Adult Dose Research Articles

Behavioural and social drivers of COVID-19 vaccination in Vietnam: a scoping review

BackgroundUnderstanding of the behavioural and social drivers (BeSD) of vaccination is key to addressing vaccine hesitancy and accessibility issues. Vietnam’s national COVID-19 vaccination programme resulted in high uptake of primary...

Time-Dosed Stereotactic Radiosurgery for the Treatment of Cerebral Arteriovenous Malformations: An Early Institution Experience and Case Series

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is an effective treatment modality used by neurosurgeons to treat cerebral arteriovenous malformations (AVMs), particularly for treating AVMs <10 cm3. Current strategies include single-staged, dose-staged, and volume-staged SRS, all of which demonstrate varying effectiveness for treating large-volume AVMs (>10 cm3). We introduce a novel refinement called time-dosed SRS for the treatment of large-volume AVMs or AVMs located in eloquent areas. This study aims to detail treatment parameters, outcomes, and complications associated with time-dosed SRS in our early experience study. METHODS: We retrospectively reviewed all patients treated using time-dosed SRS at our institution. Data, including AVM location, history of hemorrhage, history of intervention, AVM volume, Spetzler-Martin grade, presence of residual disease, and occurrence of postprocedural complications, were collected. RESULTS: Sixteen patients were included. The median total AVM volumes treated were 9.64 cm3 (0.92-46.2 cm3) and 13.2 cm3 (3.0-42.2 cm3) in adults and children, respectively. The median margin doses for adults and children at each of the 3 stages were 10 Gy, 10 Gy (8-10 Gy) and 9 Gy (8-10 Gy), and 10 Gy, 10 Gy (9-10 Gy), and 10 Gy (8-10 Gy), respectively. The median total dose delivered was 29 Gy (27-30 Gy) in adults and 30 Gy (28-30 Gy) in children. The median radiological follow-up length was 35 months (9-62 months) in adults and 31 months (4-72 months) in pediatric patients. Complete obliteration was confirmed by cerebral angiogram in 6 adult patients and 1 pediatric patient. One adult patient and 2 pediatric patients suffered radiation-related toxicity. No patients suffered postprocedural hemorrhage. CONCLUSION: Time-dosed SRS seems to be effective for treating large AVMs or those in highly eloquent areas, with a low rate of complications.

A Phase I Study of Venetoclax in Combination with Inotuzumab Ozogamicin for Relapsed or Refractory ALL in Adults

