Dosing Decisions Research Articles

IGF-1 assessment during weekly somatrogon treatment in pediatric patients with growth hormone deficiency

Abstract Context In patients with growth hormone deficiency (GHD) receiving GH treatment, IGF-1 concentrations are used by physicians to monitor treatment safety and efficacy and guide dosing decisions. Somatrogon is a long-acting GH approved as a once-weekly treatment for pediatric GHD. Somatrogon administration results in characteristic changes in the IGF-1 profile, with values measured at 96 hours post-dose representing mean IGF-1 concentrations that best reflect overall somatrogon exposure. Objective To develop a simple method to enable physicians to predict mean IGF-1 concentrations following somatrogon dosing, based on a single IGF-1 measurement taken at any point during the 7-day dosing interval. Methods Data from phase 2 and phase 3 somatrogon studies were used to develop a 2-compartment pharmacokinetic model with delayed first-order absorption. An indirect-response pharmacokinetic/pharmacodynamic model was applied to the predicted somatrogon concentrations, and model simulations were used to predict IGF-1 and IGF-1 SD score (SDS) levels for participants in both studies. Results A total of 16,213 dosing records (from 42 and 109 participants in the phase 2 and 3 studies, respectively) were used for the simulations, generating predicted values for IGF-1 and IGF-1 SDS. Predicted values were scaled against the respective values at 96 hours (Day 4). These values were used to create a table showing the adjustments required to predict mean IGF-1 and IGF-1 SDS values depending on time after dose. Conclusion We developed a simple method enabling physicians to predict mean weekly IGF-1 values using IGF-1 values measured at any point in the dosing interval. Clinicaltrials.gov: NCT01592500, NCT02968004

Challenges of Serum Creatinine Level in GFR assessment and Drug Dosing Decisions in Kidney Injury

Serum creatinine (SCr) is widely regarded as a standard biomarker for assessing glomerular filtration rate (GFR) and is commonly used to guide dose adjustments for renally eliminated drugs. However, the application of SCr as a marker for evaluating GFR and drug dosing in kidney injury has significant limitations that are often overlooked in clinical practice. This oversight can result in subtherapeutic drug concentrations or adverse drug reactions due to inappropriate dosing adjustments based on SCr levels alone. This review aimed to highlight the factors affecting serum creatinine (SCr) and the challenges associated with using SCr as a biomarker for assessing glomerular filtration rate (GFR) and adjusting drug doses with regard to its limitations and variability. The findings of this review underscore the complexity of SCr regulation, which is affected by its synthesis, metabolism, and excretion processes (glomerular filtration, tubular secretion, tubular reabsorption and extra-renal elimination), and disease states (such as trauma-induced hyperfiltration and HIV) and the use of medications (drug-creatinine interactions) lead to altered renal excretion of creatinine, either increasing or decreasing its levels. Additionally, the renal excretion pathways for drugs and creatinine are not entirely the same, making it difficult to use creatinine to evaluate drug renal excretion. In conclusion, SCr is an imperfect index of GFR and adjusting drug dosing, and the development of multi-biomarker panels, incorporating biomarkers from different excretory pathways-particularly those involving tubular transport-holds promise for improving the evaluation of renal excretory function and ensuring safer and more effective drug dosing.

FC30 Precision biologic dosing in psoriasis: development, validation and beta-testing of a therapeutic drug monitoring dashboard

