95% CI: –93%, –11%; P =0.038). No significant change in tumor H3K27Me3 levels was observed in 4 patients receiving M at 500 mg +E. Consistent with strong EZH2 inhibition observed in tumor samples from patients receiving M at 1250 mg +E, M+E increased the expression of genes reported to be repressed by the PRC2/EZH2 complex (e.g., BMP7 , CPAMD8 , EYA4 , FHL1 , IGFBP3 and NOV ), and decreased expression of EZH2 and other genes involved in the E2F pathway, the G2M checkpoint, Myc responsive genes and/or cell cycle progression (e.g., AURKA , CDK1 , FOXM1 , RAD54L , TOP2A and TYMS ). Conclusions: These data indicate M at 1250 mg BID on empty stomach in combination with E effectively inhibits EZH2 in tumor tissue and may overcome drug resistance and/or enhance androgen targeting drug activity by restoring the function of tumor suppressor genes and blocking tumor cell proliferation and cell cycle progression. These data support dose recommendation for phase 3 pivotal studies and enhance understanding of mechanism of action for M+E in mCRPC. Clinical trial information: NCT03460977 .

Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib.

Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking. This study aimed to describe the PK of once- and twice-daily cobicistat regimens in healthy volunteers and patients with rheumatoid arthritis, cancer, or HIV infection and to investigate the interplay between cobicistat and the anticancer drug olaparib. Cobicistat levels from 683 samples from 66 subjects in four clinical trials were included in the analysis. For olaparib, 261 samples from 12 subjects from one trial were included. Population PK analysis was performed by nonlinear mixed-effects modelling. Both cobicistat and olaparib PK were adequately described by a well-stirred liver model with one central compartment and Erlang type absorption. Cobicistat PK was similar across patient populations and dosing regimens. Cobicistat increased olaparib prehepatic bioavailability 1.65-fold (RSE 6%) and decreased intrinsic clearance 0.34-fold (RSE 6.5%). A correlation between olaparib PK and cobicistat exposure could not be identified. The interindividual variability in olaparib clearance was lower with cobicistat than without cobicistat. The developed pharmacokinetic models adequately described cobicistat and olaparib plasma concentrations. PK boosting with cobicistat at 150 mg twice daily led to an increase in olaparib bioavailability and decrease in clearance. This effect was not correlated with cobicistat exposure, which may reflect saturation of the boosting effect of cobicistat at this dose. NCT02565888 (30-09-2015), NCT00825929 (19-01-2009), Netherlands Trial Register NL7766 (18-12-2018), NCT05078671 (22-09-2021).

Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease.

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial. The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated. The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA). The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD. https://clinicaltrials.gov/study/NCT04693520 .

Identification of Antituberculars with Favorable Potency and Pharmacokinetics through Structure-Based and Ligand-Based Modeling.

Drug discovery is inherently challenged by a multiple criteria decision making problem. The arduous path from hit discovery through lead optimization and preclinical candidate selection necessitates the evolution of a plethora of molecular properties. In this study, we focus on the hit discovery phase while beginning to address multiple criteria critical to the development of novel therapeutics to treat Mycobacterium tuberculosis infection. We develop a hybrid structure- and ligand-based pipeline for nominating diverse inhibitors targeting the β-ketoacyl synthase KasA by employing a Bayesian optimization-guided docking method and an ensemble model for compound nominations based on machine learning models for in vitro antibacterial efficacy, as characterized by minimum inhibitory concentration (MIC), and mouse pharmacokinetic (PK) plasma exposure. The application of our pipeline to the Enamine HTS library of 2.1M molecules resulted in the selection of 93 compounds, the experimental validation of which revealed exceptional PK (41%) and MIC (19%) success rates. Twelve compounds meet hit-like criteria in terms of MIC and PK profile and represent promising seeds for future drug discovery programs.

A population pharmacokinetic analysis to evaluate the impact of renal impairment on the pharmacokinetics of iberdomide.

A population pharmacokinetic analysis to evaluate the impact of renal impairment on the pharmacokinetics of iberdomide.

Population Pharmacokinetic and Exposure-Response Analysis to Support a Dosing Regimen of CPX-351 (NS-87) in Japanese Adult and Pediatric Patients with Untreated High-Risk Acute Myeloid Leukemia

Population Pharmacokinetic and Exposure-Response Analysis to Support a Dosing Regimen of CPX-351 (NS-87) in Japanese Adult and Pediatric Patients with Untreated High-Risk Acute Myeloid Leukemia

First-in-human phase 1/2 study (MYCHELANGELO I) of first-in-class epigenomic controller OTX-2002 targeting MYC oncogene in patients with hepatocellular carcinoma (HCC) and other solid tumors.

