Comparative Analysis of Posiphen Pharmacokinetics across Different Species-Similar Absorption and Metabolism in Mouse, Rat, Dog and Human.

Posiphen is a small molecule that exhibits neuroprotective properties by targeting multiple neurotoxic proteins involved in axonal transport, synaptic transmission, neuroinflammation, and cell death. Its broad-spectrum effects make it a promising candidate for treating neurodegenerative conditions, including Alzheimer's and Parkinson's diseases. Despite extensive investigation with animal models and human subjects, a comprehensive comparative analysis of Posiphen's pharmacokinetics across studies remains elusive. Here, we address this gap by examining the metabolic profiles of Posiphen and its breakdown into two primary metabolites-N1 and N8-across species by measuring their concentrations in plasma, brain, and CSF using the LC-MS/MS method. While all three compounds effectively inhibit neurotoxic proteins, the N1 metabolite is associated with adverse effects. Our findings reveal the species-specific behavior of Posiphen, with both Posiphen and N8 being predominant in various species, while N1 remains a minor constituent, supporting the drug's safety. Moreover, in plasma, Posiphen consistently showed fast clearance of all metabolites within 8 h in animal models and in human subjects, whereas in CSF or brain, the compound has an extended half-life of over 12 h. Combining all our human data and analyzing them by population pharmacokinetics showed that there are no differences between healthy volunteers, Alzheimer's, and Parkinson's patients. It also showed that Posiphen is absorbed and metabolized in a similar fashion across all animal species and human groups tested. These observations have critical implications for understanding the drug's safety, therapeutic effect, and clinical translation.

"Getting the Dose Right"-Revisiting the Topic With Focus on Biologic Agents.

Nearly two decades after the Peck and Cross article '"Getting the dose right: facts, a blueprint, and encouragements" was published, a review of dose recommendations for biologics shows that the success in getting the dose right appears to have improved given the relatively low incidence of drug withdrawals and dosing/label changes. However, the clinical experience with monoclonal antibodies (MAbs) following approval has been less than perfect. In inflammatory diseases, the disease burden changes with time and high treatment failure rates have been reported. In addition, the use of concomitant steroids and immunosuppressant drugs with MAbs is common. These concomitant agents have their own safety issues and many immunosuppressant agents are not well-tolerated although they have been shown to reduce the incidence of anti-drug antibodies (ADA). This same complexity is seen in MAbs used in oncology as well, although with these agents the doses appear to be higher than needed, which results in high treatment costs and incidence of adverse events. Given the complexity of MAb pharmacokinetics, which makes providing a detailed description of dose options difficult, product labeling should include the options for alternative dose strategies and potentially include the use of therapeutic drug monitoring with dose individualization which have been shown to improve clinical response and reduce the incidence of ADA. So, while the recommended dosing for biologics seems improved over the issues noted 17 years ago, we still have some work to do.

Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model.

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. RESULTS: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. CONCLUSIONS: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. CLINICAL TRIAL REGISTRATION: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.

Tumor growth inhibition modeling in patients with second line biliary tract cancer and first line non-small cell lung cancer based on bintrafusp alfa trials.

This analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability in tumor dynamics by pharmacometric and machine-learning (ML) approaches. Data originated from two clinical trials in patients with biliary tract cancer (BTC; NCT03833661) receiving BA and non-small cell lung cancer (NSCLC; NCT03631706) receiving BA or pembrolizumab. Individual drug exposure was estimated from previously developed population PK models. Population tumor dynamics models were developed for each drug-indication combination, and covariate evaluations performed using nonlinear mixed-effects modeling (NLME) and ML (elastic net and random forest models) approaches. The three tumor dynamics' model structures all included linear tumor growth components and exponential tumor shrinkage. The final BTC model included the effect of drug exposure (area under the curve) and several covariates (demographics, disease-related, and genetic mutations). Drug exposure was not significant in either of the NSCLC models, which included two, disease-related, covariates in the BA arm, and none in the pembrolizumab arm. The covariates identified by univariable NLME and ML highly overlapped in BTC but showed less agreement in NSCLC analyses. Hyperprogression could be identified by higher tumor growth and lower tumor kill rates and could not be related to BA exposure. Tumor size over time was quantitatively characterized in two tumor types and under two treatments. Factors potentially related to tumor dynamics were assessed using NLME and ML approaches; however, their net impact on tumor size was considered as not clinically relevant.

Application of a Precision-Dosing Model to a Real-World Cohort of Patients on Infliximab Maintenance Therapy: Drug Usage and Cost Analysis.

Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE-predicted dose X. Net drug use and costs were evaluated. A total of 174 patients-56% men; median age, 36 (interquartile range, 29-47) years; 135 with Crohn disease; and 31 with ulcerative colitis-were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0-4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5-10 and 3-7 µg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28-75.40; P = .028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03-0.15; P < .001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 µg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater.

Personalized Dosing of Infliximab in Patients With Inflammatory Bowel Disease Using a Bayesian Approach: A Next Step in Therapeutic Drug Monitoring.

Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non-response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to maintain the efficacy of biologic agents. Reactive TDM can rationalize the management of primary non-response and secondary loss of response and has shown to be more cost-effective compared with empiric dose escalation. Proactive TDM is shown to increase clinical remission and the durability of the response to a biologic agent. However, the efficacy of proactive and reactive TDM has been questioned in recent studies and meta-analyses. Hence, we need a different approach to TDM, which addresses inflammatory burden, the individual patient, and disease factors. Bayesian approaches, which use population pharmacokinetic models, enable clinicians to make better use of TDM for dose adjustment. With rapid improvement in computer technology, these Bayesian model-based software packages are now available for clinical use. Bayesian dashboard systems allow clinicians to apply model-based dosing to understand an individual's pharmacokinetics and achieve a target serum drug concentration. The model is updated using previously measured drug concentrations and relevant patient factors, such as body weight, C-reactive protein, and serum albumin concentration, to maintain effective drug concentrations in the serum. Initial studies have found utility for the Bayesian approach in induction and maintenance, in adult and pediatric patients, in clinical trials, and in real-life situations for patients with IBD treated with infliximab. This needs confirmation in larger studies. This article reviews the Bayesian approach to therapeutic drug monitoring in IBD.

Effect of Pevonedistat, an Investigational NEDD8-Activating Enzyme Inhibitor, on the QTc Interval in Patients With Advanced Solid Tumors.

The purpose of this study was to assess the effect of pevonedistat, a neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8)-activating enzyme inhibitor, on the heart rate-corrected QT (QTc) interval in cancer patients. Patients were randomized 1:1 to receive pevonedistat 25 or 50 mg/m2 on day 1 and the alternate dose on day 8. Triplicate electrocardiograms were collected at intervals over 0-11 hours and at 24 hours via Holter recorders on days -1 (baseline), 1, and 8. Changes from time-matched baseline values were calculated for QTc by Fridericia (QTcF), PR, and QRS intervals. Serial time-matched blood samples for analysis of pevonedistat plasma pharmacokinetics were collected and a concentration-QTc analysis conducted. Safety was assessed by monitoring vital signs, physical examinations, and clinical laboratory tests. Forty-four patients were included in the QTc analysis. Maximum least square (LS) mean increase from time-matched baseline in QTcF was 3.2 milliseconds at 1 hour postdose for pevonedistat at 25 mg/m2 , while the LSs mean change from baseline in QTcF was -1.7 milliseconds 1 hour postdose at 50 mg/m2 . The maximum 2-sided 90% upper confidence bound was 6.7 and 2.9 milliseconds for pevonedistat at 25 and 50 mg/m2 , respectively. Pevonedistat did not result in clinically relevant effects on heart rate, nor on PR or QRS intervals. Results from pevonedistat concentration-QTc analysis were consistent with these findings. Administration of pevonedistat to cancer patients at a dose of up to 50 mg/m2 showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization. ClinicalTrials.gov identifier: NCT03330106 (first registered on November 6, 2017).

Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study.