Abstract Following the advent of biologic therapies for chronic plaque psoriasis, achieving clear/nearly clear skin (disease control) has become a realistic goal. Patients currently continue high-cost biologic therapy indefinitely once they have achieved disease control, which leads to a long-term drug and healthcare burden. Clinical trial data indicate that some individuals can maintain disease control with less frequent doses, especially those who have higher serum drug concentrations, indicating a role for therapeutic drug monitoring (TDM) in guiding dosing decisions. To enable real-world implementation of TDM-guided precision dosing of biologics, we developed, validated, and beta-tested an online interactive TDM dashboard, powered by a pharmacokinetic (PK) model. We searched for population PK models of the exemplar psoriasis biologic risankizumab in PKPDAI and PubMed databases. We externally validated the PK model using an independent multicentre real-world UK psoriasis dataset (n = 50 patients, BSTOP study) prior to embedding it within an online R Shiny interactive dashboard. Two rounds of beta-testing of the TDM dashboard were performed with healthcare professionals to assess usability. A two-compartment PK model with first-order absorption and elimination processes was identified. The PK model was based on Phase I–III trial data and adopted a nonlinear mixed effects approach (13 123 observations from 1899 patients; 71% male; median age, 47; median weight, 97 kg; Suleiman et al., Clin Pharmacokinet 2019). We integrated the model into an online R Shiny interactive dashboard, which generates a personalized dosing interval for risankizumab. The model is used as a Bayesian prior, to predict individual patient parameters using their serum drug concentrations, dose history and other covariates (weight, serum concentrations of anti-drug antibody, albumin and creatinine). Individual predictions were externally validated (mean absolute error 0.95 mg/L; mean percentage error 17.6%; root mean square error 1.7 mg/L; R2 0.8). Beta-testing sessions with 29 clinicians (58% female; mean age 41; 33% doctor; 42% nurse) from 8 UK dermatology centres showed above-average usability of the dashboard (mean System Usability Scale score 72/100, rating ‘good’). All participants evaluated the dashboard as user-friendly and rated it acceptable or completely acceptable. Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Our study provides a novel pipeline for the implementation of TDM-enabled precision dosing of biologics in real-world practice. Our user-friendly online TDM dashboard has the potential to incorporate other biologic therapies and can be extended across disease contexts (including non-response and other immune-mediated inflammatory diseases) for maximal real-world health benefits and cost saving.

Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin-Tazobactam in Critically Ill Patients.

Determining an effective dosing regimen for piperacillin-tazobactam in critically ill patients is challenging due to substantial pharmacokinetic variability caused by complex pathophysiological changes. To address this need, a prospective clinical study was conducted, which enrolled 112 critically ill patients and employed an opportunistic sampling strategy. Population modeling and simulation were performed to characterize the pharmacokinetics (PK) and probability of target attainment (PTA) of piperacillin-tazobactam under various dosing regimens. Both piperacillin and tazobactam final models were one-compartment models with zero-order input and first-order elimination. Significant covariates included lean body weight for piperacillin and creatinine clearance along with continuous renal replacement therapy (CRRT) for both drugs. Monte Carlo simulations demonstrated that continuous infusion can achieve higher PTA than intermittent and extended infusions. When considering the minimum inhibitory concentration (MIC) of 16 mg/L for Pseudomonas aeruginosa (a frequently encountered bacterial pathogen among critically ill patients) and a PK/PD target of 100% fT >MIC, continuous infusion of 6 g/day is recommended for critically ill patients with a CLcr <60 mL/min, 9 g/day for patients with CLcr in the range of 60 to 129 mL/min, and 12 g/day for patients with a CLcr ≥130 mL/min. In addition, extended infusion represents a good alternative, especially the 3 g q6h or 4 g q6h regimens which can achieve the designated European Committee on Antimicrobial Susceptibility Testing (EUCAST) non-species-related PK/PD breakpoint of 8 mg/L. Our study provided valuable insight into PTA outcomes, which, together with individual renal function of future patients and institution-specific piperacillin susceptibility patterns, may assist physicians when making dosing decisions.

A Comprehensive Clinical Assessment of the LumiraDx International Normalized Ratio (INR) Assay for Point-of-Care Monitoring in Anticoagulation Therapy.

