Dosing Interval Research Articles

First Results from a Phase 1, First-in-Human Study of the Bruton's Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies (BGB-16673-101)

Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria). Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent. Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash). BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks. Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

Classical Complement Inhibition By SAR445088 (BIVV020) in Adults with Cold Agglutinin Disease: Safety, Tolerability and Activity Results from the Open-Label, Non-Randomized, Single-Dose Phase 1b Study

Background:Cold agglutinin disease (CAD) is a rare, chronic autoimmune hemolytic anemia characterized by complement-mediated hemolysis. The classical complement inhibitor sutimlimab, is the first approved pharmacotherapy for treating patients with CAD. The second-generation complement inhibitor SAR445088 (BIVV020) is a humanized monoclonal antibody that selectively inhibits the activated form of C1s (sutimlimab inhibits total C1s). Furthermore, SAR445088 contains mutations that increase FcRn binding, preventing its degradation and allowing it to be recycled back into the system, resulting in reduced drug clearance and a prolonged half-life, which may allow a longer dosing interval than that of sutimlimab. Aims:This Phase 1b open-label study evaluated the safety, tolerability, effect on hemolysis, and pharmacodynamics (PD)/pharmacokinetics (PK) of a single intravenous (IV) dose of SAR445088. The study aimed to assess the impact of SAR445088 on complement-mediated hemolysis to support proof of concept for SAR445088 as a treatment for patients with CAD. Methods:The study design included up to three single-dose cohorts with a maximum of six patients per cohort. SAR445088 was administered on Day 1 with follow-up visits from Day 2 to Day 71; end of study (EOS) visit was on Day 106. The first cohort received a dose of 30 mg/kg IV with decisions about the selection of the dose for the next cohort being based on safety, biomarker activity, and PD. In the second cohort, patients received a lower dose of 15 mg/kg IV; a third, higher-dose cohort was not enrolled. To be enrolled in the study, participants needed to be aged ≥18 years with a confirmed diagnosis of CAD and a hemoglobin level ≤11.0 g/dL at time of screening. The primary endpoint was assessment of safety, with secondary endpoints of hematologic biomarkers and PD/PK. Results:Twelve patients received a single IV dose of SAR445088 (n=6, 30 mg/kg; n=6, 15 mg/kg). Patients enrolled in the study were mainly female (91.7%, n=11) with a median age (range) of 69 (54-80) years, and median (range) hemoglobin at baseline was 9.60 (4.8-10.9) g/dL. There were no treatment-emergent serious adverse events (AEs), discontinuations or deaths reported in the study. Fifty-eight treatment-emergent AEs (TEAEs) were reported in 11 patients (91.7%). There was one reported pre-treatment severe AE (Grade 3) of hemolytic anemia in a patient in the 15 mg/kg IV cohort which began prior to treatment and continued during the treatment period; the remainder of TEAEs were mild or moderate in severity (Grade 1 or 2). The most frequently reported AE was hematuria. No serious infections, meningococcal infections, hypersensitivity, or thromboembolic events were reported. Nine patients (n=4, 30 mg/kg IV cohort; n=5, 15 mg/kg IV cohort) reached an increase of hemoglobin ≥1.5 g/dL from baseline to Day 106 (EOS visit); eight patients (n=4 for both cohorts) reached an increase in hemoglobin >1.0 g/dL from baseline to Day 15 (Figure A). Total mean bilirubin decreased by Day 1 and this was sustained to Day 106 (EOS visit; Figure B).The decrease was more pronounced in the 30 mg/kg IV cohort. Improvements in clinical markers correlated with sustained reductions in CH50 in both treatment cohorts. Reductions in mean percent classical complement pathway (CP) activity were noted 1 hour after a single dose of 30 or 15 mg/kg IV, followed by gradual rebound of CP activity over the 15-week study period. Conclusion:SAR445088 was generally well tolerated; no safety concerns were identified in patients with CAD. A single IV dose of SAR445088 led to classical complement inhibition, control of hemolysis, and improvement in anemia, which was sustained for 15 weeks.

Pirtobrutinib in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Patients with Prior cBTKi: Safety and Efficacy Including High-Risk Subgroup Analyses from the Phase 1/2 BRUIN Study

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

Genomic Evolution and Resistance during Pirtobrutinib Therapy in Covalent BTK-Inhibitor (cBTKi) Pre-Treated Chronic Lymphocytic Leukemia Patients: Updated Analysis from the BRUIN Study