BACKGROUND: Scarce data are available on the use of vedolizumab in children with inflammatory bowel disease (IBD). We aimed to evaluate the safety, effectiveness, and dosing of vedolizumab to induce remission of IBD. METHODS: VEDOKIDS was a paediatric, multicentre, prospective cohort study done in 17 centres in six countries. We report the 14-week outcomes as the first analyses of the planned 3-year follow-up of the VEDOKIDS cohort. Children (aged 0-18 years) with IBD who had commenced vedolizumab were followed up at baseline and at 2, 6, and 14 weeks. Children were managed according to local prescribing practices without standardisation of dosing or criteria for escalation, but the study protocol suggested dosing of 177 mg/m2 body surface area (up to 300 mg maximum). The primary outcome was steroid-free and exclusive enteral nutrition-free remission at 14 weeks, analysed according to the intention-to-treat principle. Serum samples were taken for analysis of drug concentration and faecal calprotectin at baseline, and at 2, 6, and 14 weeks. Adverse events were recorded in real time and classified as severe or non-severe and related or unrelated to vedolizumab. This study is registered with ClinicalTrials.gov, NCT02862132. FINDINGS: Between May 19, 2016, and April 1, 2022, 142 children (76 [54%] girls and 66 [46%] boys; mean age 13·6 years [SD 3·6]) were enrolled. 65 (46%) children had Crohn's disease, 68 (48%) had ulcerative colitis, and nine (6%) had unclassified IBD (those with unclassified IBD were analysed with the ulcerative colitis group). 32 (42% [95% CI 30-54]) of 77 children with ulcerative colitis and 21 (32% [23-45]) of 65 children with Crohn's disease were in steroid-free and exclusive enteral nutrition-free remission at 14 weeks. Median drug concentrations at week 14 were higher in children with ulcerative colitis than in those with Crohn's disease (11·5 µg/mL [IQR 5·5-18·1] vs 5·9 µg/mL [3·0-12·7]; p=0·006). In children who weighed less than 30 kg, the optimal drug concentration associated with steroid-free and exclusive enteral nutrition-free clinical remission was 7 µg/mL at week 14 (area under the curve 0·69 [95% CI 0·41-0·98]), corresponding to a dose of 200 mg/m2 body surface area or 10 mg/kg. 32 (23%) of 142 children reported at least one adverse event, the most common were headache (five [4%]), myalgia (four [3%]), and fever (three [2%]). None of the adverse events were classified as severe, and only two (1%) patients discontinued treatment due to adverse events. INTERPRETATION: Vedolizumab showed good safety and effectiveness at inducing remission in children with IBD at 14 weeks, especially those with ulcerative colitis. Vedolizumab should be considered in children when other approved drug interventions for IBD are unsuccessful. In children who weigh less than 30 kg, vedolizumab should be dosed by the child's body surface area (200 mg/m2) or weight (10 mg/kg). FUNDING: The European Crohn's and Colitis Organization, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.

Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases.

Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings's regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming's slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7−30.2; OR = 21.0 CI95%: 3.4−127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.

Dashboard-Driven Accelerated Infliximab Induction Dosing Increases Infliximab Durability and Reduces Immunogenicity.

BACKGROUND AND AIMS: Accelerated infliximab (IFX) induction is often based on clinical parameters as opposed to pharmacokinetics (PK). We aimed to investigate the impact of dashboard-guided optimized induction dosing on IFX durability and immunogenicity in a real-world inflammatory bowel disease (IBD) setting. METHODS: Pediatric and adult IBD patients were enrolled in a prospective single arm intervention trial. Cumulative data from each infusion (INF), weight, albumin, C-reactive protein, IFX dose, IFX trough level, and antidrug antibody presence were used to inform subsequent INF dosing. Forecasts driven by adaptive Bayesian modeling were generated to maintain trough levels for the third (INF3) and fourth (INF4) infusions of 17 µg/mL and 10 µg/mL, respectively. The primary outcome was proportion of patients prescribed accelerated dosing (AD) intervals by INF3 (<22 days) or INF4 (<49 days). Secondary outcomes included week 52 clinical and PK outcomes. Multivariate analyses and Kaplan-Meier curves compared outcomes based on adherence to dashboard forecasts. RESULTS: Of the 180 per-protocol population, AD was forecast for 41% (INF3) and 69% (INF4) of patients with median intervals of 17 (INF3) and 39 (INF4) days. Baseline age >18 years, albumin >3.5 g/L, and 10-mg/kg dose were independently associated with lower rates of AD by INF4. Nonadherence with the INF4 forecast (n = 39) was an independent predictor of antidrug antibody (P < .0001) and IFX discontinuation (P = .0006). A total of 119 of 123 patients on IFX at week 52 were in steroid-free remission. CONCLUSIONS: The application of a PK dashboard during induction can optimize dosing early to improve IFX durability and immunogenicity.

We present the first proactive infliximab optimization study during induction guided by a pharmacokinetics dashboard in a real-world inflammatory bowel disease setting. At 1 year, clinical outcomes were impacted significantly by the timing of the first maintenance infusion.

Population Pharmacokinetics and Exposure-Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies.

Population pharmacokinetic (PK) and exposure-safety analyses of alisertib were performed in children enrolled in 2 clinical trials: NCT02444884 and NCT01154816. NCT02444884 was a dose-finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45 to 100 mg/m2 as powder-in-capsule once daily or twice daily for 7 days in 21-day cycles. Serial blood samples were collected up to 24 hours after dosing on cycle 1, day 1. NCT01154816 was a phase 2 single-arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m2 as enteric-coated tablets once daily for 7 days in 21-day cycles. Sparse PK samples were collected up to 8 hours after dosing on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed-effects modeling to support dosing recommendations in children and adolescents. A 2-compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area across the age range of 2 to 21 years, supporting the use of body surface area-based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 once daily enteric-coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg twice daily (recommended adult dose). Statistically significant relationships (P < .01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism-related toxicities.