The International Normalized Ratio (INR) monitors anticoagulant treatment but relies on laboratory-based services. This could limit access to rapid monitoring and increase the diagnostic delay, both of which may be addressed by point-of-care testing (POCT). This study investigated the LumiraDx POC platform for INR monitoring. INR was measured on recalcified residual venous (n = 94) specimens from Chris Hani Baragwanath Hospital and capillary blood specimens (n = 254) from consenting enrolled participants at Charlotte Maxeke Johannesburg Academic Hospital Anticoagulation clinic, Johannesburg, South Africa. Standard-of-care (SOC) INR was measured on sodium-citrated venous blood using the Sysmex-CS2500 platform (Siemens Healthcare) and Neoplastin-R (Roche Diagnostics and Diagnostica Stago, Paris, France) within 2 h post-venipuncture. Within run, precision was measured using 2 LumiraDx control levels. The statistical agreement of paired INR measurements was also stratified by dosing decision. The precision was within the manufacturer's claim for controls (level 1%CV: 3.63, level 2%CV: 2.24). Accuracy analysis showed a moderate overall agreement compared to the SOC INR results with a correlation coefficient of 0.94 (95% Cl, (0.9267 to 0.9497)). The overall precision (ρ > 0.9) and accuracy (Cb = 0.9842) were good with an absolute bias of 0.07. The 95% confidence intervals for the slope and intercept did not include 1.00 and 0.00, respectively; however, the total calculated error was within the minimal acceptable limits. The LumiraDx INR Test showed a good performance compared to laboratory-based testing and provided opportunity for rapid and patient-centric care. Owing to an increasing positive bias for INR > 3.5, confirmation with laboratory INR measurements may be required.

Meta-Analysis of Exposure-Adverse Event Relationships for Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) have become a vital class of therapeutics in oncology because of their ability to selectively deliver potent drug molecules to tumor cells. However, ADC-associated toxicities cause high failure rates in the clinic and hinder their full potential. Due to the complex structure and pharmacokinetics of ADCs, it is challenging to identify the drivers of their toxicities. Here, quantitative analysis was performed to correlate the incidence of clinical adverse events (AEs) with nine different commonly measured exposure parameters collected from study-level summary data. We considered ADC analytes for different classes of ADCs, to identify ADC analytes that are strongly associated with the AEs for ADCs. Published clinical exposure and safety data for any grade and grade ≥3 AEs from 40 publications across six ADCs and three payloads were collected and analyzed. Exposure-AE relationships were quantified using logit models, and the strength of the correlations and rank order were determined. The analysis suggests that deruxtecan ADC-related toxicities correlated most strongly with the exposure of the free payload; monomethyl auristatin E (MMAE) ADC-related toxicities correlated with the free MMAE area under the curve; and pyrrolobenzodiazepine ADC-related toxicities correlated with no specific analyte but the dose. These findings agree with the published literature and support the notion that AE profiles are often shared by ADCs that deliver the same cytotoxic payload. The exposure-AE relationships presented here, together with identification of the most informative ADC analytes, may facilitate more focused mechanistic studies on the drivers of clinical AEs and could support dosing decisions during clinical development of ADCs.

DDDR-14. IMPROVED ANTI-GLIOBLASTOMA EFFICACY BY BRG399, A NOVEL ORAL MICROTUBULE BINDING AGENT

Abstract Glioblastoma (GBM) is a highly malignant form of brain tumor with a poor prognosis despite advances in treatments. Therapeutic resistance/relapse remains a significant challenge necessitating the development of novel approaches. BRG399 is a brain permeant, non P-gp substrate, microtubule-targeting agent that displays anti-cancer activity in vitro and in vivo. BRG399 was well tolerated in rat and dog toxicology studies. Anti-cancer activity (IC50) of BRG399 in in vitro models of GBM was assessed to have potency ranging from 42nm to 89nM in the 3 cell lines tested. Here, in vivo tumor activity of BRG399 was assessed in Sprague Dawley rats implanted with 3x105 C6 rat glioma cells into the right entorhinal cortex/subiculum region. 14 days post successful implantation tumors were assessed by MRI, rats were randomized to receive vehicle (2% Labrasol) or BRG399 (5, 10, 20 mg/kg groups) twice daily by oral gavage for 16 days, and MRIs were performed on survivors on days 31 and 45 post implantation. BRG399 administration resulted in a marked improvement in survival (from 7.7 ± 2.6 days to 25.5 ± 15.6 days, log-rank test, p:0.007) compared to controls. Six animals receiving BRG399 remained alive beyond day 60 of post-treatment initiation. To assess biodistribution of BRG399 in the brain, rats were implanted with C6 cells and tumor establishment assessed 12 days later by MRI. Animals were treated with vehicle or BRG399 (10, 20, 25 mg/kg) and plasma and brains were collected for bioanalytical assessment. Tissue single cell biodistribution was performed using TIMSTOF FLEX spatial OMICS. These results demonstrate a therapeutic effect of BRG399 on intracranial glioma-bearing rats with survival of the BRG399 treatment groups of strong statistical significance over the control group. Analysis of drug levels in plasma and brain will serve as guidance for dose and scheduling decisions for further therapeutic development.