606 Background: The c-MYC (MYC) oncogene is a master transcription factor of tumor cell and microenvironment regulation; it is often dysregulated in cancer, including HCC. OTX-2002 is a MYC-targeted Epigenomic Controller (MYC-EC), an mRNA drug substance encapsulated in a clinical lipid nanoparticle (LNP), designed to downregulate MYC expression pre-transcriptionally with high specificity and durability, inhibiting tumor cell viability while sparing normal cells. Methods: A first-in-human dose-escalation study (NCT05497453) investigates OTX-2002 monotherapy in HCC and other solid tumors. Key outcomes include safety, tolerability, pharmacokinetics (PK) and the recommended dose for expansion. In addition to standard safety measures, LNP-associated safety measures including cytokine profiling and an assessment of the presence of anti-PEG antibodies (ADA) were included. Initial pharmacodynamic activity (PD) was assessed via measurement of DNA methylation at the MYC locus in cell-free DNA [cfDNA] from whole blood. Results: As of August 23, 2024, 24 patients were treated at 6 doses (19 HCC, 1 colorectal, 1 cervical, 1 pancreatic, 2 sarcoma). OTX-2002 was generally well-tolerated; most adverse events (89%) were low grade, with infusion-related reactions being the most common (30%). Consistent with known LNP profiles, OTX-2002 adverse events were transient and manageable, including cytokine and ADA expression levels. Plasma PK exposures of OTX-2002 were linear across the first five doses analyzed. Significant, on-target dose-dependent changes in MYC gene methylation were seen in cfDNA for all patients post-dose and were durable for at least 15 days, consistent with the designed durability of the MYC-EC. Updated data will be presented. Conclusions: OTX-2002 is well-tolerated and induces rapid and durable epigenomic changes to the MYC locus. These results provide clinical proof of mechanism of the epigenomic controller platform and support continued development of OTX-2002. Clinical trial information: NCT05497453 .

P-2031. Thorough QT/QTc Clinical Study to Evaluate the Effect of Remdesivir on Cardiac Repolarization in Healthy Participants

Abstract Background Remdesivir (RDV) is an intravenous nucleotide prodrug approved for COVID-19 treatment. Its effect on QT interval is unknown. This Phase 1 study evaluated the effects of a supratherapeutic dose of RDV on QT interval.Figure 1.Estimated ΔΔQTcF (90% CI) between RDV and Placebo-to-match RDV.ΔΔQTcF, baseline-adjusted, placebo-matched QTcF; QTcF, QT interval corrected for heart rate using the Fridericia formula; RDV, remdesivir. Methods This study included 2 cohorts of healthy participants aged 18-55 years: an RDV dose-selection cohort (Sentinel Cohort; n=6); and a randomized, placebo- and positive-controlled (moxifloxacin), single-dose crossover cohort (Thorough QT [TQT] Cohort; n=55). The Sentinel Cohort assessed pharmacokinetics (PK) and safety of a supratherapeutic RDV dose (600 mg) and was followed by the TQT Cohort. The primary endpoint for the TQT Cohort was ΔΔQTcF: the difference between baseline-adjusted QTcF (QT corrected for heart rate [HR] using the Fridericia formula) in the RDV treatment period and baseline-adjusted QTcF in the placebo period at each postdose time point. Adverse events (AEs), laboratory abnormalities, and plasma PK were also assessed.Table 1.Plasma PK Parameters for RDV and Its Metabolites (GS-704277 and GS 441524) Following a Single Dose of RDV 600 mg.AUCinf, area under the concentration-time curve extrapolated to infinite time; AUClast, area under the concentration-time curve from dosing to last measurable concentration; Cmax, maximum observed concentration; CV, coefficient of variance; PK, pharmacokinetic; RDV, remdesivir; t½, half-life; Tmax, time at which maximum concentration was observed; TQT, thorough QT. aThe TQT Cohort enrolled 55 participants; 54 participants received RDV. Results Following RDV 600 mg, PK exposures of RDV and its metabolites were similar in both cohorts (Table 1). In the TQT Cohort, the assay sensitivity was established; the estimated lower bound of 96.67% CI for ΔΔQTcF for moxifloxacin was &amp;gt;5 msec for ≥1 of the prespecified 1, 2, and 3h postdose time points. RDV had no clinically relevant effects on QT interval compared to placebo (Figure 1); the estimated upper bound of 90% CI for RDV ΔΔQTcF was &amp;lt; 10 msec at all postdose time points. Most AEs were Grade 1-2 in severity. One participant receiving RDV in the TQT Cohort had a Grade 3 AE (transaminase increased). There were no other Grade ≥3 AEs, tachycardia, or HR AEs (Table 2). 5/54 participants in the TQT Cohort had HR &amp;gt;100 bpm within 12h of receiving RDV (all resolved by 24h postdose). 3 of the 5 participants had Grade 1-2 nausea and vomiting ≤13h postdose; 1 of the 3 participants had treatment-related chills ≤7h postdose.Table 2.TEAEs and Grade ≥3 TELAsTEAE, treatment-emergent adverse event; TELA, treatment-emergent laboratory abnormality; RDV, remdesivir; TQT, thorough QT. Conclusion RDV 600 mg in healthy participants resulted in PK exposures 3-4–fold higher than those observed with RDV 200 mg in prior studies. A single dose of RDV 600 mg was generally safe; there were no AEs associated with QT prolongation, deaths, or SAEs reported. In this positive control–validated study, ΔΔQTcF for RDV was below the regulatory threshold of concern, demonstrating that its clinical regimen has no proarrhythmic potential. Disclosures Olena Anoshchenko, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Mazin Abdelghany, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Santosh Davies, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anna Kwan, BS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Ran Duan, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Aryun Kim, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