Introduction Adults with acute lymphoblastic leukemia (ALL), especially those who are older and/or have unfavorable disease biology frequently relapse. Inotuzumab ozogamicin (INO), an anti-CD22 monoclonal antibody covalently linked to calicheamicin, is approved for treatment of relapsed or refractory (R/R) CD22+ ALL. Although INO induces measurable residual disease negative (MRD-neg) complete remission (CR) in >75% of patients (pts), the duration of response (DOR) is limited (<6 months). Pre-clinical work demonstrates that malignant lymphoblasts are BCL2-dependent (Del Gaizo Moore Blood 2008). Initial results of the BCL2 inhibitor venetoclax (VEN) combination therapies for ALL are promising (Jain ASH 2019, Pullarkat Cancer Discov 2021). Due to distinct mechanisms of activity, non-overlapping toxicity, and possible synergy (Kirchhoff Blood 2021), we hypothesized that INO and VEN can be safely and effectively combined. Study Design and Eligibility This is an investigator-sponsored phase I study (NCT05016947) with a 3+3 dose escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of VEN plus INO at the FDA-approved doses in adults with R/R CD22+ ALL. Secondary objectives assess efficacy (hematologic response, MRD by multi-parametric flow cytometry [MFC] threshold <0.01%, and DOR). A 14 pt expansion cohort is planned. Dose-limiting toxicity (DLT) is defined as treatment-related CTCAE v5 non-heme toxicity grade 3+, sinusoidal obstructive syndrome (SOS) any grade, or liver toxicity during Induction (Ind) Cycle (C) 1 and/or failure of hematologic recovery (ANC ≥500, Plts ≥25 K/mL) by day 42 of Ind C1 in responding pts. Eligibility: ≥18 years (yrs); ALL (≥5% blasts) or LBL (marrow involvement not required); CD22 expression on ≥20% of blasts; R/R to one or more cycles of CC or in the case of Philadelphia-chromosome (Ph)-positive ALL, failed by two or more TKIs, or refractory to/ineligible for ponatinib; ≥60 days from bone marrow transplant (BMT), and off immune suppression ≥2 weeks; adequate liver and kidney function; no history of liver disease including SOS; blast count ≤25 K/mL prior to treatment; no symptomatic central nervous system (CNS) disease. Pts with prior INO or VEN treatment for R/R ALL are excluded. Regimen Pts are treated with a VEN Ramp-Up over 3 days (DL1: 100/200/200; DL2: 100/200/400) followed by Induction C1: IV INO days 1, 8, 15 (0.8/0.5/0.5 mg/m2) and VEN daily per DL days 1-21. DEX 10 mg/m2 IV/PO is administered during Ramp-Up and Ind C1 days 1-4 (7 days total). Pts with >5% blasts after C1 receive Ind C2 without DEX. Pts with <5% blasts after Ind (1 or 2 cycles) continue with up to four 28-day consolidation cycles (INO 0.5 mg/m2 days 1, 8, 15 plus VEN per DL days 1-21). Pts receive CNS prophylaxis with intrathecal chemotherapy. Results The 2-level dose-escalation phase has been completed; we enrolled 9 pts (5 female/4 male) with Ph-negative (n=7) or Ph-positive (n=2) ALL. The median age was 45 yrs (range 25 -74). Pts had received 1 (n=5) or 2 (n=4) prior lines of therapy. DL1 enrolled 3 pts without DLT. All DL1 pts achieved an MRD-neg CR and bridged to consolidation: 1 pt XRT to involved disease site (ankle) after 3 cycles and 2 pts to BMT after 2 cycles (Table). Three pts enrolled at DL2; no DLTs were observed. All achieved an MRD-neg CR. Two pts bridged to consolidation (donor lymphocyte infusion after 3 cycles, blinatumomab after 5 cycles) while 1 pt with KMT2A-r ALL experienced early relapse with lineage switch during second cycle. A confirmatory cohort of 3 pts enrolled at DL2 without DLT. All achieved a CR (n=2, MRD-neg; n=1, MRD-pos). The pt with MRD-pos CR as best response proceeded to blinatumomab as bridge to BMT after 2 cycles with 2 pts continuing treatment (currently cycle 2). Overall, CR was achieved in 100% (9/9) of pts with 7/8 (87%) achieving MRD-negativity. With median follow-up of 195 days (95% CI 80 - NR), 2 pts have relapsed 48 (on treatment) and 177 (after BMT) days from registration while other pts remain alive in CR. Non-heme grade 3-4 AEs include febrile neutropenia (2), DIC (1), tumor lysis syndrome (1), anxiety (1), hypertension (1), and hypotension (1). There have been no SOS. There were no delays in count recovery during C1, with median time from C1 to C2 being 30 days (range 27-42). Conclusion VEN 400mg x 21 days in combination with INO at standard doses was well tolerated and declared the recommended phase 2 dose (RP2D) with a CR rate of 100%.

A Systematic Review and Meta-Analysis to Evaluate Hydroxyurea at Escalated Dose Versus Fixed Low-Dose Hydroxyurea in Adults with Sickle Cell Disease