GenoSiS: A Biobank-Scale Genotype Similarity Search Architecture for Creating Dynamic Patient-Match Cohorts.

Many patients do not experience optimal benefits from medical advances because clinical research does not adequately represent them. While the diversity of biomedical research cohorts is improving, ensuring that individual patients are adequately represented remains challenging. We propose a new approach, GenoSiS, which leverages machine learning-based similarity search to dynamically find patient-matched cohorts across different populations quickly. These cohorts could serve as reference cohorts to improve a range of clinical analyses, including disease risk score calculations and dosage decisions. While GenoSiS focuses on finding genetic similarity within a biobank, our similarity search architecture can be extended to represent other medically relevant patient characteristics and search other biobanks.

Removal of Meropenem and Piperacillin during Experimental Hemoadsorption with the HA380 Cartridge.

Hemoadsorption can be used as adjunctive therapy for sepsis. However, there is limited evidence regarding its antibiotic removal. In this in vivo preclinical study, we aimed to evaluate the removal of meropenem and piperacillin with the HA380 hemoadsorption cartridge. Healthy adult sheep (n = 6) received 2 g of meropenem and 4 g of piperacillin intravenously for 30 min followed by hemoadsorption with a HA380 cartridge at a blood flow rate of 120 mL/min for 4 h. The sorbent-based removal ratio, clearance, and mass removal were calculated at multiple time points. The sorbent-based removal ratio of meropenem decreased from 95.4% (SD 1.8) at 10 min to less than 20% at 4 h of hemoadsorption. Its cumulative sorbent-based mass removal was 386.6 mg (SD 78.8) over 4 h with 65.6% (SD 7.1) occurring in the first 60 min. In contrast, the sorbent-based removal ratio of piperacillin decreased more gradually from 98.4% (SD 0.6) at 10 min to 37.4% (SD 7.2) at 4 h. Its cumulative sorbent-based mass removal was 647.4 mg (SD 191.3) over 4 h with 63.4% (SD 4.2) occurring in the first 60 min. The overall sorbent-based clearance of piperacillin was significantly greater than meropenem (pgroup < 0.0001). Hemoadsorption with the HA380 cartridge removed meropenem and piperacillin throughout a 4-h period, with high clearances at the start. Our findings can be used to inform dosing decisions during hemoadsorption in septic patients, there may be the need to consider increasing the doses of these antibiotics by 15-25% to prevent underdosing.

Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women.

Optimal dosing in pregnant and lactating women requires an understanding of the pharmacokinetics in the mother, fetus, and breastfed infant. Physiologically-based pharmacokinetic (PBPK) modeling can be used to simulate untested scenarios and hence supplement clinical data to support dosing decisions. A PBPK model for the antiretroviral dolutegravir (mainly metabolized by UGT1A1) was verified using reported exposures in non-pregnant healthy volunteers, pregnant women, and the umbilical cord, lactating mothers, and breastfed neonates. The model was then applied to predict the impact of UGT1A1 phenotypes in extensive (EM), poor (PM), and ultra-rapid metabolizers (UM). The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 PMs was 1.6-fold higher than in EMs. The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 UMs mothers was 1.3-fold lower than in EMs. The predicted mean systemic and umbilical vein concentrations were in excess of the dolutegravir IC90 at 17, 28, and 40 gestational weeks, regardless of UGT1A1 phenotype, indicating that the standard dose of dolutegravir (50 mg q.d., fed state) is generally appropriate in late pregnancy, across UGT1A1 phenotypes. Applying the model in breastfed infants, a 1.5-, 1.7-, and 2.2-fold higher exposure in 2-day-old neonates, 10-day-old neonates, and infants who were UGT1A1 PMs, respectively, compared with EMs of the same age. However, it should be noted that the exposure in breastfed infants who were UGT1A1 PMs was still an order of magnitude lower than maternal exposure with a relative infant daily dose of <2%, suggesting safe use of dolutegravir in breastfeeding women.

