Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)

4531 Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes. [Table: see text]

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Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05900-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 2806-2813 ◽

Cited By ~ 90

Author(s):

Michael J. Dolton ◽

John E. Ray ◽

Deborah Marriott ◽

Andrew J. McLachlan

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Fungal Infections ◽

Gastrointestinal Disease ◽

Plasma Concentrations ◽

Response To Therapy ◽

Common Finding ◽

Therapeutic Drug ◽

Response Relationship ◽

Exposure Response

ABSTRACTPosaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

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SAT-432 Pharmacokinetics (PK) and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor (IGF-1R) Blocking Antibody, in Active Thyroid Eye Disease (TED)

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1047 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Yan Xin ◽

Fengyan Xu ◽

Yuying Gao ◽

Nivedita Bhatt ◽

Jason Chamberlain ◽

...

Keyword(s):

Dose Regimen ◽

Volume Of Distribution ◽

Systemic Clearance ◽

Phase 2 ◽

Response Relationship ◽

Exposure Response ◽

Elimination Half ◽

Population Pk ◽

Igg1 Mabs ◽

Low Volume

Abstract Introduction: Teprotumumab treatment resulted in statistically and clinically meaningful improvements across multiple facets of active TED and was generally well-tolerated in Phase 2 and 3 trials.1,2 An initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks was selected based on in vitro activity and clinical PK profile, to maintain pharmacologically active exposures and >90% saturation of IGF-1R over dosing intervals and to achieve efficacy at a well-tolerated dose for this vision-threatening disease. Methods: Population PK analysis were performed on data from a Phase 1 oncology study (n=60)3 and Phase 2 and 3 trials in active TED (N=83)2,3 and covariate effect on PK was assessed. Exposure-response relationship was evaluated in TED studies for key efficacy endpoints (proptosis response rate, % patients with a clinical activity score value of 0 or 1, and diplopia responder rate) and selected safety variables (hyperglycemia and muscle spasms). Results: Teprotumumab PK was linear in TED patients and consistent with other immunoglobulin G1 monoclonal antibodies (IgG1 mAbs), with low systemic clearance (0.334 L/day), low volume of distribution (3.9 L for central compartment and 4.2 L for peripheral compartment), and long elimination half-life (19.9 days). 4,5 Model-predicted mean (± standard deviation) steady-state area under the concentration curve (AUCss), peak (Cmax,ss), and trough (Cmin,ss) concentrations in TED patients were 131 (± 30.9) mg∙hr/mL, 643 (± 130) µg/mL and 157 (± 50.6) µg/mL, respectively, suggesting low inter-subject variability. Population PK analysis indicated no significant impact of baseline age, gender, race, weight, smoking status, renal impairment (mild/moderate), and hepatic function (total bilirubin, aspartate and alanine aminotransferases) on teprotumumab PK. Female patients had 15% higher Cmax,ss but similar AUC compared to male patients, which is not considered clinically relevant. Exposure-response analysis from the TED dose regimen indicated no meaningful correlations between exposures (AUCss, Cmax,ss and Cmin,ss) and key efficacy endpoints or selected safety variables, supporting the demonstrated, favorable benefit-risk profile of the TED dose regimen.2 Conclusion: Teprotumumab PK was characterized in TED patients by long elimination half-life, low systemic clearance and low volume of distribution, consistent with other IgG1 mAbs. There was no meaningful exposure-response relationship at the selected TED dose regimen for both efficacy and safety endpoints, supporting the teprotumumab dose regimen used in TED patients. Reference: (1) Smith TJ, et al. N Engl J Med 2017;376:1748-1761. (2) Douglas RS, et al. AACE 2019 late-breaking abstract. (3) ClinicalTrials.gov: NCT00400361. (4) Dirks NL et al. Clin Pharmacokinet. 2010;49(10):633-59. (5) Ryman JT et al. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576-88.

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Initial characterization of the toxicity and efficacy of elacytarabine (CP-4055), a novel antileukemic agent, using a multidimensional exposure-response relationship model.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6619 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6619-6619

Author(s):

Murray P Ducharme ◽

Steinar Hagen ◽

Petter-Arnt Hals ◽

Tove Flem Jacobsen ◽

Francis J. Giles ◽

...