Background: The majority of patients (pts) discontinue covalent (c) Bruton tyrosine kinase (BTK) inhibitors (BTKi) for either progression or intolerance. BTK Cysteine 481 substitution is known to contribute to cBTKi acquired resistance to ibrutinib, acalabrutinib, and zanubrutinib.Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib has demonstrated broad efficacy in pts with chronic lymphocytic leukemia (CLL) following prior therapy, including those treated with a prior cBTKi, independent of BTK C481 mutational status (Mato et al, NEJM, 2023). Here we report the largest systematic evaluation of genomic evolution in pts with CLL treated with pirtobrutinib conducted to date, using a larger cohort of pts and longer follow-up than previously reported. Methods: Relapsed cBTKi pre-treated CLL pts in the phase 1/2 BRUIN trial (NCT03740529) who subsequently developed disease progression (PD) on pirtobrutinib monotherapy were included. Targeted next-generation sequencing (NGS) was centrally performed on peripheral blood mononuclear cells collected at baseline and within four months of PD . Results: As of May 5, 2023, 86cBTKi pre-treated CLL pts had paired NGS data available at baseline and pirtobrutinib progression. In this group, the median age was 69 years (range, 36-86), median number of prior lines of therapy was 4 (range, 1-10), 74 pts (86%) had discontinued prior cBTKi due to PD and 12 pts (14%) discontinued due to toxicity/other. Pts received one or more of the following prior cBTKi: ibrutinib (n=77, 90%), acalabrutinib (n=15, 17%), or zanubrutinib (n=2, 2%). Median time on pirtobrutinib treatment was 16 months (range, 1.2-39 months). Among these 86 pts who ultimately progressed on pirtobrutinib, the ORR (including partial response with lymphocytosis) was 83% (95%CI, 73-90). The most common baseline alterations were mutations in BTK (53%), TP53 (48%), SF3B1 (35%), ATM (23%), NOTCH1 (20%), XPO1 (16%), PLCG2 (14%), and BCL2 (9%). In 46 pts, 64 BTK mutations were detected at baseline and included C481S (n=45), C481F/R/Y (n=11), T474I/F/S (n=6), A428D (n=1), D149G (n=1). Among 42 pts with C481, BTK C481 VAF decrease or complete clearance was observed at PD in the majority of pts (86%, 36/42, complete clearance = 55%, 23/42). NGS of samples at PD showed 69% (59/86) of pts acquired ≥1 mutation. In 38 (44%) pts, 52 acquired BTK mutations were detected and most commonly included gatekeeper mutations (T474I/F/S/L/Y, n=25 in 22 pts), kinase-impaired (L528W, n=14 in 14 pts), C481S/R/Y (n=6 in 4 pts) and others proximal to the ATP-binding pocket (n=7 in 5 pts), including D539A/G/H (n=3 in 1 pt), V416L (n=2 in 2 pts), Y545N (n=1) and A428D ([n=1] Figure). A total of 83 non-BTK acquired mutations were observed at PD in 45 pts (52%), including 14 TP53 mutations in 12 pts (14%), 6 PLCG2 mutations in 6 pts (7%), 6 PIK3CA mutations in 6 pts (7%) and 3 BCL2 mutations in 3 pts (3%). Conclusions: Despite this cohort representing the first relapsing CLL patients from BRUIN and presenting with frequent baseline BTK mutations, response to pirtobrutinib was high, with an ORR of 83%, and substantial clearance of BTK C481 clones. At progression, the majority of pts (56%) either acquired non-BTK mutations or did not acquire any resistance mutations in this targeted panel, suggesting alternative resistance mechanisms. A smaller group of patients (44%) displayed emergence of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations. Whether similar patterns of resistance would manifest if pirtobrutinib was utilized in earlier lines of therapy or prior to cBTKi treatment remains uncertain.

Outcomes of clinical pharmacist integration in a community oncology practice.

61 Background: There is a need to optimize the education and follow-up of patients receiving oral anticancer agents (OAAs) and high emetic risk chemotherapy (HEC) due to toxicities and implications of non-adherence and decreased dose intensity. The purpose of this study was to compare outcomes before and after the integration of a clinical pharmacist in a community oncology practice. Prior to the pharmacist, patients receiving OAAs and intravenous (IV) HEC received education and symptom monitoring by a team of nurses. Methods: This single center, retrospective analysis was conducted with data from February 2020 – December 2022. Up to 200 patients in the pre- and post-intervention periods each were identified. Charts were eligible for abstraction if patients were newly prescribed an OAA or IV HEC regimen during the study period. The post-intervention period began after the pharmacist’s start in March 2021. Patients receiving endocrine therapy for breast cancer were excluded. The following data were abstracted: patient demographics, OAA and IV HEC medication, line of therapy, cancer diagnosis, prescribed date, start date, education date, follow-up visits, emergency department (ED) and hospitalizations, reason for ED/hospitalization, IV HEC dose adjustments, delays and discontinuations. Chi-square analyses compared pre and post time periods. Results: Abstraction was completed for 179 patients in the pre-intervention (n=61 IV HEC; n=118 OAA) and 162 patients in the post-intervention group (n=44 IV HEC; n=118 OAA). After the pharmacist was integrated into the practice, more patients in the OAA group received education prior to their OAA start and had their medication adherence assessed. In the IV HEC group, more patients received guideline concordant care with a 4-drug regimen (including olanzapine) and were more often able to remain on their prescribed dose and dosing interval in the group with pharmacist care. Other outcomes remained approximately the same across time periods. Conclusions: Embedded clinical pharmacist care improved patient outcomes, including improved rates of patient education, medication adherence assessment, and improved dose intensity. [Table: see text]

Oral voriconazole therapy in cats with histoplasmosis yielded mild side effects and a favorable outcome.