Approaches to handling missing or "problematic" pharmacology data: Pharmacokinetics.

Missing or erroneous information is a common problem in the analysis of pharmacokinetic (PK) data. This may present as missing or inaccurate dose level or dose time, drug concentrations below the analytical limit of quantification, missing sample times, or missing or incorrect covariate information. Several methods to handle problematic data have been evaluated, although no single, broad set of recommendations for commonly occurring errors has been published. In this tutorial, we review the existing literature and present the results of our simulation studies that evaluated common methods to handle known data errors to bridge the remaining gaps and expand on the existing knowledge. This tutorial is intended for any scientist analyzing a PK data set with missing or apparently erroneous data. The approaches described herein may also be useful for the analysis of nonclinical PK data.

Limited Systemic Exposure with Topical Glycopyrronium Tosylate in Primary Axillary Hyperhidrosis.

BACKGROUND: Glycopyrronium tosylate (GT; Qbrexza® [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged ≥ 9 years. OBJECTIVE: The objective of this study was to compare the pharmacokinetics and safety of GT to oral glycopyrrolate (phase I study) and assess the relationship between glycopyrronium pharmacokinetics and anticholinergic-related adverse events or efficacy with population pharmacokinetics using data from two phase II studies. METHODS: In the phase I study, study staff applied GT to axillae of patients with primary axillary hyperhidrosis (aged 9-65 years) once daily (5 days); oral glycopyrrolate was administered to healthy adults (aged 18-65 years) every 8 hours (15 days). In the phase II studies (NCT02016885 [20 December, 2013], NCT02129660 [2 May, 2014]), adults with primary axillary hyperhidrosis applied topical glycopyrronium (0.8-3.2%) or vehicle to axillae once daily (4 weeks). Pharmacokinetic and adverse event data were collected in all studies. RESULTS: Glycopyrronium pharmacokinetic parameters were similar between adult and pediatric patients treated with GT; there was no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events occurred with GT in the phase I study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic adverse events occurred in the phase II studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related adverse events increased with higher glycopyrronium concentration; no relationship was observed between efficacy and pharmacokinetic measures. CONCLUSIONS: These studies indicate limited absorption of GT compared to oral glycopyrrolate and a low risk of anticholinergic adverse events with proper GT administration when following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact).

Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection.

Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2-compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C-reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50-2.12); for each 10-kg increase in body weight, this was 1.19 (1.06-1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.

Multi-Criteria Decision Analysis Model for Assessing the Risk from Multi-Ingredient Dietary Supplements (MIDS).

Military personnel use dietary supplements (DS) for performance enhancement, bodybuilding, weight loss, and to maintain health. Adverse events, including cardiovascular (CV) effects, have been reported in military personnel taking supplements. Previous research determined that ingestion of multi-ingredient dietary supplements (MIDS), can lead to signals of safety concerns. Therefore, to assess the safety of MIDS, the Department of Defense via a contractor explored the development of a model-based risk assessment tool. We present a strategy and preliminary novel multi-criteria decision analysis (MCDA)-based tool for assessing the risk of adverse CV effects from MIDS. The tool integrates toxicology and other relevant data available on MIDS; likelihood of exposure, and biologic plausibility that could contribute to specific aspects of risk.Inputs for the model are values of four measures assigned based on the available evidence supplemented with the opinion of experts in toxicology, modeling, risk assessment etc. Measures were weighted based on the experts' assessment of measures' relative importance. Finally, all data for the four measures were integrated to provide a risk potential of 0 (low risk) to 100 (high risk) that defines the relative risk of a MIDS to cause adverse reactions.We conclude that the best available evidence must be supplemented with the opinion of experts in medicine, toxicology and pharmacology. Model-based approaches are useful to inform risk assessment in the absence of data. This MCDA model provides a foundation for refinement and validation of accuracy of the model predictions as new evidence becomes available.

Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial.