Introduction Hydroxyurea (HU), standard therapy for children and adults with severe sickle cell disease (SCD) in resource-rich countries, reduces the frequency of vaso-occlusive complications, increases hemoglobin, and decreases mortality. While guidelines recommend escalating HU to maximum tolerated dose (MTD), use of fixed low and moderate doses of HU are common in low resource countries. HU at MTD is superior to fixed moderate-dose HU in decreasing vaso-occlusive complications, hospitalizations, and blood transfusions in young children with SCD but has not been compared with fixed low or moderate doses in adults. We conducted a systematic review and meta-analysis to evaluate the efficacy of escalated dose HU versus fixed low-dose HU in adults with SCD. Methods This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA), to evaluate if clinical and laboratory outcomes differ between SCD patients treated with HU administered with an escalated versus fixed low-dose strategy. Primary outcomes included vaso-occlusive crisis (VOC), acute chest syndrome, hospitalizations, blood transfusions, and stroke. Secondary outcomes included hemoglobin concentration, fetal hemoglobin (HbF), absolute neutrophil count (ANC), reticulocyte count, and platelet count. Literature search was conducted in PubMed, Embase, Cochrane, and Scopus and included peer-reviewed quantitative studies published from 1995 to 2020. Abstracts and full text articles were reviewed to identify articles that met inclusion criteria. Following the initial search, 2524 citations were retrieved and screened using Rayyan, a web-based software designed to conduct and coordinate systematic literature reviews. After eliminating 385 duplicates, 2139 citations remained. Seventeen full-text articles were then assessed for eligibility, of which 10 were included in the quantitative synthesis. Blinded co-authors used Rayyan to independently check the titles and abstracts based on pre-decided exclusion criteria. This was followed by a full text review of selected articles, and any conflicts were resolved by consensus. Data were systematically extracted using a standardized spreadsheet customized for the study. Average effects across studies were estimated using means for fixed-effect meta-analysis. We calculated the difference in means: MD i = m 1 i - m 2 i with standard errors. The significance of the overall effect (escalated and fixed low-dose) combined was tested using Z tests and group differences between escalated and fixed doses were compared using chi-squared tests. Analyses were conducted in Review Manager (RevMan) version 5.3. Results Ten studies were included in the quantitative synthesis - 5 evaluated the effect of HU at escalated dose and 5 evaluated fixed low-dose HU. The average daily doses of HU in the low fixed-dose and escalated dose studies were ~10 mg/kg and 22 mg/kg, respectively. Available primary and secondary outcome data for HU at escalated and fixed low-doses from eligible studies are summarized in Table 1. There was no difference in the estimate of VOC crisis rate between the escalated dose and fixed low-dose studies (p=0.73). The mean difference in hemoglobin from baseline to follow-up was greater for fixed low-dose than escalated dose studies (1.07 g/dL vs. 0.54 g/dL, p=0.01). The mean decrease in ANC from baseline to follow-up was greater for escalated dose than low fixed-dose studies (-2.28 [x10 9/L] vs. -1.00 [x10 9/L], p=0.003). No difference was seen in the mean estimate of fetal hemoglobin between escalated dose and fixed low-dose studies. Conclusions Meta-analysis of escalated and fixed low-dose HU showed no significant differences in VOC rate, although the mean difference in hemoglobin was greater for fixed low-dose studies. Comparison of effects between escalated and fixed low-dose HU on acute chest syndrome, hospitalizations, blood transfusion and stroke were not performed due to lack of data. Based on these limited findings, there appears to be clinical equipoise regarding the most appropriate HU dosing regimen to decrease vaso-occlusive complications in adults with SCD. A controlled clinical trial comparing escalated versus low fixed-dose HU in adults with SCD is necessary in low- and middle-income countries where fixed low-dose HU is commonly administered.

Prediction of pediatric dose of tirzepatide from the reference adult dose using physiologically based pharmacokinetic modelling

Tirzepatide is an emerging hypoglycemic agent that has been increasing used in adults, yet its pharmacokinetic (PK) behavior and dosing regimen in pediatric population remain unclear. This study aimed to employ the physiologically based pharmacokinetic (PBPK) model to predict changes of tirzepatide exposure in pediatric population and to provide recommendations for its dose adjustments. A PBPK model of tirzepatide in adults was developed and verified by comparing the simulated plasma exposure with the observed data using PK-Sim&MoBi software. This model was then extrapolated to three specific age subgroups, i.e., children (10–12 years), early adolescents (12–15 years), and adolescents (15–18 years). Each subgroup included healthy and obese population, respectively. All known age-related physiological changes were incorporated into the pediatric model. To identify an appropriate dosing regimen that yielded PK parameters which were comparable to those in adults, the PK parameters for each aforementioned subgroup were predicted at pediatric doses corresponding to 87.5%, 75%, 62.5%, and 50% of the adult reference dose. According to the results of simulation, dose adjustments of tirzepatide are necessary for the individuals aged 10–12 years, as well as those aged 12–15 years with healthy body weights. In conclusion, the adult PBPK model of tirzepatide was successfully developed and validated for the first time, and the extrapolated pediatric model could be used to predict pediatric dosing regimen of tirzepatide, which will provide invaluable references for the design of future clinical trials and its rational use in the pediatric population.