Direct-Acting Oral Anticoagulants and Potential Inconsistencies with FDA-Approved Dosing for Non-Valvular Atrial Fibrillation: A Retrospective Real-World Analysis Across Nine US Healthcare Systems.

Direct-acting oral anticoagulants (DOACs) are recommended to reduce risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). However, DOAC dosing inconsistent with FDA-approved product labels is common and associated with poor clinical outcomes. Identify DOAC dosing inconsistent with FDA-approved product labels in ambulatory care patients with NVAF; identify variables associated with dosing lower and higher than label. Retrospective analysis using electronic health records from nine US healthcare systems. Adults with NVAF receiving DOAC therapy in 2022. Rates of label-inconsistent dosing; multivariable regression analysis to identify demographic and clinical variables associated with dosing lower and higher than label. Among 51,128 NVAF patients (56.1% male, 94.3% White, mean [SD] age 73.5 [10.5] years), 5008 (9.8%) were prescribed label-inconsistent doses of DOACs (6.8% lower and 3.0% higher than label). Age ≥ 75years, renal impairment, and hypertension were significantly associated with inconsistent dosing both higher and lower than label. Female sex and higher weight were significantly associated with dosing lower than label, as were heart failure, vascular or liver disease, and bleeding history. Dosing higher than label was significantly associated with male sex, race (African American/Black), weight < 60kg, and use of drugs with potential drug-drug interactions. When prescribed by primary care physicians, DOAC doses were 37% (95% CI, 27-49%) more likely to be lower than label and 30% (95% CI, 16-46%) more likely to be higher than label than when prescribed by cardiologists or electrophysiologists. Label-inconsistent dosing varied (6.7 to 15.8%) across participating systems. DOAC dosing inconsistent with label varied by demographics, clinical characteristics, prescriber specialty, and healthcare system, suggesting a need to monitor and assess dosing decisions in NVAF. Identification of variables associated with dosing inconsistencies may enable targeted interventions to ensure label-consistent dosing in vulnerable populations.

Obesity-related drug transporter expression alterations in human liver and kidneys

BackgroundPathophysiological changes associated with obesity might impact various drug pharmacokinetics (PK) parameters. The liver and kidneys are the primary organs involved in drug clearance, and the function of hepatic and renal transporters is critical to efficient drug elimination (or reabsorption). Considering the impact of an increased BMI on the drug’s PK is crucial in directing dosing decisions. Given the critical role of transporters in drug biodisposition, this study investigated how overweight and obesity affect the gene expression of renal and hepatic drug transporters.MethodsHuman liver and kidney samples were collected post-mortem from 32 to 28 individuals, respectively, which were divided into the control group (lean subjects; 18.5 ≤ BMI < 25 kg/m2) and the study group (overweight/obese subjects; BMI ≥ 25 kg/m2). Real-time quantitative PCR was performed for the analysis of 84 drug transporters.ResultsOur results show significant changes in the expression of genes involved in human transporters, both renal and hepatic. In liver tissue, we found that ABCC4 was up-regulated in overweight/obese subjects. In kidney tissue, up-regulation was only observed for ABCC10, while the other differentially expressed genes were down-regulated: ABCA1, ABCC3, and SLC15A1.ConclusionsThe observed alterations may be reflected by the differences in drug PK between lean and obese populations. However, these findings need further evaluation through the proteomic and functional study of these transporters in this patient population.