Infection by Histoplasma organisms most commonly results in disseminated systemic infection in cats. Relapse during therapy with itraconazole and fluconazole has been reported. The aim of this study was to report the clinical response, duration of therapy, side effects, and outcome in cats with histoplasmosis that were treated with voriconazole. 6 client-owned cats. Medical records were reviewed of cats with confirmed histoplasmosis that presented to the Kansas State University Veterinary Health Center and received voriconazole therapy (n = 6 cats). 4 cats were switched to voriconazole from fluconazole (n = 2), itraconazole (1), or both (1), and 2 cats received voriconazole as initial therapy. Median starting dosage was 3.51 mg/kg PO every 72 hours. Two cats required a change in dosing interval from every 72 hours to every 96 hours due to hyporexia (n = 2) and an elevated ALT (1). Remission was documented in all 6 cats with a median time to a negative urine antigen of 256 days (range, 94 to 494 days). Voriconazole therapy in 6 cats with histoplasmosis yielded mild side effects and a favorable outcome. Reported dosages provide a feasible alternative to daily dosing for owners of feline patients.

Eleven-month SARS-CoV-2 binding antibody decay, and associated factors, among mRNA vaccinees: implications for booster vaccination

Background. We examined the 11 month longitudinal antibody decay among two-dose mRNA vaccinees, and identified factors associated with faster decay. Methods. The study included samples from the COVID-19 Occupational Risk, Seroprevalence and Immunity among Paramedics (CORSIP) longitudinal observational study of paramedics in Canada. Participants were included if they had received two mRNA vaccines without prior SARS-CoV-2 infection and provided two blood samples post-vaccination. The outcomes of interest were quantitative SARS-CoV-2 antibody concentrations. We employed spaghetti and scatter plots (with kernel-weighted local polynomial smoothing curve) to describe the trend of the antibody decay over 11 months post-vaccine and fit a mixed effect exponential decay model to examine the loss of immunogenicity and factors associated with antibody waning over time. Results. This analysis included 652 blood samples from 326 adult paramedics. Total anti-spike antibody levels peaked on the twenty-first day (antibody level 9042 U ml−1) after the second mRNA vaccine dose. Total anti-spike antibody levels declined thereafter, with a half-life of 94 [95 % CI: 70, 143] days, with levels plateauing at 295 days (antibody level 1021 U ml−1). Older age, vaccine dosing interval <35 days, and the BNT162b2 vaccine (compared to mRNA-1273 vaccine) were associated with faster antibody decay. Conclusion. Antibody levels declined after the initial mRNA series with a half-life of 94 days, plateauing at 295 days. These findings may inform the timing of booster vaccine doses and identifying individuals with faster antibody decay.

OTAC: Optimization of Antibiotic Therapy in Critically ill Patients. Using beta-lactam antibiotics by continuous infusion

ObjectiveTo determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous infusion who achieved the target pharmacokinetic/pharmacodynamic (PK/PD) index, which was defined as free concentrations four times more than the minimum inhibitory concentration (CMI) for 100% of the dosing interval (100% fT ≥ 4 x MIC). MethodPreliminary data from a larger prospective clinical study analysing the PK/PD behaviour of β-lactams antibiotics continuous infusion (CI) in critical patients. The study was conducted in the intensive care units of a tertiary university hospital for adults (June 2015-May 2017). Inclusion criteria: normal renal function (glomerular renal function (GFR) CKD-EPI formula ≥ 60 mL/min/1.73 m2) and treatment with standard dose β-lactams CI. Concentrations at steady state (Css) conditions were determined using UHPLC-MS/MS. We selected the highest susceptible MIC for all likely organisms according to European Commitee on Antimicrobial Susceptibility Testing's (i.e. piperacillin/tazobactam: 8 mg/L for enterobacteriaceae and 16 mg/L for Pseudomonas aeruginosa; meropenem: 2 mg/L for any microorganism). In addition, a subanalysis of patients was conducted using actual MIC values. Results61 patients were enrolled (25 to meropenem and 36 to piperacillin/tazobactam). Average age was 59 (15) years and median GFR rate was 95 mL/min/1.73 m2 (83-115). Median meropenem and piperacillin free concentrations were 16 mg/L (11-29) and 40 mg/L (21-51), respectively.88% of patients treated with meropenem reached the PK/PD target, without differences between both microorganisms. For piperacillin/tazobactam, 61% and 11% of patients reached the target, with enterobacteriaceae and Pseudomonas as suspected microorganisms, respectively. The pathogen was isolated in 35 (57%) patients: 94% reached the target PK/PD, without differences between both antibiotic therapies. ConclusionsStandard doses of meropenem CI are sufficient to achieve a PK/PD target of 100% fT ≥ 4 x MIC in suspected infections with high MICs (Pseudomonas aeruginosa or enterobacteriaceae). However, higher doses of piperacillin/tazobactam could be considered to achieve this goal. In patients with isolated microorganisms, a standard dose of both antibiotic therapies would be sufficient to achieve the target. Therapeutic drug monitoring is highly recommended for therapeutic optimization.

