Dosing Interval Research Articles

Potential for extending the chloramphenicol dosing interval for canine urinary tract infections.

Canine urinary excretion of chloramphenicol was evaluated to optimize a dosing protocol for treating urinary tract infections. Seven healthy male intact purpose-bred Beagles and six healthy client-owned dogs of various breeds each received a single oral 50 mg/kg dose of chloramphenicol. Urine was collected at baseline, and 6, 8, 12, and 24 h after chloramphenicol. Chloramphenicol urine concentrations were measured and compared to the epidemiological cutoff value for E. coli (16 mcg/mL). At 8 h, mean chloramphenicol concentration from all dogs was 266.9 mcg/mL (90% CI 136.2-397.7 mcg/mL) but was lower in Beagles than client-owned dogs. At 12 h, mean chloramphenicol concentration from all dogs was 111.0 mcg/mL (90% CI 36.9-185.0 mcg/mL) and was lower in Beagles (10.6 mcg/mL, 90% CI 1.4-19.8 mcg/mL) than client-owned dogs (228.0 mcg/mL, 90% CI 103.0-353.1 mcg/mL). Urine half-life was similar for all dogs (1.8-3.8 h). This justifies dosing chloramphenicol 50 mg/kg PO q 8 h. All client-owned dogs additionally maintained concentrations well above 16 mcg/mL, for 12 h, suggesting that q 12-h dosing might be appropriate for non-Beagle dogs with susceptible lower urinary tract infections. A clinical trial in dogs with urinary tract infections is needed as well as further investigation into potential breed differences.

Prevalence and Factors Associated with De-escalation of Anti-TNFs in Older Adults with Rheumatoid Arthritis: A Medicare Claims-Based Observational Study.

The aim was to evaluate prevalence and factors associated with anti-tumor necrosis factor (anti-TNF) de-escalation in older adults with rheumatoid arthritis (RA). We identified adults ≥66 years of age with RA on anti-TNF therapy within 6 months after RA diagnosis with at least 6-7 months duration of use (proxy for stable use), using 20% Medicare data from 2008-2017. Patient demographic and clinical characteristics, including concomitant use of glucocorticoid (GC), were collected. Anti-TNF use was categorized as either de-escalation (identified by dosing interval increase, dose reduction, or cessation of use) or continuation. We used (1) an observational cohort design with Cox regression to assess patient characteristics associated with de-escalation and (2) a case-control design with propensity score-adjusted logistic regression to assess the association of de-escalation with different clinical conditions and concomitant medication use. We identified 5106 Medicare beneficiaries with RA on anti-TNF, 65.5% of whom had de-escalation. De-escalation was more likely with older age (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.01-1.02) or greater comorbidity (HR 1.07, 95% CI 1.05-1.09), but was less likely with low-income subsidy status (HR 0.85, 95% CI 0.78-0.92), adjusting for patient sex and race/ethnicity. Lower odds of de-escalation were associated with serious infection (odds ratio [OR] 0.79, 95% CI 0.66-0.94), new heart failure diagnosis (OR 0.70, 95% CI 0.52-0.95), and long-term GC use (OR 0.84, 95% CI 0.74-0.95), whereas higher odds were associated with concomitant methotrexate use (OR 1.16, 95% CI 1.03-1.31). Anti-TNFs are de-escalated in two-thirds of older adults with RA in usual care. Further study is needed on RA outcomes after anti-TNF de-escalation.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. Here, we quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022. We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR: 1.66; 95% CI: 1.07, 2.59; p = 0.02) after the first dose. Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal Intensive Care Unit.