Evaluating adherence to AAO hydroxychloroquine screening guidelines

PurposeHydroxychloroquine (HCQ) is commonly prescribed for autoimmune disorders but carries a risk of retinal damage, which increases over time. The American Academy of Ophthalmology (AAO) issued updated guidelines in 2016 to optimize screening for HCQ retinopathy, recommending dosing based on real body weight and specific visual field (VF) testing patterns. This study aimed to assess adherence to the AAO guidelines for HCQ retinopathy screening in a clinical setting and to identify deviations in the implementation of these guidelines. DesignWe employed a large, single-center retrospective case series study design. MethodsWe conducted a retrospective analysis of 391 patients treated with HCQ at a single academic center from 2017 to 2019. The study focused on the appropriateness of screening tests, specifically optical coherence tomography (OCT) and VF testing, based on the duration of HCQ therapy. ResultsOur analysis showed that over-testing with OCT and VF was prevalent among patients on HCQ for five years or less, occurring in 56% and 48% of encounters, respectively. Conversely, there were missed screenings in patients on HCQ for more than five years, with 12% and 16% of encounters lacking OCT and VF testing, respectively. Notably, adherence to VF testing guidelines for Asian patients was poorly implemented, with the recommended wide pattern VF testing conducted in only two of nine cases. Additionally, there were significant instances where HCQ dosages exceeded recommended levels without subsequent adjustments, despite ophthalmologists' recommendations. ConclusionsThe study highlights a critical need for improved guideline adherence to prevent unnecessary testing costs and undetected retinopathy in long-term HCQ users. It underscores the importance of using real body weight for dosing decisions and enhancing collaboration between ophthalmologists and rheumatologists to manage the delicate balance between disease control and the risk of retinopathy. Further multi-center studies are warranted to evaluate adherence variations and develop strategies for guideline implementation.

Application of physiologically-based pharmacokinetic modeling to inform dosing decisions for geriatric patients.

Application of physiologically-based pharmacokinetic modeling to inform dosing decisions for geriatric patients.

Optimizing oocyte yield utilizing a machine learning model for dose and trigger decisions, a multi-center, prospective study

The objective of this study was to evaluate clinical outcomes for patients undergoing IVF treatment where an artificial intelligence (AI) platform was utilized by clinicians to help determine the optimal starting dose of FSH and timing of trigger injection. This was a prospective clinical trial with historical control arm. Four physicians from two assisted reproductive technology treatment centers in the United States participated in the study. The treatment arm included patients undergoing autologous IVF cycles between December 2022–April 2023 where the physician use AI to help select starting dose of follicle stimulating hormone (FSH) and trigger injection timing (N = 291). The control arm included historical patients treated where the same doctor did not use AI between September 2021 and September 2022. The main outcome measures were total FSH used and average number of mature metaphase II (MII) oocytes. There was a non-significant trend towards improved patient outcomes and a reduction in FSH with physician use of AI. Overall, the average number of MIIs in the treatment vs. control arm was 12.20 vs 11.24 (improvement = 0.96, p = 0.16). The average number of oocytes retrieved in the treatment vs. control arm was 16.01 vs 14.54 (improvement = 1.47, p = 0.08). The average total FSH in the treatment arm was 3671.95 IUs and the average in the control arm was 3846.29 IUs (difference = −174.35 IUs, p = 0.13). These results suggests that AI can safely assist in refining the starting dose of FSH while narrowing down the timing of the trigger injection during ovarian stimulation, benefiting the patient in optimizing the count of MII oocytes retrieved.

Assessing predictors of adequate individual buprenorphine maintenance dosage for the treatment of opioid use disorder: Listening to the patient

ObjectiveDose optimization plays a key role in determining clinical outcomes in patients on opioid agonist treatment (OAT). The objective of this study was to identify the variables independently associated with buprenorphine/naloxone (B/N) dose adequacy in patients with opiate use disorder (OUD). MethodCross-sectional study of a convenience sample of patients with OUD treated with B/N (n = 315) in four regions in Spain. The Opiate Dosage Adequacy Scale (ODAS) was used to determine B/N dose adequacy. The ODAS evaluate the six components of the “dose adequacy” construct, as follows: continued use of heroin; narcotic blockade or crossed tolerance; objective opioid withdrawal symptoms (OWS); subjective OWS; craving for heroin; and overmedication. A binomial logistic regression analysis was performed to identify the variables associated with the condition “ODAS Adequate B/N dose”. Participants completed a battery of instruments to assess sociodemographic, substance use, clinical, and treatment variables. ResultsThe B/N dose was considered adequate in 231 of the 315 participants (73.3 %). Two variables, satisfaction with B/N as a medication (OR=5.764, 95 % CI=2.211-15.030) and patient-perceived participation in B/N dose decisions (OR=1.790, 95 % CI=1221-2623), were independently, significantly, and positively associated with the “ODAS Adequate B/N dose” condition. While the severity of heroin dependence was significantly associated with buprenorphine dose adequacy in the bivariate analyses, significance was lost in the full regression model. ConclusionSatisfaction with B/N as a medication and patient-perceived involvement in the dose decision are associated with clinician-assessed dose adequacy. In the context of good clinical practice, it is important to take into account both of these variables to individualize the prescribed dose through a shared decision-making process.