RADIOACTIVE CONTAMINATION OF WILD MUSHROOMS IN CHERNIHIV POLESIE

Purpose. We continue our retrospective investigations of radioactive contamination of wild mushrooms from Ukrainian Polesie. The aim of the current study is an assessment of radioactive contamination of wild mushrooms from some locations of Chernihiv Polesie in 1991-2021. Methodology. A study of radiocaesium activity in 66 wild mushroom species (edible, inedible, conditionally edible, poisonous) (from 2 to 25 fruitbodies per sample) and soils (0-5 cm of upper mineral layer, taken by the envelope method) from 14 locations of Chernihiv Polesie was carried out with γ-spectrometry (Ge-detector Canberra GLX 4019, USA). In some mushrooms, 90Sr activity was determined radiochemically on the basis of 90Y accumulation according to the standard method. Scientific novelty. The results of γ-spectrometric studies of the activity of radiocaesium in 66 species of wild mushrooms from the localities of Chernihiv Polesie over a 30-year period are given, the coefficients reflecting the bioaccumulation activity of each species counted, the hyperaccumulator species of radiocaesium are determined, and the potential annual equivalent doses for adults are calculated under the conditions of consumption of some valuable culinary-medicinal mushrooms (B. edulis, C. cibarius, I. badia, Suillus spp, T. equestre). Conclusions. Activity levels of 137Cs in wild mushrooms of Chernihiv Polesie varied over the years 1991-2021 depending on the mushroom species, its ecological affiliation, radioecological situation at the sampling sites, showing a certain tendency to decrease over time. Hyper-accumulative properties in relation to 137Cs are demonstrated by Cortinarius, Sarcodon, Paralepista, Tricholoma, Lactarius, Suillus spp. Widely distributed on the territory of Ukrainian Polesie - I. badia, P. involutus and L. rufus, remain representative bioindicators of radiocaesium contamination. A potential calculated annual effective doses due to the mushrooms consumption by adults, considering only the effect of the 137Cs, reached a high values in Suillus spp., T. equestre, and I. badia – 0.041, 0.035 and 0.025 mSv, respectively, which indicates a relatively insignificant dose load when consuming mushrooms in these localities compared to other localities of Ukrainian Polesie that have higher levels of soil contamination with radionuclides. However, radiation monitoring can still be recommended during mushroom procurement and mass collections.

A phase 3 study evaluating the lot consistency, immunogenicity, safety, and tolerability of a Clostridioides difficile vaccine in healthy adults 65 to 85 years of age

BackgroundA toxoid-based Clostridioides difficile vaccine is currently in development. Here, we report lot-to-lot consistency, immunogenicity, safety, and tolerability of 3 C difficile vaccine doses in healthy older adults. MethodsThis phase 3, placebo-controlled study randomized (1:1:1:1) healthy adults 65 to 85 years of age to 1 of 3 C difficile vaccine lots or placebo. Participants received C difficile vaccine (200 μg total toxoid) or placebo (Months 0, 1, 6). The primary immunogenicity objective was lot-to-lot consistency (2-sided 95 % CIs within 0.5 and 2 for comparisons of geometric mean concentration [GMC] ratios) for toxins A- and B-specific neutralizing antibody levels 1 month after Dose 3. Safety outcomes included local reactions and systemic events ≤7 days after vaccination, adverse events (AEs), and serious AEs (SAEs). ResultsOf 1317 enrolled participants, 1218 completed the study. C difficile vaccine immunogenicity was consistent across lots, with neutralizing antibody responses 1 month after Dose 3 for both toxin A (GMC [95 % CI]: lot 1, 878.8 [786.3, 982.2]; lot 2, 873.0 [779.2, 978.1]; lot 3, 872.9 [782.6, 973.5]) and toxin B (lot 1, 5823.9 [5041.0, 6728.4]; lot 2, 5462.8 [4733.4, 6304.7]; lot 3, 5426.0 [4724.4, 6231.8]). Two-sided 95 % CIs for GMC ratios were within 0.5 and 2 for toxins A and B, indicating lot-to-lot consistency was achieved. C difficile vaccine was well tolerated, with similar rates of local reactions and systemic events among vaccine lots. AE and SAE rates were similar across C difficile vaccine (36.5 % and 4.5 %, respectively) and placebo (35.3 % and 6 %). ConclusionsThree doses (Months 0,1,6) of toxoid-based C difficile vaccine induced robust neutralizing antibody responses and were well tolerated in healthy participants 65 to 85 years of age. Lot-to-lot consistency was excellent, indicating the manufacturing process for this C difficile vaccine formulation was well controlled.Clinical trial registration:ClinicalTrials.gov identifier: NCT03579459.