OBJECTIVES: Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients. METHODS: In this multicentre 1:1 'PRECISION' trial, we randomized IBD patients in clinical remission (Harvey Bradshaw Index ≤4 for Crohn's disease (CD) or a partial Mayo score ≤2 for ulcerative colitis (UC)) receiving IFX maintenance treatment. The precision group (PG) received IFX dosing guided by a Bayesian pharmacokinetic model, aiming to achieve and maintain a TL of 3 µg/ml by treatment (de)escalation as indicated by the dashboard. Patients in the control group (CG) continued treatment without dose adaptations. The primary endpoint was the proportion of patients in sustained clinical remission after 1 year. RESULTS: Eighty patients were enrolled (66 CD, 14 UC), and the median [interquartile range] age was 37 years [27-51]). After one year, 28/32 (88%) of patients in the PG were in sustained clinical remission versus 25/39 (64%) in the CG (p = .017). PG patients had lower median faecal calprotectin levels after 1 year (p = .031), whereas no significant differences in median CRP levels were found. CONCLUSION: We demonstrated that the use of a Bayesian dashboard for IFX dosing in maintenance treatment for IBD reduced the incidence of LOR compared to standard dosing. Precision dosing also resulted in lower FCP levels. CLINICALTRIALS.GOV NUMBER: NCT02453776.

Optimization of infliximab therapy in inflammatory bowel disease using a dashboard approach-an Indian experience.

PURPOSE: Infliximab (IFX) therapy in inflammatory bowel disease (IBD) is associated with loss of response in half the patients, due to complex pharmacokinetic and immunological factors. Dashboard's Bayesian algorithms use information from model and individual multivariate determinants of IFX concentration and can predict dose and dosing interval. AIM: To compare measured IFX concentrations in our laboratory with values predicted by iDose dashboard system and report its efficacy in managing patients not responding to conventional dosing schedule. METHOD: Clinical history, demographic details, and laboratory findings such as albumin and C-reactive protein (CRP) data of IBD patients (n = 30; median age 23 years (IQR: 14.25 - 33.5)) referred for IFX drug monitoring in our laboratory from November 2017 to November 2019 were entered in iDose software. The IFX concentration predicted by iDose based on this information was compared with that measured in our laboratory. In addition, a prospective dashboard-guided dosing was prescribed in 11 of these 30 patients not responding to conventional dosing and was followed to assess their clinical outcome. RESULT: IFX monitoring in our 30 patients had shown therapeutic concentration in 12, supratherapeutic in 2 and subtherapeutic concentration in 16 patients. The iDose predicted concentration showed concordance in 21 of these 30 patients. Of 11 patients managed with iDose-assisted prospective dosing, 8 achieved clinical remission, 2 showed partial response, and one developed antibodies. CONCLUSION: Retrospective data analysis showed concordance between laboratory measured and iDose-predicted IFX level in 70% of patients. iDose-assisted management achieved clinical remission and cost reduction.

Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis.

PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/µL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/µL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.

Population Pharmacokinetics of Brentuximab Vedotin in Adult and Pediatric Patients With Relapsed/Refractory Hematologic Malignancies: Model-Informed Hypothesis Generation for Pediatric Dosing Regimens.

Prior pharmacokinetic (PK) analyses of the antibody-drug conjugate (ADC) brentuximab vedotin (1.8 mg/kg every 3 weeks) in pediatric patients with relapsed/refractory hematologic malignancies found that patients aged <12 years exhibited decreased ADC area under the curve (AUC) compared with those aged ≥12 years. This population PK (POPPK) analysis used data from pediatric (NCT01492088) and adult (NCT00430846) studies of brentuximab vedotin to quantify body size effects on ADC exposure. Data were collected from 84 patients with a median age of 25.7 years (range, 7.7-87.3 years), 34 of whom (40.5%) were aged <18 years; median patient weight was 67 kg (range, 21-154 kg), and median body surface area was 1.8 m2 (range, 0.87-2.81 m2 ). ADC PK was described by a linear 3-compartment model with zero-order input and first-order elimination. POPPK modeling indicated that dosing brentuximab vedotin at 1.8 mg/kg every 3 weeks or 1.2 mg/kg every 2 weeks resulted in lower ADC AUC values in small/moderate-sized pediatric patients (<28 kg and 28-49 kg, respectively) compared with large pediatric/adult patients (50-100 kg). Dosing at 71.5 mg/m2 every 3 weeks and 47.7 mg/m2 every 2 weeks was predicted to achieve comparable AUC values across all body weight ranges and a similar AUC to that in the 50- to 100-kg group at the standard doses of 1.8 mg/kg every 3 weeks and 1.2 mg/kg every 2 weeks, respectively. These results have generated a hypothesis to support evaluation of brentuximab vedotin at 48 mg/m2 every 2 weeks in combination with adriamycin, vinblastine, and dacarbazine chemotherapy in an ongoing pediatric trial in frontline Hodgkin lymphoma (NCT02979522).