Keyword(s):

Linear Models ◽

Antineoplastic Agent ◽

Plasma Concentrations ◽

Hematologic Malignancies ◽

Toxic Exposure ◽

Response Relationship ◽

Linear Distribution ◽

Exposure Response ◽

Relationship Model ◽

Dosing Regimens

6619^ Background: Elacytarabine (CP-4055), an elaidic acid ester of ara-C, is a novel antineoplastic agent developed to treat hematologic malignancies (HM). It is metabolized to active ara-CTP and inactive ara-U. In 3 studies, diverse elacytarabine monotherapy doses and regimens were given to patients with advanced HM and solid tumours. This analysis aimed to 1) describe the pharmacokinetics (PK) of elacytarabine in these patients and 2) investigate the relationship between PK and toxicity and efficacy in HM. Methods: Population PK analyses were run with ADAPT 5 (ITS) and included 146 patients given a 2h, 4h or 120h continuous infusion (CIV) of elacytarabine. Elacytarabine, ara-C and ara-U plasma concentrations (Cp) were simultaneously modeled and explained. Standard model discrimination criteria were used to select the best model. With the model, different dosing regimens were simulated to find average exposure and % of patients with efficacious or toxic exposure. A multi-dimensional exposure-response relationship (MDERR) was developed with pre-clinical and clinical data. Results: The best model was a 2-compartment (CPT) model with linear elimination and formation rates for the metabolism of elacytarabine to ara-C. Mean PK parameters were Vc = 4.12 L/m2, CL= 5.27 L/h/m2 and T1/2 = 7.57 h. Elacytarabine PK included a peripheral CPT with a non-linear distribution process to reflect saturable binding to red blood cells, otherwise its PK was linear. Ara-C and ara-U PK were described by 2- and 1-CPT linear models, respectively. The MDERR model related efficacy and toxicity thresholds to elacytarabine dosing regimens, and indicated that a 120 h CIV dosing regimen is preferable, allowing elacytarabine to exceed efficacious Cp for longer than the other investigated regimens. A minimum dose of 1000 mg/m2/day is needed for most patients to receive efficacious exposure. Conclusions: Elacytarabine is a promising anti-leukemic agent for patients with advanced HM. Its PK, toxicity and efficacy were characterized in patients given diverse dosing regimens. An MDERR model, which will be further refined or confirmed in upcoming clinical trials, was proposed.

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1536. Population Pharmacokinetic Analysis of Baloxavir Morboxil, a Cap-Dependent Endonuclease Inhibitor, in Adult and Adolescent Healthy Subjects and Influenza Patients and Exposure-Response Relationships in the Patients at High-Risk of Influenza Complications

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1400 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S559-S560

Author(s):

Hiroki Koshimichi ◽

Sylvie Retout ◽

Valérie F Cosson ◽

Stefan De Buck ◽

Yoshiyuki Tsuda ◽

...

Keyword(s):

High Risk ◽

Plasma Concentrations ◽

Virus Titer ◽

Population Pharmacokinetic ◽

Phase 3 ◽

High Risk Patients ◽

Exposure Response ◽

Dependent Endonuclease ◽

Population Pk ◽

Risk Patients

Abstract Background Baloxavir marboxil is a prodrug of baloxavir acid which is a selective inhibitor of cap-dependent endonuclease. The global Phase 3 study conducted in the influenza patients at high-risk of influenza complications (CAPSTONE-2) enrolled adult and adolescent patients from 2016 to 2018. Baloxavir marboxil demonstrated significantly shorter time to improvement of influenza symptoms (TTIIS) than placebo. The aim of this study was to build a population pharmacokinetic (PK) model of baloxavir acid and to evaluate the exposure-response relationships in high-risk patients. Methods The population PK analysis was conducted on the pooled data from 13 clinical studies: 10 phase 1 studies, a phase 2 study, and 2 phase 3 studies. A total of 11846 plasma concentrations from 1827 subjects were used for this analysis. The influence of background characteristics including risk factors of influenza complications was assessed on the PK of baloxavir acid. The individual Cmax and AUC were estimated with an empirical Bayesian approach. Exposure-response analysis was conducted for TTIIS and virus titer in the high-risk patients. Results A 3-compartment model with first-order absorption and lag time was selected as a structural PK model, and well described the plasma concentrations. The population PK analysis suggested that (1) AUC in non-Asians was 30.7% lower than that in Asians, (2) body weight significantly affected the exposures to baloxavir acid, (3) the exposures in high-risk patients were similar to those in otherwise healthy patients, and (4) no PK differences were identified regarding the risk factors for influenza complications. The exposure-response analyses showed that the body weight-based dose regimen (40 mg for the patients weighing <80 kg and 80 mg for the patients weighing ≥80 kg) shortened TTIIS and reduced virus titer for both type A and B influenza, across the entire range of baloxavir acid exposures observed in CAPSTONE-2 although subject number in the lowest exposure group was limited and it was difficult to discuss the magnitude of the responses accurately. Conclusion The results of the population PK analysis and exposure-response analyses provide useful information for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil. Disclosures All authors: No reported disclosures.