In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown. This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7-60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin. Monte Carlo simulations (NONMEM 7.3) were used to predict steady-state exposures after a 72-hour antibiotic course per Neofax dosing. Exposure was assessed relative to drug-specific minimum inhibitory concentration (MIC) targets between 1 and 16 mcg/mL for Pseudomonas and Enterobacteriaceae species. Postdiscontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to when antibiotic concentration decreased below a specific MIC. Piperacillin-tazobactam, cefepime and tobramycin cohorts included infants with median gestation age 29, 32 and 32 weeks and postnatal age 17, 19 and 15 days, respectively. The mean PDAE was 19-68 hours, depending on the specific antibiotic/MIC combination. PDAE was longer for infants <28 days old and preterm (vs. term) infants. Cefepime exhibited the longest mean PDAE of 68 hours for Enterobacteriaceae MIC 1. Piperacillin mean PDAE was 25 hours for Enterobacteriaceae MIC 8. Tobramycin had a short mean PDAE of 19 hours. Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.

Development of a population pharmacokinetic model for the novel long-acting injectable antipsychotic risperidone ISM®.

The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg.

Immunogenicity and safety of beta variant COVID-19 vaccine AZD2816 and AZD1222 (ChAdOx1 nCoV-19) as primary-series vaccination for previously unvaccinated adults in Brazil, South Africa, Poland, and the UK: a randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study

AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated. In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed. Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2. Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants. AstraZeneca.

Ceftobiprole quantification in human serum by HPLC-UV to implement routine TDM in clinical practice

Background and aimsCeftobiprole is a recent 5th generation parenteral cephalosporin with antibacterial activity against a large range Gram+ and Gram− bacteria. Therapeutic drug monitoring (TDM) is an essential tool for maintaining plasma concentrations of antibiotics above the MIC by the end of the dosing interval, thus preventing the resistant strain diffusion. TDM is already recommended for other cephalosporins, and it is a reasonable tool contributing to the safety and efficacy of these drugs. During the treatment of patients in real-life, a number of pharmacokinetic (PK) changes not normally seen in healthy volunteers can occur which can impair the pharmacokinetic/pharmacodynamic target attainment.We aimed to develop simple and rapid HPLC-UV method for determination of ceftobiprole in human serum to implement TDM in clinical practice and support PKs and pharmacokinetic/pharmacodynamic (PK/PD) studies. Materials and methodsSamples preparation of calibration standards, QC, and anonymous patients serum samples was performed by protein precipitation by adding 0.01 ml of sulphosalicylic acid at 30 % to 0.1 ml of each sample. Then samples were vortexed and the centrifuged at 12,000 rpm for 10 min at 4 °C. Fifty microlitres of clear supernatant were diluted 1:1 with mobile phase and transferred into HPLC autosampler held at 8 °C. Chromatographic separation was carried out in a gradient mode at 35 °C on an ultra-Biphenyl column using a Thermo Scientific chromatographic system with a Diode array. Data management was performed with Chromeleon 7.4 software. ResultsThe HPLC-UV method proved to be linear over wide concentration ranges (0.5–50.0 mg/L) and was accurate and reproducible in the absence of matrix effects, allowing for robust, specific, and rapid quantification of ceftobiprole from a low amount of serum (0.1 mL). The mean steady state Ctrough and Cend values measured in the anonymous patients’ samples were 6.26 ± 3.81 mg/L and 22.56 ± 15.69 mg/L, respectively. ConclusionsWe report a broadened simple and fast HPLC with UV detection method for quantification of ceftobiprole in human serum to implement ceftobiprole TDM as clinical routine, and support future (PK/PD) studies in special patients’ population.

Titration of anti-IL-5 biologics in severe asthma: an open-label randomised controlled trial (the OPTIMAL study).