Flocculation with intermittent dosing for enhanced microalgae harvesting

One of the bottlenecks to the industrialization of algal biofuel is the high cost of harvesting. Flocculation is an efficient technique for algae harvesting, but flocculant consumption results in additional expenses. To lower the overall cost of algae harvesting, it is essential to explore approaches to reduce flocculant usage. In this study, a novel flocculant dosing strategy of intermittent dosing was investigated for enhanced algae harvesting efficiency, with comparisons to traditional one-time dosing, continuous dosing and dual dosing. The impacts of critical operational parameters were examined, and the mechanism was investigated based on floc analysis. The results demonstrated that intermittent dosing can significantly enhance harvesting efficiency. At the optimal operational conditions of 5 s dosing interval, 10 mg/L min−1 dosing speed and 5 min stirring time, the algae harvesting efficiency increased from 71.1 % to 91.3 % compared to one-time dosing when 15 mg/L CPAM was used as a flocculant. According to floc analysis, intermittent dosing tended to form larger and loosely connected flocs, while traditional one-time dosing tended to produce smaller and denser flocs. The different floc growth mechanisms can help to explain how intermittent dosing improved algae flocculation. In addition, intermittent dosing resulted in a higher removal efficiency of dissolved extracellular organic matter and improved algae recultivation. Finally, the cost estimation was performed, and the operational cost was lowered from 32.65 USD ton−1 algae for one-time dosing to 20.64 USD ton−1 algae for intermittent dosing. Through the investigation of this study, the technical, mechanical and economic feasibility of intermittent dosing for enhanced algae harvesting were established.

189 The Effects of Dose Timing / Intervals on Grow-Finish Performance, Carcass Characteristics, Carcass Cutting Yields, and Meat Quality of Market Gilts Managed with Improvest

Abstract Improvest (Zoetis Canada Inc.) immunization provides temporary suppression of ovarian function and estrus in market gilts. The product requires two sequential injections administered at least 4 weeks apart, with full suppression of ovarian function demonstrated 4 to 10 weeks after the second injection. Recent research has shown the importance of closely monitoring the durations between the injections and between the second injection and slaughter. The objective was to determine the effects of dose timing and interval on grow-finish performance, carcass cutting yields, and meat quality of market gilts managed with Improvest when days on feed remained constant. The study consisted of 1,056 market gilts (average starting body weight of 31.7 kg) in 48 pens (22 pigs/pen) with experimental treatments arranged as a 2 × 2 factorial design with main effects of interval between the first and second Improvest injection (D1-D2; 4-week interval or 6-week interval) and time between the second Improvest injection and slaughter [D2-slaughter; weighted average of 34 to 35 days post-second injection (SHORT) or weighted average of 48 to 49 days post-second injection (LONG)]. Pigs were marketed using a similar strategy where the heaviest 3 to 5 pigs from each pen were marketed during study week 12, the next heaviest 3 to 5 pigs from each pen were marketed during study week 14, and the remaining pigs in the pen were marketed during study week 15. Hot carcass weight and optical probe readings (Destron PG-203; Anitech Identification System Inc.) were collected during slaughter. Following slaughter, 288 carcasses (24/treatment for each marketing event; pigs near the population average) were selected for evaluation of carcass cutting yields and meat quality. Data were analyzed with PROC MIXED of SAS, with pen serving as the experimental unit. There were limited interactions between D1-D2 and D2-slaughter, with nonsignificant interactions (P ≥ 0.07) for average daily feed intake (ADFI), average daily gain (ADG), and feed:gain (F:G) ratio during the grow-finish period, hot carcass weight, backfat thickness, or carcass primal weights. Overall, this study illustrated the trade-offs associated with altering the duration of time between D2-slaughter. From a live production standpoint, there were significant differences (P < 0.01) for D2-slaughter for ADFI and F:G ratio, with SHORT having reduced ADFI (2.47 kg versus 2.53 kg) and more efficient F:G (2.69 versus 2.74) compared with LONG (Table 1). From a meat processing standpoint, there were meaningful differences observed in fat deposition for D2-slaughter. In terms of fat quantity, backfat thickness and belly primal weight were affected (P < 0.01) by D2-slaughter (LONG had 0.78 mm greater backfat thickness and 0.15 kg heavier trimmed bellies). In terms of fat quality, iodine value and belly firmness were affected (P < 0.01) by D2-slaughter (LONG had 1.30 units lower iodine value and superior belly flop scores).

