Steady-state Serum Concentrations Research Articles

ABCB1 Polymorphism Is Associated with Higher Carbamazepine Clearance in Children

The aim of our study was to investigate the role of ABCB1 polymorphism in the pharmacokinetics of carbamazepine (CBZ) in children. The study enrolled 47 Serbian pediatric epileptic patients on CBZ treatment. Genotyping for ABCB1 1236C<T (rs1128503), 2677G<A/T (rs2032582) and 3435C<T (rs1045642) was carried out using the TaqMan method. Steady-state CBZ serum concentrations were available from our previous study, determined by high pressure liquid chromatography (HPLC). The NONMEM software and one-compartment model were used for pharmacokinetic analysis. ABCB1 1236C<T, 2677G<A/T and 3435C<T variations were found at the frequencies of 47.9%, 48.9% and 52.1%, respectively. The equation that described population clearance (CL) was CL (L/h) = 0.175 + 0.0403 × SEX + 0.0332 × ABCB1 + 0.0176 × CYP1A2 + 0.000151 × DD where SEX has a value of 1 if male and 0 if female, ABCB1 has a value of 1 if C-G-C/T-T-T and 0 if any other ABCB1 diplotype, CYP1A2 has a value of 1 if −163A/A and 0 if −163C/C or C/A, and DD is the total CBZ daily dose (mg/day). The presence of the ABCB1 1236T-2677T-3435T haplotype is associated with an increased clearance of CBZ in pediatric epileptic patients.

Association between abatacept exposure levels and infection occurrence in patients with rheumatoid arthritis: post hoc analysis of the AVERT-2 study

ObjectiveTo determine if higher serum exposure during subcutaneous (SC) abatacept treatment was associated with an increased infection risk in adult patients with early rheumatoid arthritis (RA).MethodsData from AVERT-2 (Assessing Very Early Rheumatoid arthritis Treatment-2,NCT02504268), a randomized, placebo-controlled study in anticitrullinated protein antibody– positive patients with early RA, were analyzed. A post hoc population pharmacokinetic (PPK) analysis was performed. Association between steady-state abatacept concentration exposures (steady-state time-averaged serum concentration, steady-state trough serum concentration, steady-state maximum serum concentration) and first infection was evaluated using Kaplan–Meier plots of probability versus time on treatment and Cox proportional-hazards models.ResultsPK of SC abatacept was defined as a linear 2-compartment model with first-order absorption and elimination; higher body weight was the only covariate with a clinically relevant effect in the final PPK model. Infections occurred in 330/693 (47.6%; 11/693 [1.6%] serious infections) patients treated with abatacept+methotrexate (MTX) and 134/301 (44.5%; 4/301 [1.3%] serious infections), with abatacept placebo+MTX. Exposure–response analysis demonstrated no exposure relationship for an increased risk of first infection with concomitant use of MTX and glucocorticoids during the induction period, baseline glucocorticoid use, or higher than median body weight at baseline (> 70 kg).ConclusionThis exposure–response analysis of AVERT-2 showed no increase in the risk of first infection, regardless of abatacept exposure level in patients with RA treated with SC abatacept. Similarly, no effect on the risk of first infection was found for concomitant MTX and glucocorticoid use in patients with RA treated with SC abatacept+MTX.

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is a rare blood disorder characterized by life-threatening hemolysis and thrombosis. Complement C5 inhibitor therapy improves symptoms and life prognosis; however, it can result in insufficient hemolysis control, with residual intravascular hemolysis and extravascular hemolysis in some patients. Pegcetacoplan, the first complement C3 inhibitor approved for patients with paroxysmal nocturnal hemoglobinuria, targets both intravascular and extravascular hemolysis. This analysis evaluated population pharmacokinetic/pharmacodynamic profiles of pegcetacoplan. Pooled clinical study data were used to predict pegcetacoplan concentrations and biomarker responses indicative of hemolysis (hemoglobin and lactate dehydrogenase) over time, including the impact of patient characteristics and prior or concurrent complement C5 inhibitor treatment, to support the approved dose of subcutaneous pegcetacoplan 1080 mg twice weekly. The population pharmacokinetoc analysis included 284 subjects, and the pharmacokinetic/pharmacodynamic analysis included 165 subjects. Subcutaneous pegcetacoplan 1080 mg twice weekly resulted in rapid serum exposures and robust biomarker response within 4 weeks after treatment initiation. Steady-state serum concentrations demonstrated consistent exposure (median ≥ 600 µg/mL) with minimal peak-to-trough variation. The median effective half-life was 8.6 days in patients with paroxysmal nocturnal hemoglobinuria. Body weight significantly impacted pegcetacoplan exposure, and other covariates impacted hemoglobin (sex and creatinine clearance) or lactate dehydrogenase (prior or concurrent complement C5 inhibitor treatment); however, effects were not clinically meaningful. The approved dose of pegcetacoplan is predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in adult patients with paroxysmal nocturnal hemoglobinuria, with no initial dose adjustments required for any specific patient population.