Anti-interleukin (IL)-5 biologics effectively reduce exacerbations and the need for maintenance oral corticosteroids (mOCS) in severe eosinophilic asthma. However, it is unknown how long anti-IL-5 treatment should be continued. Data from clinical trials indicate a gradual but variable loss of control after treatment cessation. In this pilot study of titration, we evaluated a dose-titration algorithm in patients who had achieved clinical control on an anti-IL-5 biologic. In this open-label randomised controlled trial conducted over 52 weeks, patients with clinical control (no exacerbations or mOCS) on anti-IL-5 treatment were randomised to continue with unchanged intervals or have dosing intervals adjusted according to a titration algorithm that gradually extended dosing intervals and reduced them again at signs of loss of disease control. The OPTIMAL algorithm was designed to down-titrate dosing until signs of loss of control, to enable assessment of the longest dosing interval possible. Among 73 patients enrolled, 37 patients were randomised to the OPTIMAL titration arm; 78% of patients tolerated down-titration of treatment. Compared to the control arm, the OPTIMAL arm tended to have more exacerbations during the study (32% versus 17%; p=0.13). There were no severe adverse events related to titration, and lung function and symptoms scores remained stable and comparable in both study arms throughout. This study serves as a proof of concept for titration of anti-IL-5 biologics in patients with severe asthma with clinical control on treatment, and the OPTIMAL algorithm provides a potential framework for individualising dosing intervals in the future.

Screening indicators to evaluate the clinical significance of drug-drug interactions in polypharmacy among older adults with psychiatric disorders: a delphi study

BackgroundPolypharmacy is common in older adults with psychiatric disorders, but no consensus has reached about the reliable indicators evaluating the benefits and risks of drug-drug interactions (DDIs) in polypharmacy. We aimed to identify indicators suitable for evaluating the clinical significance of DDIs in polypharmacy in older adults with psychiatric disorders.MethodsThe online tools were used to distribute and collect the questionnaires. The Delphi method was applied to analyze experts’ opinions. The degree of authority and coordination of experts were analyzed using the coefficient of variation, coefficient of coordination, expert’s judgment factor, familiarity with the study content factor, and Kendall coordination coefficient. Statistical analysis was conducted using the IBM SPSS® Statistics Package version 26.0.ResultsAfter three rounds of expert consultation, five primary and eleven secondary indicators were identified. The primary “pharmacodynamic indicator” included “severity of adverse drug reactions”, “duration of adverse drug reaction”, “symptom relief”, “time to onset of symptomatic relief”, “number of days in hospital”, and “duration of medication”. The secondary “pharmacokinetic indicator” contained “dosage administered” and “dosing intervals”. The primary “patient tolerance indicator” contained one secondary indicator of “patient tolerability”. The primary indicator “patient adherence” contained one secondary indicator of “patient adherence to medication”. The primary indicator “cost of drug combination” contained one secondary indicator of “readmission”. These indicators were used to determine the clinical significance of DDIs during polypharmacy.ConclusionsThe clinical significance of drug combinations should be taken into account when polypharmacy is used in the elderly. The five primary indicators and eleven secondary indicators might be preferred to evaluate their risks and benefits. Medication management in this population requires a multidisciplinary team, in which nurses play a key role. Future research should focus on how to establish efficient multidisciplinary team workflows and use functional factors to assess DDIs in polypharmacy for psychiatric disorders.

Simulated Target Attainment of Multidose Regimens of Dalbavancin for Prolonged Durations of Therapy

Abstract Background Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food and Drug Administration approval for these indications. There is no consensus regarding optimal dosing of dalbavancin for these infections and no available pharmacokinetic studies to identify optimal dosing for long-term use. Methods An in silico pharmacokinetic simulation was performed to assess the predicted dalbavancin concentration resulting from commonly utilized dosing regimens, in addition to modified regimens. The primary endpoint evaluated was days of median 24-hour free area under the curve over the minimum inhibitory concentration (AUC/MIC) &amp;gt;27.1, the established PK target. Results A dosing regimen of 1500 mg on day 0 and day 7 resulted in median AUC/breakpoint value above the target for 57 days (lower 95% confidence interval [CI], 37 days). A modified regimen of 1500 mg on day 0 and day 21 resulted in an additional 11 days of median AUC/breakpoint target attainment. The other standard dosing regimen modeled was 1000 mg on day 0, then 500 mg weekly for 5 doses. This regimen achieved the AUC/breakpoint target for 76 days (lower 95% CI, 59 days). This regimen was modified to 1000 mg on day 0, then 500 mg on days 14 and 28, which shortened the median effective treatment duration by 14 days but required 3 fewer doses. Conclusions These simulated results, when combined with the favorable observational data, support the use of commonly reported dalbavancin regimens for prolonged therapy durations. In addition, these pharmacokinetic/pharmacodynamic data support extending the dosing interval beyond the frequently reported weekly regimens, which should be investigated further with a clinical trial.