Prevalence and factors associated with inappropriate dosing of apixaban and rivaroxaban in hospitalized older adults with atrial fibrillation: a cross-sectional study.

Atrial fibrillation (AF) is a common condition among older adults, requiring anticoagulation therapy to prevent thromboembolic events. Direct oral anticoagulants (DOACs) are now recommended as first-line therapy for this purpose. Apixaban and rivaroxaban are two direct-factor Xa inhibitors whose dosing is based on various factors (age, weight, creatinine, and creatinine clearance) that can affect the pharmacokinetics of the medication. This study aimed to evaluate factors associated with inappropriate dosing of apixaban or rivaroxaban based on the summary of product characteristics. A retrospective, single-center study included 777 hospitalizations of patients treated with apixaban or rivaroxaban for AF between 1 January 2018 and 31 December 2022. Primary endpoint assessed whether the dose of apixaban or rivaroxaban was within the summary of product characteristics used by European Medicine Agency (EMA). Inappropriate dosing of apixaban or rivaroxaban is noted for approximately 30% of hospitalizations mostly underdosing. Factors associated with the risk of inappropriate dosing were the presence of cognitive impairment [adjusted odds ratio (OR*) 1.65, 95% confidence interval (CI) 1.19-2.29, p value (p) = 0.002], weight per kilogram increase (OR* 1.03, 95% CI 1.01-1.04, p < 0.0001), and history of bleeding under apixaban or rivaroxaban (OR* 1.94, 95% CI 1.24-3.03, p = 0.003). This study highlighted the high prevalence of inappropriate apixaban or rivaroxaban doses in older adults, particularly underdosing, which increases the risk of thromboembolism.

Pediatric model-based dose optimization using a pooled exposure-response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma.

An exposure-response (E-R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab-ipilimumab daily average exposure and time to grade 2+ immune-mediated adverse events (gr2+ IMAEs). Results from the E-R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first-line than later-line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio [HR]: 0.830 for 15-year-olds versus 60-year-olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents greater than or equal to 40 kg and BW-based dosing for adolescents less than 40 kg. These results also support adult weight-based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune-mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab.

Current Recommended Estrogen Dosing for Pubertal Induction in Turner Syndrome Results in Normal Uterine Growth.

Most individuals with Turner syndrome (TS) require estrogen for pubertal induction. Current estrogen dosing guidelines are based on expert consensus opinion. Evaluate whether current international guidelines for estrogen dosing during pubertal induction of individuals with TS result in normal uterine growth. We hypothesized that uterine size in individuals with TS who reached adult estrogen dosing is smaller than in mature females without TS. Cross-sectional study of patients with TS at the Cincinnati Center for Pediatric and Adult Turner Syndrome Care. Twenty-nine individuals (age 15-26 years) with primary ovarian insufficiency who reached adult estrogen dosing (100 µg of transdermal or 2 mg of oral 17β-estradiol) were included. Comparison of uterine measurements with a published sample of 292 age-appropriate (age 15-20 years) controls without TS. Uterine length, volume, and fundal-cervical ratio (FCR) were measured. Clinical information (karyotype, Tanner staging for breast development, laboratory data) was extracted from an existing institutional patient registry. There was no evidence of compromise of the uterine size/configuration in the TS cohort compared with the controls; in fact, uterine length, mean 7.7 cm (±1.3) vs 7.2 cm (±1.0) (P = .03), and volume, mean 60.6 cm3 (±26.6) vs 50.5 cm3 (±20.5) (P = .02), were both larger in individuals with TS. Current international guidelines for hormone replacement using 17β-estradiol in individuals with TS appear adequate to allow for normal uterine growth by the end of pubertal induction.