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Population pharmacokinetic (PK) and exposure-response analyses from the pivotal ALTA-1L study: Model-based analyses supporting the brigatinib dose in patients with anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21725 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21725-e21725

Author(s):

Neeraj Gupta ◽

Karen L. Reckamp ◽

D. Ross Camidge ◽

Huub Jan Kleijn ◽

Aziz Ouerdani ◽

...

Keyword(s):

Kinase Inhibitor ◽

Objective Response ◽

Population Pharmacokinetic ◽

Efficacy And Safety ◽

Time Data ◽

Time Curve ◽

Anaplastic Lymphoma ◽

Exposure Response ◽

Concentration Time ◽

Population Pk

e21725 Background: Brigatinib is a next-generation ALK tyrosine kinase inhibitor (TKI) with differential activity by dose (90 mg vs 180 mg [with a 7-day lead-in at 90 mg] qd) in the phase 2 post-crizotinib ALTA trial (NCT02094573). Herein, we describe results from population PK and exposure-response analyses of the efficacy and safety of brigatinib 180 mg qd (with a 7-day lead-in at 90 mg) from data in the first-line phase 3 ALTA-1L study (NCT02737501). Methods: Brigatinib plasma concentration-time data were described by a 3-compartment model with transit compartment absorption. Post hoc individual apparent clearance estimates for brigatinib were obtained using Bayesian re-estimation and used to calculate time-averaged area under the concentration-time curve (AUC) values for logistic regression analyses of relationships to response endpoints (confirmed objective response rate [ORR], intracranial ORR) and time-varying AUC values for parametric time-to-event models of relationships to progression-free survival (PFS). Population PK modeling, covariate analysis, and simulations were performed using NONMEM (version 7.3 or higher), running under PsN (Perl-speaks-NONMEM, version 4.6 or higher), while exposure–efficacy and safety analyses were performed using R (version 3.5.2 or higher). Results: Brigatinib PK parameters and estimated systemic exposures for patients in ALTA-1L (ALK TKI–naive setting) were similar to those in the 180 mg qd arm of ALTA. Patient covariates including weight, sex, age, race, and renal function (CrCL ≥30 mL/min) were not found to impact brigatinib exposure, suggesting no dose adjustment based on these covariates. In the exposure-response analyses, brigatinib exposure was not a significant predictor of response (≥partial response) or PFS. This suggests that the efficacy benefit was consistent across the range of exposures achieved with the 180 mg dosing regimen including after dose modifications. There was a significant relationship ( P< 0.05) between exposure and certain laboratory abnormalities (increased amylase and lipase). There was no relationship between exposure and CPK elevation, and brigatinib exposure had no effect on time to first dose reduction. Conclusions: These results support a favorable benefit/risk profile of the proposed 180 mg qd brigatinib dose (with a 7-day lead-in at 90 mg) for the front-line treatment of patients with ALK+ NSCLC. Clinical trial information: NCT02737501.

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Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01744-20 ◽

2021 ◽

Cited By ~ 1

Author(s):

Santosh Wagh ◽

Chetan Rathi ◽

Pradeep B. Lukka ◽

Keyur Parmar ◽

Zaid Temrikar ◽

...

Keyword(s):

Mouse Model ◽

Plasma Concentrations ◽

Dose Fractionation ◽

Population Pharmacokinetic ◽

Response Relationship ◽

Postantibiotic Effect ◽

Bacterial Killing ◽

Exposure Response

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of anti-tuberculosis agents, and lead spectinamide 1810 has demonstrated excellent efficacy, safety and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of M. tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of colony-forming units in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by fC max /MIC and fAUC/MIC rather than f%T MIC . A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis .

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The Effect of an Alternative Definition of “Percent Highly Annoyed” on the Exposure–Response Relationship: Comparison of Noise Annoyance Responses Measured by ICBEN 5-Point Verbal and 11-Point Numerical Scales

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18126258 ◽

2021 ◽

Vol 18 (12) ◽

pp. 6258

Author(s):

Makoto Morinaga ◽

Thu Lan Nguyen ◽

Shigenori Yokoshima ◽

Koji Shimoyama ◽

Takashi Morihara ◽

...