Standard atezolizumab leads to severe overexposure in real-world patients with lung cancer: How far could we go in extending dosing intervals and saving money?

3085 Background: Immune checkpoint inhibitors are given as fixed doses, which may lead to drug exposure exceeding the plasma concentrations required for target engagement. If confirmed, this could pave the way for de-escalating treatments without compromising efficacy while reducing drug-costs. Methods: We monitored plasma concentrations of Atezolizumab in 40 real-world patients. A final set of 33 patients with SCLC or NSCLC were available for full PK/PD analysis. Individual PK parameters were derived using a population pharmacokinetics approach. Individual PK parameters allowed to simulate the full concentration-time profiles and to further simulate for each patient the time to reach the target threshold after the first dose of Atezolizumab. In addition, efficacy (RECIST criteria) and immune-related adverse events, (IRAEs, CTCAE grading) were monitored and statistical analysis was performed to search for possible exposure-response relationships. Results: Overall Response Rate was 55% and no severe IRAEs were observed. All patients had Cmin levels significantly above the target threshold on the first cycle of Atezolizumab. The mean Cmax after the first dose on cycle 1 was 426.1 µg/ml and the mean Cmin was 68.5 µg/ml, i.e. 11-time higher than the target threshold associated with target engagement (i.e., 6 µg/ml). The mean AUC at the first cycle was 4763 µg.d/ml. Exposure metrics and PK parameters at baseline and simulated prior RECIST evaluation were tested together with other covariates (i.e. age, sex, smoking, NLR, number of metastatic sites, line of treatment) as possible predictive markers of response or toxicity. None of the parameters related to Atezolizumab pharmacokinetics or exposure levels were associated with efficacy or toxicity, most likely because all patients had plasma levels well above pharmacologically active concentrations. First-line therapy was associated with better response on univariate analysis, but this effect was lost on multivariate analysis. Further simulations based on time required to fall below the efficacy threshold suggest that dosing intervals could be extended from Q7W to Q19W (mean: Q12W). Considering the annual budget for Atezolizumab at our institution, further simulations showed that the annual drug cost could thus be reduced from 2.5 M€ to 0.6 M€ while ensuring that all patients remain above active concentrations. Conclusions: Our study demonstrates in a real-world setting that standard Atezolizumab given as 1200 mg Q3W infusion leads to severe overexposure of the drug. This strong overexposure was not associated with more severe treatment-related toxicities. Finally, our study suggests that PK-guided dosing with Atezolizumab could help customizing the dosing interval while maintaining efficacious trough levels and that Q12W could be an alternate scheduling leading to significant cut in drug costs.

Effect of alternative dosing strategies on sustainable healthcare: A carbon footprint analysis of nivolumab and pembrolizumab treatment in the Netherlands.