Cefepime Daily Exposure and the Associated Impact on the Change in Sequential Organ Failure Assessment Scores and Vasopressors Requirement in Critically Ill Patients Using Repeated-Measures Mixed-Effect Modeling.

Sepsis and septic shock are major healthcare problems that need early and appropriate management. To evaluate the association of daily cefepime pharmacokinetic/pharmacodynamic (PK/PD) parameters with change in Sequential Organ Failure Assessment (SOFA) score and vasopressors requirement. This is a retrospective study. Adult ICU patients who received cefepime for Gram-negative pneumonia or bloodstream infection (BSI) and had cefepime concentrations measured were included. Daily cefepime exposure was generated and PK/PD parameters calculated for patients. Repeated-measures mixed-effect modeling was used to evaluate the impact of PK/PD on the outcomes. Change in daily SOFA score and vasopressors requirement. A total of 394 and 207 patients were included in the SOFA and vasopressors analyses, respectively. The mean (±sd) age was 55 years (19) and weight 81 kg (29). For the change in SOFA score, daily SOFA score, mechanical ventilation, renal replacement therapy, and number of vasopressors were included. In the vasopressors analysis, daily SOFA score, day of therapy, and hydrocortisone dose were significant covariates in the final model. Achieving cefepime concentrations above the minimum inhibitory concentration (MIC) (T>MIC) for 100% of the dosing interval was associated with 0.006 µg/kg/min decrease in norepinephrine-equivalent dose. Cefepime PK/PD did not have an impact on the daily change in SOFA score. Achieving 100% T>MIC was associated with negligible decrease in vasopressors requirement in ICU patients with Gram-negative pneumonia and BSI. There was no impact on the change in SOFA score.

Rituximab bij auto-immune blaarziekten

Rituximab for autoimmune bullous diseases For a long time, the treatment of autoimmune blistering diseases consisted of classical immunosuppressants. Recently, biologicals, including rituximab, directed against the pan B-cell marker CD20, are used. Currently, practical guidelines for the optimal use of rituximab in the treatment of autoimmune blistering diseases are still under discussion. This literature review provides an overview of the efficacy, side effects, indication, optimal dosage and administration interval of rituximab in this population. In total, 37 publications were included, based on a systematic search strategy and selection procedure. The reported efficacy of rituximab in pemphigoid, expressed as complete remission without further therapy, ranges from 20% to 79%. For pemphigus, this amounts to 89% in the RITUX-3 study, which formed the basis for approval as first-line therapy. Side effects occur in 24% to 85% of the cases. The most important are infusion-related reactions and infections. In general, the safety profile corresponds to the known side effects of rituximab in other indications. The evidence for the practical guidelines is mainly built around pemphigus. Currently, the ‘high-dose rheumatoid arthritis protocol’ is preferred, although randomised, comparative studies are lacking. The high relapse rate justifies the need for repeated administrations. Further research should clarify whether repeated administration should be done systematically or based on different parameters. Rituximab is an effective and relatively safe therapy in autoimmune blistering diseases in both first and second line. In terms of practical use, further research is recommended.

Pharmacokinetic–pharmacodynamic cutoff values for benzylpenicillin in horses to support the establishment of clinical breakpoints for benzylpenicillin antimicrobial susceptibility testing in horses