P-1099. Correlation Analysis of Cefiderocol In vitro Activity and In vivo Efficacy Against Acinetobacter baumannii Strains with Difficult-to-Read MIC Endpoints

Abstract Background Cefiderocol (FDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria, including Acinetobacter baumannii. For some isolates, determining the minimum inhibitory concentration (MIC) endpoints for FDC can be difficult due to the trailing growth phenomenon. Recently guidance on how to determine the MIC when trailing occurs has been updated in the CLSI M100 document, to enhance MIC reproducibility. In this study, we determined MICs of A. baumannii strains that show difficult to determine MIC endpoint due to trailing according to the updated CLSI guidance and analyzed correlations between MICs and in vivo efficacy. In vivo bacterial growth or reduction from start of treatment with cefiderocol against Acinetobacter baumannii in the neutropenic murine thigh infection model using humanized pharmacokinetic exposure of cefiderocol. In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change &amp;lt;0 log10 colony forming unit (CFU) /thigh) CFU/thigh), in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). MIC values shown blue, orange, and red indicate susceptible, intermediate, and resistant, respectively, according to CLSI guideline 2024. Methods MICs were determined according to the 2024 CLSI guidance using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) from BD-BBL for 43 A. baumannii isolates, including 13 strains that show severe trailing. All strains had been evaluated in vivo in the murine thigh infection model using humanized pharmacokinetic exposure of FDC (1). Categorical agreements between MICs and in vivo efficacy in murine thigh infection model Susceptible (S), Non-susceptible (NS), breakpoints as published by CLSI (2024), In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change &amp;lt;0 log10 colony forming unit (CFU)/thigh, in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). Results FDC MIC range of tested A. baumannii strains was 0.12 to &amp;gt;32 μg/mL. Among 19 strains that showed a reduction in bacterial load after treatment with FDC in the murine thigh infection model, 94.7% (18/19 strains) were categorized as FDC susceptible (Figure and Table 1). Among 24 strains that showed increase in bacterial load after treatment with FDC in vivo, 87.5% (21/24 strains) were categorized as FDC non-susceptible. The categorical agreement of MICs and in vivo efficacy was 90.7% (39/43). As for the 13 strains that showed severe trailing, the categorical agreement of MICs and in vivo efficacy was 84.6% (11/13, Table 2). The updated CLSI guidance did not impact the overall agreement that was obtained earlier using the previous CLSI guidance (Table 1, 2). Categorical agreements between MICs and in vivo efficacy in murine thigh infection model for 13 strains that showed severe trailing Susceptible (S), Non-susceptible (NS), breakpoints as published by CLSI (2024), In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change &amp;lt;0 log10 colony forming unit (CFU)/thigh, in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). Conclusion Our correlation analysis between MICs and in vivo efficacy in thigh infection model confirms the validity of MIC endpoint determinations described in CLSI M100 document, including strains that show severe trailing. Reference: 1. Monogue L, et al. Antimicrob Agents Chemother. 2017;61(11):e01022-17. Disclosures Hidenori Yamashiro, Shionogi &amp; Co., Ltd.: Employee Motoyasu Onishi, PhD, Shionogi &amp; Co., Ltd.: Employee Naomi Anan, MSc, Shionogi &amp; Co., Ltd.: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi &amp; Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi &amp; Co., Ltd.: Employee

Pharmacokinetic exposure and treatment outcomes of lenvatinib in patients with renal cell carcinoma and differentiated thyroid carcinoma.