Subcutaneous versus intravenous nivolumab for renal cell carcinoma

The evolving oncology treatment paradigm has created an unmet need for administration options that improve patient experiences and health care efficiencies. CheckMate 67T (NCT04810078) was a phase III, open-label, multicenter, noninferiority trial in which patients with advanced/metastatic clear cell renal cell carcinoma were randomized to subcutaneous nivolumab (1200 mg every 4 weeks; coformulated with recombinant human hyaluronidase PH20 20 000 units) or intravenous nivolumab (3 mg/kg every 2 weeks). The primary objective was to assess the noninferiority of subcutaneous versus intravenous nivolumab by coprimary endpoints determined from a population pharmacokinetics analysis [time-averaged serum concentration over the first 28 days (Cavgd28), and minimum steady-state serum concentration (Cminss); noninferiority threshold: lower boundary of 90% confidence interval (CI) of the geometric mean ratios (GMR) ≥0.8]. Objective response rate (ORR) was a key secondary endpoint powered for noninferiority [noninferiority threshold: lower boundary of 95% CI of relative risk of ORR (subcutaneous versus intravenous nivolumab) ≥0.60]. Overall, 495 patients were randomized. Relative exposure in the subcutaneous versus intravenous arm reported by the GMR of Cavgd28 and Cminss was 2.098 (90% CI 2.001-2.200) and 1.774 (90% CI 1.633-1.927), respectively. After 8 months of minimum follow-up, ORR was 24.2% with subcutaneous nivolumab (95% CI 19.0%-30.0%) versus 18.2% with intravenous nivolumab [95% CI 13.6%-23.6%; relative risk: 1.33 (95% CI 0.94-1.87)]. Coprimary endpoints and ORR met noninferiority thresholds. Additional efficacy and safety measures were similar. Subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR. No new safety signals were observed.

Population pharmacokinetics of tamsulosine in patients with benign prostatic hyperplasia.

The study aimed to determine the typical clearance and volume of distribution values of tamsulosin in patients with benign prostatic hyperplasia (BPH), and to identify factors with a measurable impact on the drug's elimination. This open-label, single-arm population pharmacokinetic study involved 65 adult men with BPH who had been on tamsulosin therapy for at least seven days. The steady-state serum concentrations of tamsulosin were measured using liquid chromatography-tandem quadrupole mass spectrometry. Population pharmacokinetic parameters, their variability, and influencing factors were estimated based on a two-compartment pharmacokinetic model using NONMEM software. The estimated tamsulosin clearance in BPH patients was 0.719L/h, and the steady-state volume of distribution was 32L. Neither renal nor liver function parameters had a statistically significant effect on tamsulosin clearance. However, a positive correlation was observed between hemoglobin levels and tamsulosin clearance in the BPH patient cohort. Our investigation reveals significant associations between tamsulosin pharmacokinetics and specific characteristics of patients with lower urinary tract symptoms (LUTS) due to BPH. The study highlights that tamsulosin clearance is associated with hemoglobin levels in patients with LUTS/BPH. This study underscores the importance of considering patient-specific factors when managing BPH treatment with tamsulosin, emphasizing associations rather than causative relationships.

Folliculogenesis and steroidogenesis alterations after chronic exposure to a human-relevant mixture of environmental toxicants spare the ovarian reserve in the rabbit model

BackgroundIndustrial progress has led to the omnipresence of chemicals in the environment of the general population, including reproductive-aged and pregnant women. The reproductive function of females is a well-known target of endocrine-disrupting chemicals. This function holds biological processes that are decisive for the fertility of women themselves and for the health of future generations. However, insufficient research has evaluated the risk of combined mixtures on this function. This study aimed to assess the direct impacts of a realistic exposure to eight combined environmental toxicants on the critical process of folliculogenesis.MethodsFemale rabbits were exposed daily and orally to either a mixture of eight environmental toxicants (F group) or the solvent mixture (NE group, control) from 2 to 19 weeks of age. The doses were computed from previous toxicokinetic data to reproduce steady-state serum concentrations in rabbits in the range of those encountered in pregnant women. Ovarian function was evaluated through macroscopic and histological analysis of the ovaries, serum hormonal assays and analysis of the expression of steroidogenic enzymes. Cellular dynamics in the ovary were further investigated with Ki67 staining and TUNEL assays.ResultsF rabbits grew similarly as NE rabbits but exhibited higher total and high-density lipoprotein (HDL) cholesterol levels in adulthood. They also presented a significantly elevated serum testosterone concentrations, while estradiol, progesterone, AMH and DHEA levels remained unaffected. The measurement of gonadotropins, androstenedione, pregnenolone and estrone levels yielded values below the limit of quantification. Among the 7 steroidogenic enzymes tested, an isolated higher expression of Cyp19a1 was measured in F rabbits ovaries. Those ovaries presented a significantly greater density/number of antral and atretic follicles and larger antral follicles without any changes in cellular proliferation or DNA fragmentation. No difference was found regarding the count of other follicle stages notably the primordial stage, the corpora lutea or AMH serum levels.ConclusionFolliculogenesis and steroidogenesis seem to be subtly altered by exposure to a human-like mixture of environmental toxicants. The antral follicle growth appears promoted by the mixture of chemicals both in their number and size, potentially explaining the increase in atretic antral follicles. Reassuringly, the ovarian reserve estimated through primordial follicles number/density and AMH is spared from any alteration. The consequences of these changes on fertility and progeny health have yet to be investigated.

Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

Insulin degludec in pregestational diabetes: evidence and perspectives

Pregestational diabetes is described when a woman with diabetes before the onset of pregnancy becomes pregnant and consequently she is vulnerable to higher risk for adverse outcomes in the embryo/foetus. Strict glycaemic control, with minimal glucose variability, starting from before conception and maintained throughout pregnancy decreases significantly adverse foetal and maternal outcomes; maternal hypoglycaemic episodes are the major barrier in achieving this goal. Insulin degludec is an ultralong-acting analogue, which has half-life of over 25 h and full duration of effect of more than 42 h, reaching a steady-state serum concentration after 2–3 days of its administration. It promotes flat, steady, peakless and predictable insulin concentrations, with minor intra-individual and inter-individual variability. It also exerts a low mitogenic/metabolic potency ratio. This review examines thoroughly all current evidence of the administration of insulin degludec in pregestational diabetes as well as its future role in this population.

Abstract 5962: Novel xCT-targeted biologics significantly suppress metastasis, improve survival, and sensitize primary tumors to chemotherapy in TNBC xenograft models

Abstract Background: Triple negative breast cancer (TNBC) is a highly heterogeneous subset of breast cancer, which has the worst prognosis and lacks specifically targeted therapeutic options. The TNBC subtype termed M/MSL is enriched with cells of high mesenchymal state and increased stemness, and is particularly resistant to current therapies1,2. But this cancer cell phenotype is susceptible to ferroptosis, hence targeting these aggressive tumors with ferroptosis inducers such as xCT inhibitors (xCTi) is an attractive alternative. The cystine/glutamate exchanger xCT/SLC7A11 plays a key role in maintaining redox homeostasis in cancer cells. xCT is expressed on subsets of most solid tumors, including stem/progenitor and metastatic tumor cells. xCT inhibition yields a variety of anti-proliferative phenotypes including death by ferroptosis3. xCT knockout mice exhibit normal development and lifespan. Altogether, targeting xCT outside of CNS may potentially have widespread clinical utility in cancer treatment. Results: We present preclinical data demonstrating development of novel, first-in-class xCT-targeted biotherapeutics (AX68c, AX76c) using studies in TNBC cell lines in vitro and in xenograft. We find that these agents have highly favorable pharmacokinetics, with FcRn-dependent serum half-lives greatly exceeding those of known small molecule xCTi. In vitro, AX68c or AX76c reduces glutathione levels in TNBC cells in accord with inhibition of xCT function. Analysis of anti-proliferative effects in a panel of TNBC cell lines revealed particular potency against those of M/MSL phenotype (IC50s 0.3-1uM). We further tested the susceptibility of the mesenchymal phenotype to AX68c and found that EMT induction in epithelial cancer cells significantly increased sensitivity in a ferroptosis-dependent manner. In wildtype and immunodeficient mice, AX68c is well tolerated at steady-state serum concentrations that are 15-300 fold of its in vitro IC50s in tested TNBC cells. In orthotopic MDA-MB-231 xenografts, AX68c treatment significantly reduced tumor metastasis and sensitized primary tumors to cisplatin and paclitaxel. Bulk RNAseq and GSEA analysis on primary tumors revealed treatment associated alterations in key cancer signaling pathways such as TGFβ, INFγ and TNFα/NFκB. In MDA-MB-436 orthotopic xenografts, AX68c alone led to significantly improved survival primarily through abrogating metastasis. Combining AX68c and cisplatin further prolonged survival through concurrent suppression of metastasis and primary tumor growth. Conclusions: We conclude that our anti-xCT biologics may provide novel targeted therapies for M/MSL-subtype TNBC and metastatic tumors with a large mesenchymal component. 1. Viswanathan, et al., Nature, 2017; 2. Wang, et al., npj Precision Oncology, 2021; 3. Koppula, et al., Protein and Cell, 2021 (review). Citation Format: He Gong, Jun Li, Cyrus Becker, Luika Timmerman, Shaheen Sikandar, Yong Huang. Novel xCT-targeted biologics significantly suppress metastasis, improve survival, and sensitize primary tumors to chemotherapy in TNBC xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5962.