Pharmacokinetics of Anti-rheumatic Drugs Methotrexate and Tofacitinib with its Metabolite M9 in Rats by UPLC-MS/MS.

Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The clinical efficacy and safety of an administered tofacitinib, either monotherapy or in combination with conventional synthetic disease-modifying anti-rheumatic drugs, mainly methotrexate (MTX), have been evaluated. The high plasma concentration with delayed medicine clearance may affect the liver and/or kidney functions. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC- MS/MS) method for the quantitative analysis of methotrexate, tofacitinib, and metabolite M9 in plasma of Sprague Dawley (SD) rats was developed, and its effectiveness was validated as well. Methotrexate, tofacitinib, M9 and fedratinib (internal standard, IS) were separated by gradient elution. The chromatography was performed on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 μm) column with the mobile phases of acetonitrile and 0.1% formic acid aqueous solution with different proportions at the flow rate of 0.30 mL/min. In the positive ionization mode, the analyzes were detected using a Xevo TQ-S triple quadrupole tandem mass spectrometer, with the following mass transition pairs: m/z 313.12 → 148.97 for tofacitinib, m/z 329.10 → 165.00 for M9 and m/z 455.12 → 308.05 for methotrexate. The obtained results manifested good calibration linearity over the ranges of tofacitinib at 0.1-100 ng/mL, M9 at 0.05-100 ng/mL, and methotrexate at 0.05-100 ng/mL. The lower limit of quantifications (LLOQs) of methotrexate, tofacitinib and M9 were 0.05 ng/mL, 0.1 ng/mL and 0.05 ng/mL, respectively. Intra-day and inter-day accuracy values were confirmed with a range of -6.3% to 12.7%, while intra-day and inter-- day precision values were ≤14.4%. Additionally, recoveries were greater than 86.5% for each compound without significant matrix effects. The currently established analytical method exhibited great potential for the evaluation of plasma concentrations of methotrexate, tofacitinib and M9 simultaneously, greatly reducing the detection time, which would serve as a supplementary role in formulating dose decisions to achieve personalized treatment, identify drugs that cause adverse reactions and finally, to assess drug-drug interactions on clinical studies.

Primary treatment modification strategies among older adults with advanced cancer.

1512 Background: Primary treatment modification (PTM; any change in dose or agents of the planned chemotherapy regimen from the standard guidelines) is a common therapeutic approach among older adults with advanced cancer due to their geriatric vulnerabilities. However, strategies to employ these modifications are understudied. This study compares a PTM strategy based on Geriatric Assessment (PTM-GA) intervention vs. usual care strategy based on oncologist’s impression (PTM-UC) on treatment tolerability in older adults with advanced cancer starting new chemotherapy regimens. Methods: In this subgroup analysis of the GAP 70+ study (NCT02054741; PI: Mohile), we included patients aged ≥ 70 with incurable solid tumors who initiated a chemotherapy course with PTM (n=298). For the first (PTM-GA) group, PTM was guided by GA results and recommendations while for the second (PTM-UC) group, PTM was guided by the treating oncologist's estimate only. Tolerability outcomes were assessed within 3 months of treatment and included: 1) any grade 3-5 clinician-rated toxicity according to National Cancer Institute Common Toxicity Criteria; 2) subsequent dose reduction; 3) Activity of Daily Living (ADL) decline; 4) unplanned hospitalization. We used multivariable, cluster-weighted generalized estimating equations models to examine the association of PTM-GA vs. PTM-UC and outcomes adjusting for confounders. Results: Mean age was 77 years. The most common cancer types were gastrointestinal (37%) followed by lung cancer (26%). PTM-GA versus PTM-UC was associated with reduced risk of grade 3-5 toxicity (relative risk (RR)= 0.77, 95% CI, 0.61- 0.90) and subsequent dose reduction (RR, 0.46; 95% CI, 0.29-0.73). Point estimates suggest that patients with PTM-GA may have a lower risk of unplanned hospitalization but results did not reach statistical significance (RR, 0.69; 95% CI, 0.46–1.02). PTM-GA vs. PTM-UC was not associated with ADL decline (RR, 1.05; 95% CI, 0.74–1.49). Conclusions: Older patients with advanced cancer who had PTM guided by GA recommendations had improved treatment tolerability compared to those who PTM based on oncologist’s estimate only. Integrating GA into treatment dosing decisions may lead to improved outcomes in this vulnerable population.