IntroductionThe aim of this international project was to establish a species-specific Clinical Breakpoint for interpretation of Antimicrobial Susceptibility Testing of benzylpenicillin (BP) in horses.MethodsA population pharmacokinetic model of BP disposition was developed to compute PK/PD cutoff values of BP for different formulations that are commonly used in equine medicine around the world (France, Sweden, USA and Japan). Investigated substances were potassium BP, sodium BP, procaine BP, a combination of procaine BP and benzathine BP and penethamate, a prodrug of BP. Data were collected from 40 horses that provided 63 rich profiles of BP corresponding to a total of 1022 individual BP plasma concentrations.ResultsA 3-compartment disposition model was selected. For each of these formulations, the PK/PD cutoff was estimated for different dosage regimens using Monte Carlo simulations. The fAUC/MIC or fT>MIC were calculated with a free BP fraction set at 0.4. For fAUC/MIC, a target value of 72 h (for a 72h treatment) was considered. For fT>MIC, efficacy was assumed when free plasma concentrations were above the explored MIC (0.0625-2 mg/L) for 30 or 40 % of the dosing interval. For continuous infusion, a fT>MIC of 90 % was considered. It was shown that a PK/PD cutoff of 0.25 mg/L can be achieved in 90 % of horses with routine regimen (typically 22,000 IU/kg or 12.4 mg/kg per day) with IM procaine BP once a day (France, Japan, Sweden but not USA1) and with IM sodium BP at 14.07 mg/kg, twice a day or IV sodium BP infusion of 12.4 mg/kg per day. In contrast, penethamate and the combination of procaine BP and benzathine BP were unable to achieve this PK/PD cutoff not even an MIC of 0.125 mg/L.DiscussionThe PK/PD cutoff of 0.25 mg/L is one dilution lower than the clinical breakpoint released by the CLSI (0.5 mg/ L). From our simulations, the CLSI clinical breakpoint can be achieved with IM procaine BP twice a day at 22,000 IU i.e. 12.4 mg/kg.

Utilizing Ceftazidime/Avibactam Therapeutic Drug Monitoring in the Treatment of Neurosurgical Meningitis Caused by Difficult-to-Treat Resistant Pseudomonas aeruginosa and KPC-Producing Enterobacterales.

Central nervous system (CNS) infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales and difficult-to-treat resistant (DTR) Pseudomonas aeruginosa represent a formidable clinical challenge. Antimicrobial regimens that efficiently penetrate the cerebrospinal fluid (CSF) and achieve sufficient concentrations associated with microbiologic and clinical cure are limited. We evaluated therapy with ceftazidime-avibactam (CAZ-AVI) in order to guide precise dosing in the treatment of CNS infections. Therapeutic drug monitoring (TDM) was performed in 3 patients with health care-associated ventriculitis and meningitis (HAVM) using CAZ-AVI 2.5 g infused intravenously every 8 hours as standard and extended infusion. Simultaneous CSF and plasma samples were obtained throughout the dosing interval in each patient. Concentrations of CAZ and AVI were determined by liquid chromatography/mass spectrometry. Bacterial identification revealed KPC-producing Klebsiella pneumoniae (KPC-Kp), DTR Pseudomonas aeruginosa, and KPC-producing Enterobacter cloacae (KPC-Ent.c). All isolates were resistant to carbapenems. The minimum inhibitory concentrations (MICs) of CAZ-AVI were 0.25/4, 4/4, and 0.25/4 μg/mL, respectively. CAZ and AVI concentrations were determined in CSF samples ranging from 29.0 to 15.0 µg/mL (CAZ component) and 4.20 to 0.92 µg/mL (AVI component), respectively. AVI achieved concentrations ≥1 µg/mL in 11 out of 12 CSF samples collected throughout the dosing interval. Clinical and microbiologic cure were attained in all patients. Postinfusion concentrations of CAZ-AVI were measured in plasma and CSF samples obtained from 3 patients with complicated CNS infections caused by antimicrobial-resistant isolates. The measured concentrations revealed that standard CAZ and AVI exposures sufficiently attained values correlating to 50% fT > MIC, which are associated with efficient bacterial killing.

Effect ofthe extended dosing interval ofanti-TNF-α NANOBODY® compound ozoralizumab inpatients with low disease activity rheumatoid arthritis.

This article aims to evaluate the effect of the extended dosing interval on the efficacy and safety of ozoralizumab in patients with rheumatoid arthritis (RA). In a long-term extension study (HOSHIZORA trial) for patients who had completed a phase II/III study with methotrexate or a phase III study without methotrexate, the dosing interval of ozoralizumab was allowed to extend from every 4 weeks (Q4W) to every 8 weeks (Q8W), at the physician's discretion, for patients who had maintained a 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) <3.2 at the last two time points. The continuation rate, efficacy, and safety were examined in patients who had completed 24 weeks after the change in the dosing interval by the data cut-off point. Of the 32 patients who maintained DAS28-ESR <3.2 and changed the interval from Q4W to Q8W, 28 (87.5%) remained on Q8W for 24 weeks. At Week 24, the percentages of patients who remained on Q8W and achieved DAS28-ESR <2.6 and <3.2 were 71.9% and 84.4%, respectively. No safety concerns were observed for 24 weeks in the Q8W group. In patients with RA and maintained DAS28-ESR <3.2 with ozoralizumab, efficacy was sustained and well tolerated after the dosing interval was extended from Q4W to Q8W.