Guía internacional para una dosificación más segura de la clozapina en adultos mediante el uso de 6 titulaciones personalizadas de dosis basados en la etnicidad, la proteína C reactiva y los niveles de clozapina

This is the Spanish translation of an international guideline which proposes improving clozapine package inserts worldwide by using ancestry-based: 1) dosing and 2) titration. Adverse drug reaction (ADR) databases suggest clozapine: 1) is the third most toxic drug in the United States (US), and 2) produces worldwide pneumonia mortality four times greater than that of agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers require the lowest dose and male smokers the highest dose). Poor metabolizer (PM) status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity or inflammation with C-reactive protein (CRP) elevations. People with ancestry from Asia (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/ml. Daily doses of 300-600 mg/day are recommended in the US. Slow personalized titration may prevent early ADRs (including syncope, myocarditis and pneumonia). The core of this guideline consists of six personalized titration schedules for inpatients: 1) Asian/Amerindian ancestry with lower metabolism (in cases of obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) Asian/Amerindian ancestry with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (in cases of obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US of non-Asian/Amerindian ancestry with lower clozapine metabolism (in cases of obesity or valproate) needing 150-300 mg/day, and 6) in the US of non-Asian/Amerindian ancestry with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least 4 weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Efficacy and influencing factor analysis of Voriconazole in the treatment of invasive fungal infections

Current study aims to explore the correlation between the administered dose and efficacy of voriconazole in the treatment of invasive fungal infection (IFI). The correlation between different doses of Voriconazole and plasma concentrations as well as clinical efficacy was counted. Consequently, 40 strains of pathogenic micro-organisms were isoninelated and cultured from etiological samples. A total of 66 patients with steady-state trough serum concentrations ranging from 1.0 to 5.5 μg/mL were measured, with a compliance rate of 79.5%. Chi-square test showed that there was a significant correlation between Voriconazole steady-state serum trough concentration and treatment efficacy. In addition, the result of Pearson test showed that steady-state trough serum concentration of Voriconazole was significantly positively correlated with the administered dose (γ = 0.866, P < 0.001). On conclusion, Voriconazole is effective in treatment of IFI, and there is a significant dose-plasma concentration correlation with efficacy.

Differences in the pharmacokinetics and steady-state blood concentrations of orally administered lenvatinib in adult and juvenile rats.

Objective: The aim of this study was to compare the pharmacokinetics and steady-state serum concentrations of lenvatinib in adult and juvenile rats. Experimental study: An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method was developed to quantify lenvatinib in the serum and liver of rats. Six juvenile and six adult rats in each group were orally administered with a single dose of 7.0mg/kg lenvatinib suspension for pharmacokinetics. Another 12 juvenile and adult rats were subjected to oral gavage with 7.0mg/kg lenvatinib once daily for 5days. Biofluild samples were pre-treated by protein precipitation and sorafenib was used as the internal standard for UPLC-MS analysis. The pharmacokinetic parameters were estimated by compartment and statistical model. The mRNA expression of CYP3A2 and SLC22A1 in liver of adult and juvenile rats was measured by real-time fluorescence quantitative PCR (RT-qPCR). Results: The UPLC-MS method met the requirements for quantitative analysis of lenvatinib in serum and liver. The pharmacokinetic results showed that the mean retention time (MRT(0-∞)) was 19.64 ± 7.64h and 126.38 ± 130.18h, with AUC(0-∞) values of 3.97 ± 0.73μg‧mL-1h and 5.95 ± 2.27μgmL-1h in adult and juvenile rats, respectively. When comparing adult rats (0.35 ± 0.15μg/mL) to juvenile rats, no significant differences were observed in steady-state serum lenvatinib (0.32 ± 0.11μg/mL), but a noteworthy decrease to one-third of steady-state liver lenvatinib was observed after multiple oral doses of lenvatinib in juvenile rats. Additional findings revealed that the mRNA expression of CYP3A2 and SLC22A1 was notably increased by 6.86 and 14.67 times, respectively, in juvenile rats compared to adult rats. Conclusion: Juvenile rats exhibit lower levels of lenvatinib in the liver's steady-state, potentially due to the disparity in CYP3A2 mRNA expression. These results imply that the dosage of lenvatinib for pediatric patients may need to be augmented in order to attain the desired clinical outcome.

Oxycodone, Morphine, and Fentanyl in Patients With Chronic Pain: Proposal of Dose-Specific Concentration Ranges.