ASC4KIDS: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Chronic Myeloid Leukemia in the Chronic Phase

Background Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients with chronic myeloid leukemia in the chronic phase (CML-CP). More treatment options with improved efficacy and safety profiles are needed for pediatric patients. Asciminib is a first-in-class allosteric inhibitor of ABL (non-receptor tyrosine) kinases, specifically targeting the ABL myristoyl pocket (STAMP), and does not inhibit other protein kinases. Asciminib was approved by the US Food and Drug Administration (FDA) with subsequent approvals worldwide for patients aged ≥18 years with Philadelphia chromosome-positive (Ph+) CML-CP treated with ≥2 prior TKIs in October 2021. Asciminib 40 mg twice daily (bid) has demonstrated improved major molecular response rates (25.5% vs 13.2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). This study aims to characterize the pharmacokinetics (PK), long-term safety profile, and antileukemic effects of asciminib in pediatric patients and identify a pediatric formulation dose that will lead to asciminib exposure comparable to 80 mg qd or 40 mg bid in adult patients. Methods This multicenter, open-label study (NCT04925479) includes patients aged 1 to &amp;lt;18 years with Ph+ CML-CP, without a BCR::ABL1 T315I mutation, treated with ≥1 prior TKI. For the pediatric formulation group, at least 15 patients will be included in each of the two age groups (1 to &amp;lt;12 years and 12 to &amp;lt;18 years), consisting of Part 1, 2 and 3. The study started with an exploratory adult formulation group of Adolescent patients (aged 14 to &amp;lt;18 years, body weight ≥40 kg) treated with the adult formulation dose (40 mg bid or 80 mg qd tablet) under fasting conditions. The primary endpoint includes PK parameters; secondary endpoints include: hematologic and molecular responses, safety, and acceptability/palatability of the pediatric formulations. Part 1 (dose-determining cohort): 4 to 6 patients will receive the asciminib pediatric formulation bid (a mini-tablet of 1.3 mg/kg with food) to assess safety, and to assess if the exposure in pediatric patients is comparable to exposure with the adult formulation over the first 28 days (patients either from pediatric or adult categories). After the interim analysis, if a dose adjustment is required, an additional 4 to 6 patients will be assessed at an adjusted dose. Part 2 (expansion cohort, 40 mg bid regimen): 14 to 16 patients will receive the dose determined in part 1. The second interim PK and safety analysis will be conducted after all patients from parts 1 and 2 complete 28 days of treatment. Part 3 (expansion cohort, 80 mg qd regimen): 10 patients (5 from each age group) will receive the same total daily dose of asciminib qd. The PK, safety profile, and pharmacodynamic endpoints will be assessed for the bid regimen after all patients in parts 1 and 2 complete 52 weeks of treatment. The primary analysis for the combined bid and qd regimen will be performed after all patients complete 52 weeks of treatment (total treatment period: 5 years [ Figure]). A final analysis will be performed after all patients complete treatment. Patients who discontinue treatment early will be followed up for survival until the end of the study. There are 32 study sites open out of planned 35 study sites in 14 countries worldwide. The exploratory and the pediatric formulation groups recruited 4 patients and 9 patients, respectively, as of June 07, 2023, with a total of 13 patients in the study. The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

Use of apixaban in children awaiting heart transplantation.

The use of apixaban in the pediatric cardiac population is expanding. We describe our apixaban dosing and monitoring strategy in children and young adults awaiting heart transplantation, along with outcomes related to bleeding and thrombosis during wait-list and early post-transplant periods. This study is a retrospective, single-center analysis of all patients receiving apixaban while awaiting cardiac transplantation. Weight-based dosing was monitored with peak drug-specific anti-Xa chromogenic analysis. Significant post-operative bleeding defined by chest tube output or need for surgical intervention. From September 2020 to December 2022, 19 patients, median age 13.5 years (6.1, 15.8 years), weighing 48.9 kg (15.4, 67.6) received apixaban while awaiting transplant. Indication for apixaban was prophylaxis (n = 18, 3 with ventricular assist devices) and treatment of thrombus (n = 1). There were no clinically relevant non-major or major bleeding, nor thrombotic events while awaiting transplant. The median time from last apixaban dose to arrival in the operating room was 23.2 h (15.6-33.8), with median random apixaban level of 37 ng/mL (28.3, 59), 6.3 h (4.8, 8.4) prior to arrival in the operating room. In this study, 32% of patients had significant post-operative bleeding based on chest tube output post-transplant or need for intervention. No patients meeting criteria for significant post-operative bleeding were thought to be attributable to apixaban. Careful use of apixaban can be safe and effective while awaiting heart transplant. There was no appreciable increase in peri-operative bleeding. The use of apixaban is promising in providing safe, predictable and efficacious anticoagulation while avoiding additional patient stressors.