Comparison of the efficacy of BCG intravesical immunotherapy using the conventional Rotisserie method with the non-Rotisserie method

BackgroundIntravesical BCG injections are administered following transurethral resection of the superficial bladder tumor in order to increase the success rate and decrease the risk of tumor recurrence. BCG therapy has been examined extensively in terms of dosage and injection time intervals to determine its effectiveness. However, no study has yet been conducted to compare the two qualitatively different methods of administering BCG (Rotisserie and non-Rotisserie).MethodsThis study included 30 patients with non-muscle-invasive bladder TCC, whose tumor stage was Ta or T1. Two groups of 15 patients were randomly selected. The first intravesical injection of BCG was administered 2 weeks following transurethral resection of the bladder tumor and then continued as the maintenance treatment. But, in one group, the injection was done by Rotisserie method, and in the other group, non-Rotisserie method was performed. Then, the patients underwent periodic follow-up by cystoscopy to determine if recurrences had occurred.ResultsA total of 23 participants (76.66%) were males, while seven patients (23.34%) were females. There were 20 participants (66.66%) with tumors in the Ta stage and ten participants (33.34%) with tumors in the T1 stage. There were 22 patients (73.3%) with low-grade tumors and eight (26.7%) with high-grade tumors. Five participants (16.66%) experienced tumor recurrence during the study, three of whom were in the Rotisserie group and two in the Non-Rotisserie group. In terms of preventing tumor recurrence, there were no significant differences between Rotisserie and non-Rotisserie methods (P value = 0.6).ConclusionDue to the lack of significant difference in the rate of tumor recurrence between the two methods of intravesical BCG injection (Rotisserie and non-Rotisserie), it is not necessary to rotate the patients after BCG injection. This will also allow patients to be discharged from the hospital earlier and reduce the likelihood of complications.

Pharmacokinetics and Drug-Drug Interaction of Allisartan Isoproxil and Indapamide Sustained-Release Formulation.

Allisartan isoproxil (AI) is an angiotensin II type 1 receptor blocker and be converted into the active substance EXP3174 in vivo. We evaluated the drug-drug interactions of AI and an indapamide sustained-release (Ind SR) preparation, as well as the pharmacokinetic characteristics and safety of AI and Ind SR in healthy subjects. The trial was set up in 6 sequences and 3 cycles, and each cycle contained a 7-day washout period. Subjects received 3 different trial drugs (A, AI; B, Ind SR; C, AI+Ind SR) during 3 different cycles. Twenty-four subjects were enrolled in the clinical trial. Of these, 22 completed the study, 2 subjects dropped out due to adverse events (AEs). For subjects given AI alone or combined with Ind SR, the pharmacogenetic parameters Cmax and the geometric mean ratio of steady state (combined/single) of EXP3174 was 130%. The geometric mean ratio of area under the concentration-time curve over the dosing interval at steady state (combined/single use) was 144.5%. Therefore, the combination of Ind SR had an impact on the pharmacokinetics of AI. Then, the results indicated that the AI combination had no effect on the pharmacokinetics of Ind SR. Serious AEs did not occur. The AEs in this clinical trial were the same as those for AI and Ind SR. Combined administration resulted in 2 cases (2 subjects) of Grade 3 hypotension and 1 case of Grade 3 hypotension with AI alone. Considering that this trial included healthy volunteers, the risk of hypotension was expected to be manageable.

Efficacy and safety of bone management agents administered at 12 weeks vs. 4 weeks in patients with bone metastases: A systematic review.

Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks. PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs). The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33). This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA.

THU174 Model-Based Analysis Of IGF-I Response, Dosing, And Monitoring For Once-Weekly Somapacitan In Children With GH Deficiency

Abstract Disclosure: R.J. Kildemoes: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. Y. Kamal Lyauk: Employee; Self; Novo Nordisk. J.C. Blair: Speaker; Self; Novo Nordisk, Pfizer, Inc., Ipsen. Other; Self; Novo Nordisk. B.S. Miller: Consulting Fee; Self; Novo Nordisk, Abbvie, Endo Pharmaceuticals, Ascendis Pharma, Bristol-Myers Squibb, Pfizer, Inc., EMD Serono, BioMarin Pharmaceutical, Tolmar. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Novo Nordisk, Lysogene, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. J. Mori: None. M. Højby Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P.F. Backeljauw: Consulting Fee; Self; Novo Nordisk, Novartis Pharmaceuticals, Ascendis Pharma, BioMarin Pharmaceutical, Tolmar Pharmaceuticals, Cavalry Biosciences, Ipsen. Research Investigator; Self; Novo Nordisk, Novartis Pharmaceuticals, Ipsen. Growth hormone (GH) replacement therapy improves overall health and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor-I (IGF-I) release, the biomarker commonly used for guiding GH dose adjustments to ensure optimal long-term safety and efficacy. This study aims to provide model-based insights into the dose-IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared to daily GH in pediatric patients with GHD. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to characterize somapacitan dose-IGF-I response and to predict the response to change of dosing day and missed dosing of somapacitan. Analyses included dosing information and 1473 PK samples from 210 GHD patients treated with somapacitan across three trials: phase 1 (NCT01973244), phase 2 (NCT02616562; REAL3), and phase 3 (NCT03811535; REAL4), as well as 1381 IGF-I samples from 186 GHD patients treated with somapacitan from REAL3 and REAL4. A clear dose-response relationship was observed with increasing somapacitan exposure and increasing change from baseline IGF-I SDS. A linear model permitted the development of a tool to calculate the estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool will require knowledge of the timing of the somapacitan injection relative to the timing of the IGF-I sample collection. IGF-I SDS simulations support flexible dosing day changes while maintaining a minimum of 4 days between doses. In this study, we present a practical guide that may inform clinicians about the expected weekly average IGF-I concentration in somapacitan-treated pediatric patients with GHD from a single sample taken on any chosen day during the weekly dosing interval. The ability to determine weekly average IGF-I enhances our understanding of somapacitan dosing and should support physicians in monitoring long-term safety and efficacy of this therapy. Furthermore, we provide insights on flexibility to change of dosing day and missed dosing of somapacitan. Presentation: Thursday, June 15, 2023