Interpreting opioid concentrations is challenging because of the lack of reference ranges. Therefore, the authors aimed to propose dose-specific concentration ranges in serum for oxycodone, morphine, and fentanyl in patients with chronic pain, based on concentration measurements from a large number of patients and supported by theoretical pharmacokinetic calculations and previously published concentrations. The opioid concentrations in patients undergoing therapeutic drug monitoring (TDM) for various indications (TDM group) and patients with cancer (cancer group) were investigated. Patients were divided based on the daily opioid doses, and the 10th and 90th percentiles of the concentrations in each dose interval were evaluated. In addition, the expected average serum concentrations were calculated for each dose interval based on published pharmacokinetic data, and a targeted literature search for previously reported dose-specific concentrations was performed. The opioid concentrations in 1054 patient samples were included: 1004 in the TDM group and 50 in the cancer group. In total, 607 oxycodone, 246 morphine, and 248 fentanyl samples were evaluated. The authors proposed dose-specific concentration ranges based mainly on 10th-90th percentiles of the concentrations measured in patient samples, whereas the calculated average concentrations and previously published concentrations were used to adjust the ranges. In general, results from calculations and concentrations retrieved from previous literature were within the 10th-90th percentiles of concentrations from patient samples. However, the lowest calculated average concentrations of fentanyl and morphine were below the 10th percentiles of patient samples in all dose groups. The proposed dose-specific ranges may be useful for interpreting steady-state opioid serum concentrations in clinical and forensic settings.

0895 Pharmacokinetics of pitolisant in breast milk and serum of healthy lactating women

Abstract Introduction Pitolisant is a potent and highly selective histamine-3-receptor antagonist/inverse agonist approved for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. A phase 4, open-label study was conducted to evaluate the pharmacokinetics (PK) of pitolisant and its major metabolite, BP1.3484, in breast milk and serum following a single dose of pitolisant administered to healthy lactating women. Methods In this study, eight healthy lactating women (aged 22-42 years) who met eligibility criteria were enrolled and received a single oral dose of pitolisant (35.6 mg). Serial breast milk samples were collected at pre-dose on Day 1 and at various intervals through 24 hours post-dose. Serial blood samples for PK analyses were collected at pre-dose and through 120 hours post-dose. Since the total infant dosage calculated from single dose data may be under-estimated, steady-state serum concentrations were predicted using noncompartmental methods and then multiplied by the 24-hour breast milk:serum ratio (AUCBM/S) to estimate a more appropriate total infant dose. Results Pitolisant was excreted in breast milk, with mean CmaxBM/S and AUCBM/S ratios of 85.2% and 123%, respectively. Concentrations of pitolisant in breast milk were only slightly lower than concentrations in serum. However, since the volume of breast milk was low, the percentage of the maternal dose expressed in breast milk was very low. Steady state calculations for a 6-month-old infant resulted in a mean total infant dosage of 0.005 mg/kg/day (SD 0.002), which is 1.15% of the maternal dose. For BP1.3484, maternal exposure and the calculated mean daily infant exposure were much lower than pitolisant. All subjects completed the study as planned. Five subjects (62.5%) reported a total of 8 treatment-emergent adverse events, which were mild in severity and resolved by end of the study. Conclusion Pitolisant is present in human milk, but the mean daily infant dosage in a 6-month-old infant after steady-state dosing of pitolisant in healthy lactating women was estimated to be very low. Overall, a single oral dose of pitolisant 35.6 mg was well-tolerated in healthy lactating women. Support (if any) The study was sponsored by Harmony Biosciences LLC.

P14 Improving adherence to and effectiveness of an adult critical care vancomycin continuous infusion protocol: a pilot quality improvement and administration data accuracy project