Treatment Outcomes With Licensed and Unlicensed Stimulant Doses for Adults With Attention-Deficit/Hyperactivity Disorder

Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. Change in ADHD symptoms and discontinuations due to adverse events. A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.

A Mechanistic Physiologically-Based Pharmacokinetic Platform Model to Guide Adult and Pediatric Intravenous and Subcutaneous Dosing for Bispecific T Cell Engagers.

Bispecific T cell engagers (Bi-TCEs) have revolutionized the treatment of oncology indications across both liquid and solid tumors. Bi-TCEs are rapidly evolving from conventional intravenous (i.v.) to more convenient subcutaneous (s.c.) administrations and extending beyond adults to also benefit pediatric patients. Leveraging clinical development experience across three generations of Bi-TCE molecules across both liquid and solid tumor indications from i.v./s.c. dosing in adults and pediatric subjects, we developed a mechanistic-physiologically-based pharmacokinetic (PBPK) platform model for Bi-TCEs. The model utilizes a full PBPK model framework and was successfully validated for PK predictions following i.v. and s.c. dosing across both liquid and solid tumor space in adults for eight Bi-TCEs. After refinement to incorporate physiological ontogeny, the model was successfully validated to predict pediatric PKs in 1 month - < 2 years, 2-11 years, and 12-17 years old subjects following i.v. dosing. Following s.c. dosing in pediatric subjects, the model predicted similar bioavailability, however, a shorter time to maximum concentration (Tmax ) for the three age groups compared with adults. The model was also applied to guide the dosing strategy for first generation of Bi-TCEs for organ impairment, specifically renal impairment, and was able to accurately predict the impact of renal impairment on PK for these relatively small-size Bi-TCEs. This work highlights a novel mechanistic platform model for accurately predicting the PK in adult and pediatric patients across liquid and solid tumor indications from i.v./s.c. dosing and can be used to guide optimal dose and dosing regimen selection and accelerating the clinical development for Bi-TCEs.

Radiological risk assessment and characteristics of 210Po in selected water sources in Quang Nam and Da Nang, Vietnam

210Po, one of the harmful natural isotopes with a long enough half-life, plays a significant role in environmental processes. 48 samples, including groundwater (dug wells, thermal water, and drill wells) and surface water (lakes, rivers, and streams) in the Da Nang - Quang Nam region of Vietnam were analyzed by an alpha spectrometer. Relatively low activities of 210Po have been observed, whose mean values ranged from 0.15 to 4.58 and 1.34 mBq.L-1. There is no significant variation in 210Po activities between groundwater and surface water groups. The average 210Po activity of those groups is 1.28 and 1.40 mBq.L-1, respectively. The geological conditions of the study area, neutral pH values, and predominant oxidizing conditions supported the low 210Po activities in the selected water sources. Average annual effective doses for adults, children, and infants due to the consumption of water containing 210Po were found to be 1.15, 1.21, and 2.94 µSv.y-1, respectively.

OR31-01 The Dose-dependent Effect Of Estrogen On Bone Mineral Density In Trans Girls