e13564 Background: Hospitals contribute significantly to greenhouse gas (GHG) emissions and face a moral obligation to prioritize reduction of GHG emissions. Drugs constitute an important component of the GHG emissions of hospitals. Alternative dosing strategies (ADS) have been implemented to improve the cost-effectiveness of pembrolizumab and nivolumab (Table). However, the impact of these ADS on GHG emissions remains unknown. Therefore, this study aimed to analyse the effect of ADS implementation on the carbon footprint of treatment with pembrolizumab and nivolumab. Methods: Life Cycle Assessment (LCA) methodology was used to quantify the environmental impact. The impact category climate change was used to quantify the carbon emissions (CO2e). The GHG Protocol was used to categorize the emissions into scopes 1, 2 and 3. Life Cycle Inventory and Impact data from an academic hospital in Rotterdam were used in the LCA to calculate the CO2e for pembrolizumab and nivolumab, their different dosing intervals, and the impact of ADS. Results: In 2022, the carbon emissions related to nivolumab and pembrolizumab treatment were 445 tons CO2e, with an average of 94 kg CO2e per dosage. Pharmaceutical production was the main driver of treatment-related GHG emissions (93% of total emissions on average). Applying ADS, resulted in carbon emission reductions of 21.4-26.2% and 9.3-11.2% for pembrolizumab and nivolumab respectively (table 1). Conclusions: This study shows the substantial environmental impact of cancer treatments with pembrolizumab and nivolumab and calls for further implementation of ADS for pembrolizumab and nivolumab and other anti-PD-(L)1 monoclonal antibodies and more sustainable pharmaceutical production processes. These findings help to create environmental awareness and contribute to the promotion and understanding of sustainable low-carbon healthcare practices. Overview of registered doses of pembrolizumab and nivolumab, alternative dosing strategies and potential reductions in GHG emissions, based on real world data in The Erasmus University Medical Center in Rotterdam, the Netherlands. [Table: see text]

Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors.

e15114 Background: This open-label, first-in-human, phase 1 study evaluates the safety, pharmacokinetics, and maximum tolerated dose (MTD) of ATG-017, an oral, potent, and highly selective inhibitor of ERK1/2, in patients with refractory advanced solid tumors. Methods: Twenty-one patients with solid tumors harboring activating alterations in the RAS-MAPK pathway were enrolled in the 3+3 design dose-escalation phase for continuous dosing: 5 mg QD (n=1), 5 mg BID (3), 10 mg BID (3), 20 mg BID (7), 30 mg BID (4), and 40 mg BID (3). Results: Safety: All patients reported at least 1 treatment-emergent adverse event (TEAE). Fourteen patients (66.7%) experienced serious adverse events. At 40mg BID, 2 of 3 patients experienced a dose-limiting toxicity (DLT) (grade 3 diarrhea and grade 3 retinopathy). At 30mg BID, 2 of 4 patients experienced a DLT (grade 3 acneiform dermatitis and grade 2 blurred vision). All DLTs resolved with drug interruption. At 20mg BID, a potentially biologically active dose, 7 patients were treated with no DLTs observed. At all dose levels, the most commonly observed TEAEs were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events). Pharmacokinetics: Between 5mg BID and 30mg BID, exposure increased proportionally. At doses 20mg BID or higher, the concentration in the whole dosing interval (≥ 328ng/mL, geometric mean) was higher than the target concentration (231 ng/mL) for effective ERK inhibition derived from preclinical PK/PD models. Efficacy: Of the 21 treated patients, one patient (4.8%) with mesonephric-like ovarian adenocarcinoma (KRAS G12V mutation) in the 30 mg BID cohort achieved a best response of partial response (sustained for six cycles of treatment), and 8 (38%) patients were assessed as having stable disease (sustained over an average of five cycles), based on RECIST v1.1. Conclusions: In patients with solid tumors, 20mg BID continuous dosing of ATG-017 was identified as the MTD and delivers exposure that is likely to be active in inhibiting ERK. This dose is currently being explored in a dose expansion phase. A combination regimen with nivolumab is also being investigated. Clinical trial information: NCT04305249 .

Evaluation of cytokine release syndrome (CRS) in patients with relapsed or refractory multiple myeloma (RRMM) receiving step-up priming doses and longer dosing intervals of elranatamab: MagnetisMM-9.