Abstract Background Vancomycin treats serious Gram-positive infections. In St George's Hospital (SGH) intensive care unit (ICU) settings, vancomycin is administered intravenously by continuous infusion. Steady-state serum concentrations are monitored daily with a 20–25 mg/L therapeutic target. Non-therapeutic concentrations are associated with patient harm and prolonged stay.1 A service evaluation revealed variable adherence to/effectiveness of the vancomycin prescribing/administration/monitoring protocol. Electronic prescribing and medicine administration (ePMA) system interface issues may have contributed.2 Consequently, multifaceted interventions were devised and piloted on General ICU. Objectives To (i) improve combined protocol prescribing/administration/monitoring adherence; (ii) enhance therapeutic protocol dosing; and (iii) ascertain accuracy of patients’ paper drug administration (PDA) charts compared with the ePMA system. Methods The quality improvement project (QIP) was approved by SGH clinical governance/audit teams. Over a 9 month period (September 2021 to May 2022) system/person-focused interventions were implemented. Protocol dosing2 was revised; introducing a &amp;gt;90 kg patient 2 g loading dose, new renal-function categories and an increased maintenance dose for creatinine clearance (CLCR) &amp;gt;90 mL/min. Protocol accessibility was increased via ePMA and CliniBee/Microguide app integration. Educational protocol presentations were incorporated into medical/nursing induction training. Vancomycin prescribing/administration/monitoring data for non-renal replacement patients during the intervention period, was extracted retrospectively from the ePMA system. This was compared with baseline informing ICU data collected July 2020 to July 2021.2 Patient's drug administration accuracy data (PDA charts/ePMA system) was extracted retrospectively from January to May 2022 and analysed. Results Compared with baseline, the proportion of patients receiving per protocol prescribing/administration of vancomycin loading/maintenance doses with daily monitoring increased [39% (7/18) to 68% (15/22)]. Within 48 h 54% (7/13) of vancomycin serum concentrations in all patients were therapeutic, demonstrating a baseline increase of 21% (3/9 to 7/13). In per protocol treated patients, serum concentrations increased 16% (2/7 to 4/9) therapeutically, decreased 20% (3/7 to 2/9) supra-therapeutically and increased 4% (2/7 to 3/9) sub-therapeutically. Supra-therapeutic concentrations were associated with CLCR &amp;lt;50 mL/min. Sub-therapeutic concentrations were associated with CLCR &amp;gt;90 mL/min and obesity. Compared with the ePMA system, there was 38% (5/13) less PDA charts recording both loading/maintenance doses. Administration time differences &amp;gt;60 min were recorded for 38% (3/8) of loading and 31% (4/13) maintenance doses. Discussion Staff turnover periods were associated with decreased protocol compliance. Further education is required around prescribing/administration of standardized vancomycin infusion bags, with associated rate changes. Integration of pharmacists into daily Microbiology ward rounds may alleviate these issues. Higher 20 mg/kg loading doses for &amp;gt;100 kg patients and maintenance dose revisions may reduce non-therapeutic concentrations.3 Multidirectional variation in vancomycin administration timings recorded between PDA charts/ePMA system, requires further investigation. Infusion-pump data may offer the most accurate administration time for calculating pharmacokinetic variables. Conclusions Multifaceted interventions were successful at improving adherence to/effectiveness of the vancomycin protocol. Findings will inform QIP roll-out across all three SGH ICUs, which will incorporate infusion-pump data collection to facilitate pharmacokinetic modelling. This will inform local dosing strategies and research into patient variability.

Accumulation and risk prioritization of psychoactive substances in the critically endangered Yangtze finless porpoise.

Psychoactive substances have been identified as a kind of emerging contaminants in aquatic environment and pose potential adverse effects on aquatic animals. Yangtze finless porpoise, a critically endangered species in China, is also facing the threat of psychoactive substances. In this study, the accumulation characteristics and risk prioritization of psychoactive substances were investigated in Yangtze finless porpoise collected from Poyang Lake (PYL) and Tian-E-Zhou Oxbow (TZO) in Yangtze River basin. The levels of psychoactive substances were detected in the range of below method detection limits (MDLs) to 98.4ng/mL in the serum of Yangtze finless porpoise. Codeine (COD) and methamphetamine were identified as the major substances due to the highest residual levels with a median concentration of 0.72ng/mL and 0.33ng/mL, respectively. The total concentrations of psychoactive substances in the porpoise collected from TZO was significantly higher than those from PYL. Risk analysis based on effect ratio derived from the ratio of steady-state psychoactive substance serum concentration in the porpoise and human therapeutic plasma concentration revealed that COD was the substance with the highest risk among the psychoactive substances detected, followed by lysergic acid diethylamide (LSD), morphine, alprazolam (ALPZ) and lormetazepam. Location-specific risk prioritization of psychoactive substances found that the top 3 substances are LSD, lorazepam (LORZ) and ALPZ in PYL, and COD, LSD and LORZ in TZO. The results disclose the accumulation of psychoactive substances in Yangtze finless porpoise and suggest that the potential adverse effects should be concerned.