Abstract Disclosure: L.S. Boogers: None. M.A. van der Loos: None. C.M. Wiepjes: None. A. van Trotsenburg: None. M. den Heijer: None. S.E. Hannema: None. Introduction: Treatment in transgender girls can consist of puberty suppression with Gonadotrophin-releasing hormone agonists (GnRHa) followed by estrogen treatment. A decrease in bone mineral density (BMD) Z-scores is a known effect of GnRHa. After initiation of estradiol BMD Z-scores remain relatively low, even after several years of treatment. It has been hypothesized that the estradiol dosage may be insufficient, explaining the persistently low Z-scores. Some trans girls are treated with a higher dosage of estradiol or ethinylestradiol in order to limit growth. This provides the opportunity to evaluate if a higher estradiol dosage results in a greater increase in BMD Z-scores. Methods: Trans girls diagnosed with gender dysphoria were included if they were treated with GnRHa for a minimum of one year prior to treatment with estradiol. Estradiol was increased to the regular dosage (2 mg), or high growth-reductive dosages of estradiol (6 mg) or ethinyl estradiol (100-200 μg (EE)) before the age of 18 years. BMD was assessed using DXA scans performed regularly during GnRHa and estrogen treatment. Z-scores of the lumbar spine were adjusted for height, and the development over time was compared between the different treatment groups. Results: A total of 100 trans girls were included with a mean duration of GnRHa treatment of 2.3±0.7 years. Mean BMD Z-score of the lumbar spine at start of PS was -0.26±0.84. During PS, Z-scores decreased in all three treatment groups to a mean Z-score of -0.99±0.86. After two years of estrogen treatment, Z-scores increased by 0.15 (95% CI 0.00 to 0.30) in the 2 mg estradiol group (n=65) versus 0.35 (95%CI 0.08 to 0.62) in individuals treated with 6 mg estradiol (n=21), and 0.74 (95%CI 0.27 to 1.21) in the EE group (n=14). Compared with 2 mg estradiol, the increase in trans girls treated with EE was significantly higher (0.59, 95% 0.10 to 1.08). There was no difference in individuals treated with 2 mg or 6 mg estradiol (0.20 , 95%CI -0.11 to 0.51). After three years of estrogen treatment, only in the individuals treated with EE, Z-scores were not significantly different from start of GnRHa (-0.01, 95%CI -0.38 to 0.36). Conclusion: When compared to the regular 2 mg dosage of estradiol, a higher estradiol dose, and especially treatment with EE resulted in a greater increase in BMD Z-scores in the lumbar spine in trans girls. This might indicate that 2 mg estradiol is insufficient as a maintenance dose during adolescence and that a higher adult dose is required to optimise BMD. Presentation: Sunday, June 18, 2023

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain.

Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0-8 ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.

Reconsideration of the current models of estimated kidney function-based drug dose adjustment in older adults: The role of biological age.

Human lifespan has increased from a median of 46.5 years in 1950 to 71.7 years in 2022. As people age, one of the inevitable consequences is a decline in kidney function and glomerular filtration rate (GFR) which can have direct or indirect effects on the pharmacokinetic and pharmacodynamic profiles of many drugs. Numerous equations have been developed to generate estimated GFR (eGFR) using the two principal biomarkers: serum creatinine and serum cystatin C. However, the trajectory of changes with aging is dissimilar in these equations. In addition, there is recognition that chronological age (lifespan) often does not reflect biological age (healthspan) as an essential parameter in kidney function equations. In the past decade, there has been an increasing interest in quantifying biological age and new commercially available assays have entered the marketplace. In this narrative review, we illustrate how dominant equations of eGFR model the fractional change in this parameter very differently across chronological age. In addition, we review various biological age indicators (aging clocks) and challenges to their application in clinical practice. Importantly, by comparing vancomycin's mean clearance as a drug with limited metabolism and unchanged elimination between two age milestones in some recent population pharmacokinetic models, we show how efforts to quantify kidney function in older adults optimally remain under-explored, particularly those at the upper end of their lifespan. We also propose considering new models that integrate biological age as a new pathway to improve precision drug dosing in older adults.

Ustekinumab trough levels in children with Crohn's disease refractory to anti-tumor necrosis factor agents: a prospective case series of off-label use.

Background: Ustekinumab is used off-label in pediatric Crohn's disease refractory to anti-tumor necrosis factor. Data on optimal dosing, target trough levels, and potential benefit of therapeutic drug monitoring in children treated with ustekinumab are limited. Materials and Methods: We describe a series of six adolescents who consented to be treated with ustekinumab. We measured their trough levels, C-reactive protein, and fecal calprotectin before every administration. Results: Standard adult dosing was effective to achieve biochemical remission (fecal calprotectin < 250mg/kg) in one patient and clinical remission (resolution of symptoms) in another. The other four patients failed to respond on standard dosing and underwent intravenous re-induction and interval shortening to increase ustekinumab trough levels. This resulted in biochemical remission in one patient and clinical remission in another, suggesting an exposure-response relationship. The remaining two patients had no therapeutic benefit, and ustekinumab was discontinued. Conclusion: In this report, we show that ustekinumab can induce remission in pediatric patients with anti-tumor necrosis factor refractory Crohn's disease. It is worth escalating the dose before abandoning the drug as ineffective. Prospective studies in children are needed to determine long-term efficacy of ustekinumab, usefulness of therapeutic drug monitoring strategies, and, if applicable, optimal target trough levels.