7522 Background: Elranatamab (ELRA) is a humanized BCMA-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA was given as 2 step-up priming doses (12 mg on C1D1 and 32 mg on C1D4) followed by 76 mg QW in patients (pts) with RRMM. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses 4+. Recurrent CRS (&gt;1 event) occurred in 15.1% of pts (Lesokhin Nat Med 2023). Methods: MagnetisMM-9 (MM-9; NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA examining an alternative 2-dose step-up priming regimen (4 and 20 mg on C1D1 and C1D4, respectively). Eligible pts had RRMM and were refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg Q2W for 5 cycles (Part 2A). The RP2D from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per ASTCT criteria during C1 is the primary endpoint for both parts. Secondary endpoints include evaluation of AEs and PK. Here, we report the overall safety and CRS profile associated with the 4/20 mg priming regimen. Results: For 85 treated pts, median age was 64.0 y; 49.4% were male; 23.5% had EMD; 31.8% had high-risk cytogenetics. Pts had a median of 5.0 (range, 1-12) prior LOTs; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 mo, the most common (&gt;50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). ICANS occurred in 4.7% of pts (all grade ≤2). The grade ≥2 CRS rate in C1 was 14.1% (90% CI, 8.4-21.9). CRS rates after the first 3 doses are in the the table. For doses 4+, any grade (grade ≥2) CRS was observed in 10.6% (3.5%) of pts overall, 12.1% (3.0%) of pts continuing to receive 76 mg (n=33), 25.0% (0%) of pts receiving 116 mg (n=12), and 5.0% (5.0%) of pts receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of pts. The geometric means (CV%) of free ELRA concentrations 24 h (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%). Conclusions: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. Clinical trial information: NCT05014412 . [Table: see text]

Exposure-response analyses for optimal therapeutic dose selection of ABBV-383 in patients with relapsed/refractory multiple myeloma (RRMM).

7541 Background: ABBV-383 is a fully human, B-cell maturation antigen (BCMA) × CD3 T-cell–engaging IgG4 bispecific with an effector-silenced Fc region, 2 high-affinity BCMA- and a low-affinity CD3-binding domains. ABBV-383 monotherapy has shown promising activity in patients (pts) with RRMM (Blood 2023;142[suppl 1]:3378). Here, exposure-response (ER) analyses of efficacy and safety endpoints supporting the optimal therapeutic ABBV-383 dose selection are reported in alignment with US FDA’s Project Optimus. Methods: Efficacy (n=218) and safety (n=220) data from the phase 1 study (NCT03933735) escalation cohorts of 0.025 - 120 mg Q3W and expansion cohorts of 20, 40, 60 mg Q3W and 60 mg Q4W including objective response rate (ORR), very good partial response or better (≥VGPR), stringent complete response (sCR)/CR, adverse events (≥G3 and serious), infections (≥G3, overall and serious), cytokine release syndrome (CRS; any-grade, G1, G2, and ≥G2) were modeled. Total(unbound + bound to soluble BCMA) and free (unbound + partially bound to soluble BCMA) Cycle 1 AUCinf, Cmax, and Ctrough and population pharmacokinetic model-derived up to the time of event Cavg and avgCtrough metrics were utilized in the ER analyses (logistic regression; R Version 4.2.2). Relevant pt-specific covariates were tested. Dexamethasone premedication (36 vs 10 mg) was included in CRS models. The ER relationships were utilized to predict the probabilities of efficacy and safety endpoints for relevant doses and thereby, support justification of the optimal therapeutic dose selection. Results: Based on overall assessment, ORR, ≥VGPR, sCR/CR and ≥G3 neutropenia strongly correlated with free Cavg; CRS endpoints (any-grade CRS and G1 only CRS) strongly correlated with Cycle 1 total Cmax (p &lt;0.05). No other endpoints had ER relationships (p &gt;0.05). Only MM type (IgG vs Others) was selected in ≥VGPR and sCR/CR models. ER relationships suggested high response rates of &gt;63% ORR, &gt;53% ≥VGPR, and ≥30% sCR/CR for 40, 60 mg Q3W and 60 mg Q4W. Predictions demonstrated that 20 mg Q3W (&lt;39% ORR and ≥VGPR; &lt;13% sCR/CR) and untested 40 mg Q4W (&lt;60% ORR, &lt;45% ≥VGPR and &lt;23% sCR/CR) provide suboptimal efficacy. The 60 mg Q4W with 36 mg dexamethasone in Cycle1 (limited follow-up and data) was predicted to have ~30% sCR/CR and 31% ≥G3 neutropenia (≈ 40 mg Q3W) and substantially lower any-grade CRS events compared with 40 and 60 mg doses with 10 mg dexamethasone in Cycle 1. Conclusions: While ER analyses indicated promising efficacy and acceptable safety profiles for 40, 60 mg Q3W, and 60 mg Q4W, they support 60 mg Q4W as the optimal ABBV-383 therapeutic dose due to its predicted better therapeutic benefit/risk profile (high response rates, improved/equivalent ≥G3 neutropenia, and lower CRS events) and extended dosing interval. ABBV-383 at 60 mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM.