Improving adherence to and effectiveness of a vancomycin continuous infusion protocol, a pilot quality improvement project

Abstract Introduction Vancomycin treats serious Gram-positive infections such as methicillin-resistant Staphylococcus aureus. In St George’s University Hospital’s (SGH) intensive care unit (ICU) settings, vancomycin is administered by continuous infusion. Steady-state serum concentrations are measured daily with a 20-25 mg/L target. Non-therapeutic concentrations are associated with adverse drug reactions/prolonged length of stay.1 A SGH service-evaluation conducted across all three ICUs, revealed variable adherence to/effectiveness of its vancomycin prescribing/administration/monitoring protocol.2 Consequently, multifaceted interventions were devised using the Institute-for-Healthcare-Improvement’s model Plan-Do-Study-Act (PDSA) cycles and piloted on General ICU (GICU). Aim (1) To improve adherence to/effectiveness of the vancomycin protocol. (2) To ascertain administration accuracy of paper-fluid-balance-charts compared to the electronic-prescribing-and-medicines-administration (ePMA) system to assist with identifying per protocol treated patients. Methods PDSA Cycle-1 was conducted over a 9-month period (09/2021-05/2021) in which a mix of system/person-focused interventions were implemented. Protocol dosing2 was revised, introducing a &amp;gt;90kg patient 2g loading dose, renal-function category revision and increased maintenance dose for creatinine clearance (CLCR) &amp;gt;90ml/min. Protocol accessibility was increased via integration into an ePMA prescribing interface, plus CliniBee/Microguide apps. Educational slides on relevant protocol aspects were incorporated into medical/nursing induction training. Data relating to vancomycin prescribing/administration/monitoring for all non-renal replacement patients was extracted retrospectively from the ePMA system between 09/2021-05/2022. This data was compared to baseline GICU data (07/2020-07/2021).2 The project and associated interventions were approved by Trust Clinical Governance and Audit Teams. Data was collected by pharmacists directly involved in patient’s care and stored/analysed on the Trust’s secure server in line with Data Protection Act principles. Due to local generalisability, ethics approval wasn’t required. Results Compared to baseline, the proportion of patients receiving per protocol prescribing/administration of loading/maintenance doses with daily monitoring, nearly doubled (39% (7/18) to 68% (15/22)). 48-hour vancomycin serum concentrations in all patients increased therapeutically by 21% (3/9 to 7/13). In per protocol treated patients, concentrations increased 15% (2/7 to 4/9) therapeutically, decreased 21% (3/7 to 2/9) supra-therapeutically and increased 4% (2/7 to 3/9) sub-therapeutically. Supra-therapeutic concentrations were associated with CLCR&amp;lt;50ml/min. Sub-therapeutic concentrations were associated with CLCR&amp;gt;90ml/min and obesity. Compared to the ePMA system, there was 36% (8/22) less paper-fluid-balance-charts recording both loading/maintenance doses. Maintenance dose administration times in 9% (2/22) of cases differed by &amp;gt;60 minutes. Discussion/Conclusion Staff-turnover periods were associated with decreased protocol compliance. Observations suggest further education is required around prescribing/administration of standardised infusion bags for maintenance dosing. Pharmacist integration into daily Microbiology ward rounds may increase protocol compliance. Higher 20mg/kg loading doses for obese patients and maintenance dose revision should be considered to reduce non-therapeutic concentrations.3 Limitations include heterogenous/small sample sizes due to data paucity and vancomycin requirement. This can be addressed by involving all ICU’s in PDSA Cycle-2. Due to disparities, both the ePMA system and paper-fluid-balance-charts should be used to identify protocol adherence. Utilisation of digital-infusion-pump data to quantify administration accuracy may offer a promising solution. Piloted multifaceted interventions were successful at improving adherence to/effectiveness of the vancomycin protocol. Findings have informed further interventions and data capture methods for PDSA Cycle-2 implementation across all ICUs.

Pharmacokinetic Modeling of Optimized Midazolam and Pentobarbital Dosing Used in Treatment Protocols of Refractory Status Epilepticus.

To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status epilepticus (RSE). One- and two-compartment in silico pharmacokinetic models of midazolam and pentobarbital. Not applicable. Not applicable. We compared the model variables used in midazolam and pentobarbital protocols for standard RSE. Standard RSE treatment protocols result in steady-state serum concentrations that are 6.2-9.0-fold higher for the one-compartment model and 2.3-4.7-fold higher for the two-compartment model. In the model, not including bolus doses delays the achievement of serum steady-state concentration by 0.5 and 2.7 hours for midazolam and pentobarbital, respectively. Abrupt discontinuation of these medications reduces modeled medication exposure by 1.1 and 6.4 hours, respectively. Our in silico pharmacokinetic modeling of standard midazolam and pentobarbital dosing protocols for RSE suggests potential variables to optimize in future clinical studies.