Keyword(s):

Sound Pressure ◽

Response Relationship ◽

Alternative Definition ◽

Exposure Response ◽

Noise Annoyance ◽

Numerical Scale ◽

Verbal Scale ◽

Sound Pressure Levels ◽

Acoustic Surveys ◽

Definition Of

Since the development of the 5-point verbal and 11-point numerical scales for measuring noise annoyance by the ICBEN Team 6, these scales have been widely used in socio-acoustic surveys worldwide, and annoyance responses have been easily compared internationally. However, both the top two categories of the 5–point verbal scale and the top three ones of the 11-point numerical scale are correspond to high annoyance, so it is difficult to precisely compare annoyance responses. Therefore, we calculated differences in day–evening–night-weighted sound pressure levels (Lden) by comparing values corresponding to 10% highly annoyed (HA) on Lden_%HA curves obtained from measurements in 40 datasets regarding surveys conducted in Japan and Vietnam. The results showed that the Lden value corresponding to 10% HA using the 5-point verbal scale was approximately 5 dB lower than that of the 11-point numerical scale. Thus, some correction is required to compare annoyance responses measured by the 5-point verbal and the 11-point numerical scales. The results of this study were also compared with those of a survey in Switzerland.

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POS0101 ADVERSE HEALTH-RELATED QUALITY OF LIFE OUTCOME DESPITE ADEQUATE CLINICAL RESPONSE TO TREATMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1472 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 260.2-261

Author(s):

A. Gomez ◽

J. Lindblom ◽

V. Qiu ◽

A. Cederlund ◽

A. Borg ◽

...

Keyword(s):

Clinical Response ◽

Physical Functioning ◽

Lupus Erythematosus ◽

Response To Treatment ◽

Black African ◽

Link Type ◽

Severe Fatigue ◽

Sf 36 ◽

Related Quality ◽

Health Related

Background:Despite improvements in medical care that have contributed to prolonged life expectancy for people living with systemic lupus erythematosus (SLE) over the past decades, they still suffer from substantial diminutions of health-related quality of life (HRQoL) compared with the general population and with other chronic diseases.Some studies have demonstrated that conventional synthetic and biological disease-modifying agents contribute to improvements in SLE patients’ HRQoL, and responders to treatment have been shown to report greater improvements than non-responders. Although these observations are clinically relevant, improvement following a therapeutic intervention does not necessarily signify that the individual has achieved a satisfactory health state perception. In rheumatoid arthritis, significant pain and severe fatigue persist in a substantial proportion of patients who achieve a good clinical response to treatment or remission. This paradoxical observation has not been thoroughly explored in SLE.Objectives:To determine the prevalence of adverse HRQoL outcomes in patients with SLE who achieved an adequate clinical response after a 52-week long period on standard therapy plus belimumab or placebo, within the frame of two phase III clinical trials. We further aimed to compare frequencies of adverse HRQoL outcomes across different age categories and ethnic groups, and sought to identify contributing factors.Methods:We included patients who met the primary endpoint of the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (N=760/1684), i.e. attainment of the SLE Responder Index 4 at week 52. Accordingly, evaluation of adverse HRQoL outcomes was based on patient reports at week 52 from treatment initiation, using the Medical Outcomes Study Short Form 36 (SF-36) health survey and the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) scale. Adverse HRQoL outcomes were defined as (i) SF-36 scale scores ≤ the 5th percentile derived from age- and sex-matched US population-based norms from the SF-36 health survey user manual; and (ii) FACIT-Fatigue scores <30.Pearson’s chi-square or Fisher’s exact tests were used to investigate associations between dichotomous variables. Comparisons of continuous data between SLE patients and age- and sex-matched norms were performed using the Wilcoxon signed-rank test. Multivariable logistic regression models were created in order to assess independence and priority of potential factors associated with adverse HRQoL outcomes.Results:We found clinically important diminutions of HRQoL in SLE patients compared with matched norms and high frequencies of adverse HRQoL outcomes, the highest in SF-36 general health (29.1%), followed by FACIT-Fatigue (25.8%) and SF-36 physical functioning (25.4%). Overall, frequencies were higher with increasing age. Black/African American and White/Caucasian patients reported higher frequencies than Asians and Indigenous Americans, while Hispanics experienced adverse HRQoL less frequently than non-Hispanics. Increasing organ damage was associated with adverse physical but not mental HRQoL outcomes; disease activity showed no impact. In multivariable logistic regression analysis, addition of belimumab to standard therapy was associated with lower frequencies of adverse SF-36 physical functioning (OR: 0.59; 95% CI: 0.39–0.91; P=0.016) and FACIT-F (OR: 0.53; 95% CI: 0.34–0.81; P=0.004).Conclusion:Substantial proportions of SLE patients reported adverse HRQoL outcomes despite adequate clinical response to treatment, especially in physical aspects. Particularly high proportions were seen within Black/African American and White/Caucasian patients. Add-on belimumab may be protective against adverse physical functioning and severe fatigue. Our results corroborate that HRQoL diminutions constitute a substantial burden in patients with SLE, and highlight the limitations of current therapeutic strategies.Acknowledgements:The authors would like to thank GlaxoSmithKline (Uxbridge, UK) for sharing the data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials with the Clinical Study Data Request (CSDR) consortium, Dimitris Ladakis, Joaquin Matilla and Martin Pehr for contributing to the management of data, as well as all participating patients.Disclosure of Interests:Alvaro Gomez: None declared, Julius Lindblom: None declared, Victor Qiu: None declared, Arvid Cederlund: None declared, Alexander Borg: None declared, Sharzad Emamikia: None declared, Yvonne Enman: None declared, Jon Lampa: None declared, Ioannis Parodis Grant/research support from: Research funding and/or honoraria from Amgen, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline and Novartis.