A phase 1 study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD), and to determine the recommended phase 2 dose (RP2D) of subcutaneous (SC) cetrelimab (CET) in patients (pts) with advanced solid malignancies.

e14602 Background: In part (P) 1 and P2 of LUC1001 (NCT02908906), the RP2D of intravenous (IV) CET was established as 240 mg IV once every 2 weeks (Q2W) or 480 mg IV Q4W, and the PK/PD characteristics, safety profile, and clinical activity were consistent with known and approved PD-1 inhibitors (Felip et al. Cancer Chemother Pharmacol 2022). CET administered SC was investigated in P3 and P4 of LUC1001. Methods: In P3 and P4 of LUC1001, safety, PK, PD, and clinical activity of low- (30 mg/mL [CET-LC]) and high- (150 mg/mL [CET-HC]) concentration SC CET formulations, respectively, were evaluated. Key entry criteria were advanced or refractory solid tumors, previous receipt of or ineligibility for standard treatment, and being anti-PD-1/PD-L1/2–naïve. In P3, SC CET-LC injection was administered at a dose level of 600 mg with a 6-week dosing interval between doses 1 and 2, then Q3W dosing after dose 2. In P4, SC CET-HC injection was administered as a single loading dose of 900 mg, followed by 600 mg Q3W. Results: Among 30 enrolled pts (P3: n = 11; P4: n = 19), median age was 54.5 years; 17 (57%) were male; most (29 [97%]) were White and heavily pretreated, with a median of 3 (range, 1-8) prior lines of therapy. Most common tumor types were colorectal cancer (6 [20%]), breast cancer (4 [13%]), cholangiocarcinoma and NSCLC (3 [10%] each). Most commonly reported adverse events (AE) were fatigue (11 [37%]), ALT increased (7 [23%]), abdominal pain, constipation and AST increased (6 [20%] each). Overall, 20 (67%) pts had CET-related AEs, 1 (3%) of which led to CET discontinuation. Eight (27%) pts had ≥1 CET-related ≥Grade 3 AE. Immune-related AEs were reported in 9 (30%) pts. No pts experienced systemic-administration–related reactions, and 2 (6%) pts experienced Grade 1 administration-site reactions. No CET-related serious AEs were reported. Durable responses were observed in 2 (7%) patients (cholangiocarcinoma in P3 and thymoma in P4). Stable disease ≥24 weeks was observed in 4 (13% [P3, 0 (0%); P4, 4 (21%)]) pts. According to PK data, the 900-mg SC CET loading dose followed by 600-mg SC CET Q3W would likely result in comparable exposure as observed at steady state with IV RP2Ds. No differences in PK, including absorption, were observed between CET-LC and CET-HC formulations. Maximum PD-1 receptor occupancy was achieved, consistent with historical IV and SC data. Incidence of anti-CET antibodies (P3, 3/11 [27%]; P4, 0/13 [0%]) was low, and no neutralizing antibodies (0/24 [0%]) were detected. Conclusions: SC CET demonstrated a safety profile similar to IV CET. Based on safety, PK, and PD data, the RP2D of SC CET was established as a loading dose of 900 mg followed by 600 mg Q3W. Studies are planned to further evaluate the safety and efficacy of SC CET in combination with other agents. Clinical trial information: NCT02908906 .

Population Pharmacokinetics of Cabozantinib in Metastatic Renal Cell Carcinoma Patients: Towards Drug Expenses Saving Regimens.