First-in-Human Phase I Trial of a ROR1 Targeting Bispecific T Cell Engager (NVG-111) in Combination with Ibrutinib or As Monotherapy in Subjects with Relapsed Refractory Chronic Lymphocytic Leukaemia (CLL) and Mantle Cell Lymphoma (MCL)

Background: NVG-111 is a first in class, humanized, tandem scFv, ROR1xCD3 bispecific T cell engager that mediates potent killing of ROR1+ tumor by engaging an epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder that has been engineered for lower cytokine release. Methods: This multi-center, open-label, phase I study is evaluating NVG-111 in relapsed/refractory CLL and MCL subjects who have received ≥2 prior systemic therapies. An adaptive trial design was used for dose escalation, starting with accelerated dose titration (ATD) followed by a Bayesian continual reassessment method with overdose control. Each patient received at least one dose of NVG-111, administered as a continuous intravenous infusion (cIV) over 21 days followed by 7 days off drug (=1 cycle). NVG-111 was administered in combination (cohorts 1-4) with ibrutinib to patients who had achieved a stable or partial response to >1 year of ibrutinib therapy, or as monotherapy in patients who had progressed after BTKi / BCL2 (cohort 4b). Measurable residual disease (MRD) was assessed using a flow cytometric method with sensitivity 1e4 (MRD4). Mesoscale discovery electrochemiluminescence assay (MSD-ECLA) was used for pharmacokinetic analysis of NVG-111. Serum cytokine levels were determined using a human high sensitivity cytokine A premixed magnetic Luminex assay. Primary endpoints consisted of safety, tolerability and determination of maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D). Additional end-points included overall response rates as well as duration of response. Results: As of July 2022, 10 subjects (8 males and 2 females, median age 60 years) had been enrolled to the study; three into single subject ATD cohorts, 3 into 30 µg/day flat dosing cohort (cohort 4) and 4 into cohort 4b that entailed a step-up dosing of NVG-111 in cycle 1 only; (first week cycle 1: 3 µg/day, second week, cycle 1: 10 µg/day and week 3, cycle 1: 30 µg/day dose). Eight subjects had CLL and 2 MCL. cIV was well tolerated. Adverse events (AEs) were largely limited to week 1 of cycle 1 and all were reversible. The most common AEs were Grade 1 or 2 nausea (70%), headaches (60%), and fatigue (50%) and thrombocytopenia (30%). Grade 1/2 cytokine release syndrome (CRS) was observed in (40%) of subjects. Grade 3 dose limiting toxicities occurred in two subjects consisting of immune effector cell-associated neurotoxicity syndrome-like symptoms (ICANS) in one (cohort 4) and ALT and AST elevation (cohort 4b) in the other. Both subjects recovered upon stopping NVG-111. Average steady-state serum concentration (Cavg.ss) of NVG-111 in serum of patients who received a 10µg/day and 30µg/day dose were 168-288pg/mL and 425-610pg/mL respectively. This was in line with the predicted drug levels from the single species allometric scaling. Evidence of T cell activation was observed in all evaluable subjects (9/10) with cytokine levels at the 30µg/day dose level being: TNFα, 21±6pg/ml; IL6, 206±178pg/ml; IFNɣ, 7±4pg/ml; and IL10, 47±21pg/ml. Objective clinical responses were observed in 66% of subjects and included 2 MRD4 negative clinical remissions (CR). These two subjects remained in MRD4 negative CRs at 6 months after completion of treatment. Conclusion: Early data shows that NVG-111 is generally well tolerated with a predictable and manageable safety profile. Promising evidence of efficacy was observed which appears to be durable in two subjects with MRD4 negative CR. Dose escalation is ongoing in combination or as monotherapy to determine the MTD/RP2D.

Trough-guided Versus AUC/MIC-Guided Vancomycin Monitoring: A Cost Analysis

PurposeRecent vancomycin dosing and monitoring guidelines recommend monitoring vancomycin area under the 24-hour time–concentration curve instead of traditional trough-only monitoring. This study aimed to compare the total costs of vancomycin dosing and monitoring between trough-guided and AUC-guided approaches in a quaternary hospital from Brazil. MethodsIn this retrospective cohort study, patients were divided into 2 groups according to the monitoring method. Patients with previous renal impairment were excluded. Vancomycin AUC was estimated by using 2 steady-state serum concentrations and first-order kinetics equations. The primary outcome was total cost of vancomycin therapy and monitoring from the hospital perspective, which included costs of cumulative doses, laboratory fees, materials used in blood collection, nursing time for collection, and pharmacist time for result interpretation. FindingsA total of 68 patients were included in the AUC/MIC–guided monitoring group, and 76 patients were included in the trough-guided monitoring group. There were no significant differences between groups regarding baseline serum creatinine level, duration of vancomycin therapy, and cumulative vancomycin dose. The median (interquartile range) total vancomycin drug and monitoring cost was $298.32 ($153.81–$429.85) for the AUC/MIC–guided group compared with $285.59 ($198.81–$435.57) for the trough-guided group (P = 0.9658). ImplicationsVancomycin AUC estimation using 2 steady-state serum concentrations and first-order kinetics equations is a feasible alternative for limited-resource institutions that intend to transition from a trough approach to AUC/MIC–guided monitoring.