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

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 Pharmacokinetics and Exposure-Response Relationships of Baloxavir Marboxil in Influenza Patients at High Risk of Complications

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00119-20 ◽

2020 ◽

Vol 64 (7) ◽

Cited By ~ 1

Author(s):

Hiroki Koshimichi ◽

Sylvie Retout ◽

Valerie Cosson ◽

Vincent Duval ◽

Stefan De Buck ◽

...

Keyword(s):

Influenza Virus ◽

Plasma Concentration ◽

High Risk ◽

Virus Titer ◽

Population Pharmacokinetic ◽

Concentration Data ◽

First Order ◽

High Risk Patients ◽

Exposure Response ◽

Risk Patients

ABSTRACT Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11,846 plasma concentration data items from 1,827 subjects, including 2,341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications. Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients. The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.

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Abstract OT-03-01: Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05)

10.1158/1538-7445.sabcs20-ot-03-01 ◽

2021 ◽

Author(s):

Charles E Geyer ◽

Michael Untch ◽

Aleix Prat ◽

Priya Rastogi ◽

Naoki Niikura ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Neoadjuvant Therapy ◽

Early Breast Cancer ◽

Trastuzumab Emtansine ◽

Her2 Positive ◽

Phase 3 ◽

High Risk Patients ◽

Risk Patients

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Evaluation of posaconazole plasma concentrations achieved with the delayed‐release tablets in Korean high‐risk patients with haematologic malignancy

Mycoses ◽

10.1111/myc.13031 ◽

2019 ◽

Vol 63 (2) ◽

pp. 131-138 ◽

Cited By ~ 1

Author(s):

Hyojin Chae ◽

Sung‐Yeon Cho ◽

Yunmi Yi ◽

Jeong Joong Lee ◽

Kyoungho Cha ◽

...

Keyword(s):

High Risk ◽

Plasma Concentrations ◽

High Risk Patients ◽

Delayed Release ◽

Risk Patients

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Elastography and Metalloproteinases in Patients at High Risk of Preterm Labor

Journal of Clinical Medicine ◽

10.3390/jcm10173886 ◽

2021 ◽

Vol 10 (17) ◽

pp. 3886

Author(s):

Izabela Dymanowska-Dyjak ◽

Aleksandra Stupak ◽

Adrianna Kondracka ◽

Tomasz Gęca ◽

Arkadiusz Krzyżanowski ◽

...

Keyword(s):

High Risk ◽

Preterm Delivery ◽

Plasma Concentrations ◽

Cervical Length ◽

Control Group ◽

Study Group ◽

Median Length ◽

High Risk Patients ◽

Ultrasound Evaluation ◽

Risk Patients

Preterm birth (PTB) is the leading cause of perinatal morbidity and mortality. Its etiopathology is multifactorial; therefore, many of the tests contain the assessment of the biochemical factors and ultrasound evaluation of the cervix in patients at risk of preterm delivery. The study aimed at evaluating the socioeconomic data, ultrasound examinations with elastography, plasma concentrations of MMP-8 and MMP-9 metalloproteinases, and vaginal secretions in the control group as well as patients with threatened preterm delivery (high-risk patients). The study included 88 patients hospitalized in the Department of Obstetrics and Pregnancy Pathology, SPSK 1, in Lublin. Patients were qualified to the study group (50) with a transvaginal ultrasonography of cervical length (CL) ≤ 25 mm. The control group (38) were patients with a physiological course of pregnancy with CL > 25 mm. In the study group, the median length of the cervix was 17.49 mm. Elastographic parameters: strain and ratio were 0.20 and 0.83. In the control group, the median length of the cervix was 34.73 mm, while the strain and ratio were 0.20 and 1.23. In the study group, the concentration of MMP-8 in the serum and secretions of the cervix was on average 74.17 and 155.46 ng/mL, but in the control group, it was significantly lower, on average 58.49 and 94.19 ng/mL. The concentration of MMP-9 in both groups was on the same level. Evaluation of the cervical length and measurement of MMP-8 concentration are the methods of predicting preterm delivery in high-risk patients. The use of static elastography did not meet the criteria of a PTB marker.

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Efficacy of daratumumab + SOC versus SOC in myeloma induction regimens, by risk-stratification: Meta-analysis of phase III randomized control trials.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e20512 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e20512-e20512

Author(s):

Nisha Joseph ◽

Craig C. Hofmeister ◽

Madhav V. Dhodapkar ◽

Lawrence Boise ◽

Sagar Lonial ◽

...