SAT642 Effective Gh Replacement With Once-weekly Somapacitan In Children With Gh Deficiency: 2-year Results From Real4

Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Bristol-Myers Squibb, Novo Nordisk, Pfizer, Inc., EMD Serono, Endo Pharmaceuticals. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Abbvie, Amgen Inc, Novo Nordisk, Pfizer, Inc. J. Blair: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Ipsen. Other; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A.K. Maniatis: Research Investigator; Self; Novo Nordisk, Pfizer, Inc. J. Mori: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Pfizer, Inc. V. Boettcher: Advisory Board Member; Self; Merck. Speaker; Self; Novo Nordisk, Merck. Other; Self; Ferring Pharmaceuticals, Lilly USA, LLC, Merck, Novo Nordisk. H. Kim: None. R. Beck Bang: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. M. Polak: Advisory Board Member; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Ipsen, Novo Nordisk, Pfizer, Inc., Sandoz, Merck, Sanofi. Speaker; Self; Novo Nordisk, Ipsen. R. Horikawa: Advisory Board Member; Self; Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Sandoz. Speaker; Self; Novo Nordisk, Pfizer, Inc. Growth hormone (GH) has a short half-life that necessitates daily subcutaneous (s.c.) injections for replacement therapy in children with GH deficiency (GHD). Although essential to achieve desired clinical outcomes, daily injections are often burdensome for both patients and their caregivers. Somapacitan (Novo Nordisk A/S) is a long-acting reversible albumin-binding human GH derivative in development for once-weekly s.c. administration in children with GHD, with the aim to overcome the treatment burden of daily injections. REAL4 is an ongoing multi-national, randomized, open labelled phase 3 trial consisting of a 52-week main phase followed by a single-group three-year extension period (NCT03811535). During the main phase, 132 patients received once-weekly 0.16 mg/kg/week somapacitan and 68 received daily GH (0.034 mg/kg/day Norditropin®, Novo Nordisk). After 52-weeks of treatment, patients in the daily GH group were switched to 0.16 mg/kg/week somapacitan (switch group) while patients receiving somapacitan continued treatment (soma/soma group). 104-week results are presented here. One hundred and ninety-four patients (67 and 127 for switch and soma/soma groups, respectively) completed 104 weeks of treatment. A small, numerical difference was observed at week 52 for mean height velocity (HV) between treatments and this minor difference was sustained from week 52 to 104 (8.7 vs. 8.4 cm/year for the switch and soma/soma groups, respectively). Underlying growth characteristics in year 1 persisted in year 2 for both groups, including when switching to somapacitan, indicating the treatment arm per se did not influence any difference in growth, but rather the baseline characteristics for each group was the cause of the difference. Other height-related endpoints supported these findings, for example a continuous trend towards increased Height SDS was observed in both groups (change from baseline to week 104 of 1.97 and 1.75 for the switch and soma/soma groups, respectively). Pharmacokinetic/pharmacodynamic modelling suggests similar mean average IGF-I SDS levels over the weekly dosing interval within normal range (-2 to +2 SDS) for both groups (0.754 and 0.725 for the switch and soma/soma groups, respectively) in year 2. Somapacitan was well tolerated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to changes in glucose metabolism and no neutralizing anti-somapacitan antibodies detected. A low proportion of children reported injection-site reactions in the second year (2.9% and 2.3% in the switch and soma/soma groups, respectively) with no injection site pain reported in either group. In conclusion, once-weekly somapacitan showed sustained efficacy over 2 years and after one year following switch from daily GH treatment with a safety and tolerability profile similar to the well-known profile for daily GH. Presentation: Saturday, June 17, 2023