Cabozantinib is one of the preferred treatment options in the latest metastatic renal cell carcinoma (mRCC) guidelines. Cabozantinib is also associated with high drug expenses irrespective of the used dose, because a flat-prizing model has been implemented. In addition, concomitant intake with a high-fat meal increases its bioavailability on average by 57%. Combined with the long terminal half-life of cabozantinib (99h), this creates possibilities to extend the dosing interval to reduce drug expenses whilst maintaining equivalent exposure. The primary objective was to evaluate the population pharmacokinetic (POPPK) model of cabozantinib developed for its registration using real-world patients' therapeutic drug monitoring (TDM) data. The secondary objective was to design, simulate, and evaluate alternative dose regimens with the aim to reduce drug expenses whilst maintaining comparable exposure. Retrospective TDM data from mRCC patients treated with cabozantinib were obtained. The data were evaluated using the published Food and Drug Administration (FDA) cabozantinib POPPK model, a two-compartment disposition model with a dual (fast and slow) lagged first-order absorption process derived from FDA registration documents, as a basis. Subsequently, simulations of alternative drug expenses saving regimens were evaluated. Twenty-seven mRCC patients with 75 pharmacokinetic observations were included. Patients were treated for a median of 75 days with a median dose of 40 mg. Model evaluation results showed that the cabozantinib TDM concentrations were adequately predicted by the published FDA cabozantinib POPPK model, except for a slightly higher clearance(CL) of 3.11 L/h compared to the reported value (2.23 L/h). The simulation study indicated that an alternative dose regimen that consists of taking 60 mg of cabozantinib for 2 days and then skipping 1 day results in comparable average exposure when compared with a 40mg daily dose, both without food interaction, while saving 33.3% of the total drug expenses per month. The food effect of a high-fat meal was also taken into account when simulating other alternative dose regimens; 40 mg every 72h combined with a high-fat meal resulted in comparable exposure when compared with a 20mg daily dose fasted, while saving 66.7% in drug expenses. In this study, the optimized cabozantinib POPPK model resulted in adequate prediction of real-world cabozantinib pharmacokinetic data. Alternative dosing regimens with and without using known food interactions were proposed that resulted in potential strategies to significantly reduce cabozantinib drug expenses.

A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (&lt;75 × 109/L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to &gt;75 × 109/L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts &gt;75 x 109/L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .

Degree of Cyclooxygenase-2 Inhibition Modulates Blood Pressure Response to Celecoxib and Naproxen.

Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI2) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION. Sixteen healthy participants (19-61 years) were treated with celecoxib (100 mg every 12h), naproxen (250 mg every 12h), or placebo administered twice daily for seven days in a double-blind, crossover design randomized by order. On Day 7 when drug levels had reached steady state, the degree of COX inhibition was assessed ex vivo and in vivo. Ambulatory blood pressure was measured throughout the final 12h dosing interval. Both NSAIDs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9±21.7%) than celecoxib (35.7±25.2%; p<0.05). Similarly, naproxen treatment inhibited PGI2 formation in vivo (48.0±24.9%) to a greater degree than celecoxib (26.7±24.6%; p<0.05). Naproxen significantly increased blood pressure compared to celecoxib (differences in least-square means of mean arterial pressure: 2.5 mm Hg (95% CI: 1.5, 3.5); systolic blood pressure: 4.0 mm Hg (95% CI: 2.9, 5.1); diastolic blood pressure: 1.8 mm Hg (95% CI: 0.8, 2.8); p<0.05 for all). The difference in systolic blood pressure relative to placebo was associated with the degree of COX-2 inhibition (p<0.05). Celecoxib 200 mg/day inhibited COX-2 activity to a lesser degree than naproxen 500 mg/day, resulting in a less pronounced blood pressure increase. While the PRECISION trial concluded the non-inferiority of celecoxib regarding cardiovascular risk, this is based on a comparison of doses that are not equipotent.ClinicalTrials.gov identifier: NCT02502006 (https://clinicaltrials.gov/study/NCT02502006).

A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.