Keyword(s):

High Risk ◽

Meta Analysis ◽

Phase 3 ◽

High Risk Patients ◽

Hazard Ratios ◽

Risk Patients ◽

Q Statistic ◽

The Impact ◽

Standard Risk

e20512 Background: Addition of daratumumab, a CD38 monoclonal antibody, to standard of care (SOC) myeloma induction regimens resulted in deeper responses. Phase 3 trials comparing daratumumab + SOC vs SOC consistently favored the daratumumab combinations. The objective of this analysis is to test the hypothesis that high-risk patients benefit from the addition of daratumumab to SOC induction regimens. Methods: We identified four phase 3 clinical trials (RCT) that randomized newly diagnosed myeloma patients to receive daratumumab +SOC vs. SOC. The GRIFFIN trial did not have PFS events and was excluded. A meta-analysis of 3 RCTs with updated data from ASH 2019 (ALCYONE, MAIA, CASSIOPEIA) was performed using the fixed (Mantel-Haenszel) model to calculate the impact of daratumumab + SOC versus SOC. The consistency of results (effect sizes) among studies was investigated by means of two heterogeneity tests, the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P value of the Cochran's Q test was < 0.1 and I2 statistic was > 50%. Results: The pooled hazard ratios (HR) for standard risk patients for PFS was HR 0.589 (95% CI 0.502-0.691; P < 0.001) in favor of daratumumab. Q-statistic for PFS ( P= 3.462; df= 2; I2 = 42.23) suggests homogeneity across studies. The pooled hazard ratios (HR) for high risk patients for PFS was HR 0.799 (95% CI 0.609-1.047; P= 0.104) in favor of daratumumab. Q-statistic for PFS ( P= 1.306; df= 2; I2 = 0.00) suggests homogeneity across studies. Conclusions: Our meta-analysis demonstrates that addition of daratumumab to SOC myeloma induction regimens prevented progression in both standard and high-risk patients, though the impact was more pronounced in the standard-risk patients. This benefit seems to improve with longer follow up, as seen both in ALCYONE (Mateos et al ASH 2019) and MAIA trial (Bahlis et al ASH 2019). Focused accrual of high-risk patients in larger daratumumab induction trials and longer follow up of the existing trials are further needed.

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Trastuzumab-Deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer (BC) after neoadjuvant therapy (NAT): a randomized, phase 3 trial (DESTINY-Breast05)

10.1055/s-0041-1730235 ◽

2021 ◽

Author(s):

M Untch ◽

CE Geyer Jr ◽

A Prat ◽

P Rastogi ◽

N Niikura ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Neoadjuvant Therapy ◽

Early Breast Cancer ◽

Trastuzumab Emtansine ◽

Her2 Positive ◽

Phase 3 ◽

High Risk Patients ◽

Risk Patients

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Efficacy and Safety of Intravenous Peramivir Compared With Oseltamivir in High-Risk Patients Infected With Influenza A and B Viruses: A Multicenter Randomized Controlled Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx129 ◽

2017 ◽

Vol 4 (3) ◽

Cited By ~ 15

Author(s):

Shigeki Nakamura ◽

Taiga Miyazaki ◽

Koichi Izumikawa ◽

Hiroshi Kakeya ◽

Yutaka Saisho ◽

...

Keyword(s):

High Risk ◽

Influenza A ◽

Seasonal Influenza ◽

Virus Titer ◽

Controlled Study ◽

Efficacy And Safety ◽

High Risk Patients ◽

Randomized Controlled ◽

Significant Difference ◽

Risk Patients

Abstract Background Clinical studies comparing the different neuraminidase inhibitors for treatment of at-risk patients with influenza have not been performed. To optimize such treatments, we assessed the efficacy and safety of intravenous peramivir compared with oral oseltamivir in treating seasonal influenza A or B virus infection. Methods A multicenter, randomized, controlled clinical trial was conducted from December 2012 to May 2014 in high-risk patients infected with seasonal influenza. A total of 92 adult inpatients and outpatients with high risk factors (HRFs) were treated by either a single intravenous infusion of peramivir (600 mg) or oral administration of oseltamivir (75 mg, twice per day for 5 days). Results The median times to clinical stability (time to reach <37°C) were 40.0 hours (95% confidence interval [CI] = 23.3–64.5) and 37.8 hours (95% CI = 26.3–45.3) in the peramivir and oseltamivir groups, respectively; these values did not reveal a significant difference. The virus titer and change of mean total symptom scores decreased similarly with both treatments. Results of step-wise regression suggested that virus type was a significantly effective prognostic factor with respect to illness resolution. Adverse events (AEs) with peramivir and oseltamivir occurred in 2.2% (n = 1/46) and 13.0% (n = 6/46) of patients, respectively. The severity of AEs was mild in all cases except 2 patients who showed pneumonia or COPD aggravation; both were in the oseltamivir group. Conclusions Intravenous peramivir was effective based on the result of direct comparison with oral oseltamivir. Thus our data show that peramivir is a useful option for the treatment of influenza-infected patients with HRFs.

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