After initial approval of lenvatinib for radioiodine-refractory differentiated thyroid cancer (DTC), it has also shown promising outcomes in among others metastatic renal cell carcinoma (mRCC). Given that trial populations typically do not represent routine clinical care populations, questions arise about how applicable trial outcomes are in clinical practice. This study aims to compare the pharmacokinetics (PK), toxicity patterns, and survival data of lenvatinib in a real-world cohort with DTC and mRCC to those observed in pivotal clinical trials. Patients were included when diagnosed with DTC or mRCC, had received current or prior treatment with lenvatinib, and had at least one available lenvatinib plasma concentration measurement. A descriptive comparison was made between the baseline characteristics, PK data, toxicity and survival data in this real-world cohort and those described in the phase III trials. Overall, 29 patients with mRCC and 35 patients with DTC were included. For mRCC, median time to treatment discontinuation (mTTD) was shorter than observed in the phase III trial (7.5 versus 11.0 months) with fewer dose-limiting toxicities, likely because 66% of the patients started with a reduced dose. mRCC patients were more pretreated and had a worse performance status than trial participants. This was resembled in overall lower PK exposure in mRCC patients. For DTC, mTTD was longer in our cohort (17.1 versus 13.8 months), with similar toxicity patterns and PK exposure as in the phase III trial. Our data suggests that patient characteristics and outcomes in routine clinical care deviate from clinical trials and show the need for alternative treatment strategies to manage tolerability to lenvatinib.

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.

Population Pharmacokinetics of Trofinetide in a Pediatric Population Aged 2-4Years with Rett Syndrome.

Weight-banded trofinetide dosing improved physician- and caregiver-rated efficacy measures and had acceptable tolerability in patients aged 2‒4years (DAFFODIL study) and 5‒20years (LAVENDER study) with Rett syndrome (RTT). Selection of weight-banded dosing regimens for these studies was based on population pharmacokinetic (popPK) modeling and exposure simulations. This study applied an updated popPK model to confirm steady-state trofinetide exposures achieved in DAFFODIL patients were within target range. A popPK model was developed using data from 14 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER and DAFFODIL studies. Individual exposure measures (area under concentration-time curve over 0-12h [AUC0-12] were generated via integration of the predicted concentration-time profile for each DAFFODIL study participant based on the popPK model and individual empiric Bayesian pharmacokinetic parameter estimates. Distributions of steady-state AUC0-12 values for each body-weight group were compared against target exposure (AUC0-12 = 800‒1200µg·h/mL). Distribution and box plots of simulated steady-state AUC0-12 values achieved with the weight-banded DAFFODIL dosing regimen used in younger individuals aged 2-4years with RTT (twice daily trofinetide 5g[≥ 9 to < 12kg] or 6g [≥ 12 to < 20kg]) indicated good overlap with the target exposure range. Median steady-state AUC0-12 values for both body-weight bands fell within the target exposure range. PopPK model-based simulations confirm that the weight-banded dosing regimen used in DAFFODIL is adequate to achieve target trofinetide exposure in 2- to 4-year-olds with RTT.

A Phase I Study of FHD-609, a Heterobifunctional Degrader of Bromodomain-Containing Protein 9, in Patients with Advanced Synovial Sarcoma or SMARCB1-Deficient Tumors.

FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors. In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5-80 mg; n = 40) or once weekly (40-120 mg; n = 15). Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate-corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to the downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients. FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.

Phase 1 study of the safety, tolerability, and pharmacokinetics of a synthetic macrocyclic peptide antibiotic (BRII-693) in healthy adult participants.

BRII-693 is a next-generation intravenous (IV)-administered synthetic macrocyclic peptide antibiotic for infections caused by drug-resistant gram-negative pathogens. This single-center, randomized, double-blind, placebo-controlled phase 1 study investigated the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of BRII-693 in 104 healthy participants. In single-dose cohorts, 10-400 mg of BRII-693 was evaluated in eight participants (six active; two placebo) per cohort. In the 7-day repeat-dose cohorts, 100-200 mg of BRII-693 was evaluated in eight participants (six active; two placebo) per cohort. In two 14-day repeat-dose cohorts, 150 mg of BRII-693 was evaluated in 12 participants (10 active, two placebo) each of non-Chinese and Chinese descent. No participant reported a severe or serious adverse event (AE) or an AE leading to death. Across all cohorts and for non-Chinese and Chinese participants, most AEs were mild. Cmax and area under the concentration-time curve (AUC) increased in a dose-proportional manner over the dose range of single- and repeat-dosing. Mean t1/2 was 2.58-4.37 hours and generally similar across single doses. An accumulation of exposure was observed following multiple doses with an accumulation ratio of 1.5 to 1.7 which was within the expected 1.3 to 2.5 range at steady state. Mean total clearance (CL) was similar between single and multiple dose administration, suggesting time-independent pharmacokinetics (PK). PK exposure was statistically equivalent between non-Chinese and Chinese participants. This phase 1 study demonstrates a favorable safety, tolerability, and PK profile of BRII-693 in healthy non-Chinese and Chinese participants.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04808414.