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Evaluating the Possibility of Translating Technological Advances in Non-Invasive Continuous Lactate Monitoring into Critical Care

Sensors ◽

10.3390/s21030879 ◽

2021 ◽

Vol 21 (3) ◽

pp. 879

Author(s):

Robert D. Crapnell ◽

Ascanio Tridente ◽

Craig E. Banks ◽

Nina C. Dempsey-Hibbert

Keyword(s):

Critical Care ◽

Continuous Monitoring ◽

Performance Monitoring ◽

Plasma Concentrations ◽

Lactate Production ◽

Anaerobic Exercise ◽

Response To Treatment ◽

Diverse Range ◽

Non Invasive ◽

Technological Advances

Lactate is widely measured in critically ill patients as a robust indicator of patient deterioration and response to treatment. Plasma concentrations represent a balance between lactate production and clearance. Analysis has typically been performed with the aim of detecting tissue hypoxia. However, there is a diverse range of processes unrelated to increased anaerobic metabolism that result in the accumulation of lactate, complicating clinical interpretation. Further, lactate levels can change rapidly over short spaces of time, and even subtle changes can reflect a profound change in the patient’s condition. Hence, there is a significant need for frequent lactate monitoring in critical care. Lactate monitoring is commonplace in sports performance monitoring, given the elevation of lactate during anaerobic exercise. The desire to continuously monitor lactate in athletes has led to the development of various technological approaches for non-invasive, continuous lactate measurements. This review aims firstly to reflect on the potential benefits of non-invasive continuous monitoring technology within the critical care setting. Secondly, we review the current devices used to measure lactate non-invasively outside of this setting and consider the challenges that must be overcome to allow for the translation of this technology into intensive care medicine. This review will be of interest to those developing continuous monitoring sensors, opening up a new field of research.

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Exposure–Response Analysis for Selection of Optimal Dosage Regimen of Anifrolumab in Patients With Systemic Lupus Erythematosus

Rheumatology ◽

10.1093/rheumatology/keab176 ◽

2021 ◽

Author(s):

Yen Lin Chia ◽

Linda Santiago ◽

Bing Wang ◽

Denison Kuruvilla ◽

Shiliang Wang ◽

...

Keyword(s):

Type I Interferon ◽

Drug Clearance ◽

Optimal Dosage ◽

Type I ◽

Efficacy And Safety ◽

Response Relationship ◽

Phase 3 ◽

Optimal Dosage Regimen ◽

Exposure Response ◽

Selection Of

Abstract Objectives The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I interferon receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure–response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. Methods The exposure–response relationship, pharmacokinetics (PK), and SLE Responder Index (SRI[4]) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. Results The population PK model found that type I IFN test–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I interferon alpha receptor–mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. Conclusions Based on PK, efficacy, and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.

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