Replacing the Clinical Institute Withdrawal Assessment-Alcohol revised with the modified Richmond Agitation and Sedation Scale for alcohol withdrawal to support management of alcohol withdrawal symptoms: potential impact on length of stay and complications.

We evaluated impact on length of stay and possible complications of replacing the Clinical Institute Withdrawal Assessment-Alcohol Revised (CIWA-Ar) scale with a slightly modified Richmond Agitation and Sedation Scale (mRASS-AW) to support managing patients admitted with alcohol withdrawal symptoms in a community hospital. Since mRASS-AW is viewed as easier and quicker to use than CIWA-Ar, provided use of mRASS-AW does not worsen outcomes, it could be a safe alternative in a busy ED environment and offer an opportunity to release nursing time to care. Retrospective time-series analysis of mean quarterly length of stay. All analyses exclusively used our hospital's administrative discharge diagnoses database. During April 1st 2012 to December 14th 2014, the CIWA-Ar was used in the ED and in-patient units to guide benzodiazepine dosing decisions for alcohol withdrawal symptoms. After this point, CIWA-Ar was replaced with mRASS-AW. Data was evaluated until December 31st 2020. mean quarterly length of stay. delirium, intensive care unit (ICU) admission, other post-admission complications, mortality. N = 1073 patients. No association between length of stay and scale switch (slope change 0.3 (95% CI - 0.03 to 0.6), intercept change, 0.06 (- 0.03 to 0.2). CIWA-Ar (n = 317) mean quarterly length of stay, 5.7 days (95% 4.2-7.1), mRASS-AW (n = 756) 5.0 days (95% CI 4.3-5.6). Incidence of delirium, ICU admission or mortality was not different. However, incidence of other post-admission complications was higher with CIWA-Ar (6.6%) than mRASS-AW (3.4%) (p = 0.020). This was the first study to compare patient outcomes associated with using mRASS-AW for alcohol withdrawal symptoms outside the ICU. Replacing CIWA-Ar with mRASS-AW did not worsen length of stay or complications. These findings provide some evidence that mRASS-AW could be considered an alternative to CIWA-Ar and potentially may provide an opportunity to release nursing time to care.

Therapeutic Drug Monitoring and Biomarkers; towards Better Dosing of Antimicrobial Therapy.

Due to variability in pharmacokinetics and pharmacodynamics, clinical outcomes of antimicrobial drug therapy vary between patients. As such, personalised medication management, considering both pharmacokinetics and pharmacodynamics, is a growing concept of interest in the field of infectious diseases. Therapeutic drug monitoring is used to adjust and individualise drug regimens until predefined pharmacokinetic exposure targets are achieved. Minimum inhibitory concentration (drug susceptibility) is the best available pharmacodynamic parameter but is associated with many limitations. Identification of other pharmacodynamic parameters is necessary. Repurposing diagnostic biomarkers as pharmacodynamic parameters to evaluate treatment response is attractive. When combined with therapeutic drug monitoring, it could facilitate making more informed dosing decisions. We believe the approach has potential and justifies further research.