scholarly journals Pharmacokinetic /Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19

2021 ◽  
Author(s):  
Elizabeth Leung ◽  
Sarah C.J. Jorgensen ◽  
Ryan L. Crass ◽  
Sumit Raybardhan ◽  
Bradley Langford ◽  
...  
Keyword(s):  
Therapeutic Benefit ◽  
Distribution Data ◽  
Patient Needs ◽  
Approval Process ◽  
Current Review ◽  
Fda Approval ◽  
Exposure Distribution ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
The Relationship

Tocilizumab is one of few treatments that have been shown to improve mortality in patients with COVID-19, but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters which likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, though weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/PD insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.

scholarly journals DOSE-EXPOSURE SIMULATION FOR PIPERACILLIN-TAZOBACTAM DOSING STRATEGIES IN INFANTS AND YOUNG CHILDREN

2017 ◽  
Vol 24 (3) ◽  
pp. e33-e44
Author(s):  
Céline Thibault ◽  
Nastya Kassir ◽  
Yves Théorêt ◽  
France Varin ◽  
Catherine Litalien ◽  
...  
Keyword(s):  
Age Groups ◽  
Volume Of Distribution ◽  
Distribution Data ◽  
Parameter Estimates ◽  
Target Attainment ◽  
Minimal Inhibitory Concentrations ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Post Hoc ◽  
Infants And Young Children

Background: Extended piperacillin-tazobactam (TZP) infusions have been associated with favorable outcomes. There are currently no pediatric dosing recommendations. Objective: To determine appropriate TZP dosing strategies in children 2 months – 6 years according to age and different minimal inhibitory concentrations (MICs). Methods: Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal. Results: PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ≥ 90% at MICs ≥ 16 mg/L. Standard 0.5h infusions reached PTAs ≥ 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs ≥ 90% for MICs ≥ 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m. Conclusion: Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs ≥ 90%.

Mesenchymal Stem Cells Differentiation: Mitochondria Matter in Osteogenesis or Adipogenesis Direction

2020 ◽  
Vol 15 (7) ◽  
pp. 602-606
Author(s):  
Kun Ji ◽  
Ling Ding ◽  
Xi Chen ◽  
Yun Dai ◽  
Fangfang Sun ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Mesodermal Cell ◽  
Cell Lineages ◽  
Current Review ◽  
Differentiation Factors ◽  
The Relationship ◽  
Msc Differentiation

Mesenchymal Stem Cells (MSCs) exhibit enormous therapeutic potential because of their indispensable regenerative, reparative, angiogenic, anti-apoptotic, and immunosuppressive properties. MSCs can best differentiate into mesodermal cell lineages, including osteoblasts, adipocytes, muscle cells, endothelial cells and chondrocytes. Specific differentiation of MSCs could be induced through limited conditions. In addition to the relevant differentiation factors, drastic changes also occur in the microenvironment to conduct it in an optimal manner for particular differentiation. Recent evidence suggests that the mitochondria participate in the regulating of direction and process of MSCs differentiation. Therefore, our current review focuses on how mitochondria participate in both osteogenesis and adipogenesis of MSC differentiation. Besides that, in our current review, we try to provide a further understanding of the relationship between the behavior of mitochondria and the direction of MSC differentiation, which could optimize current cellular culturing protocols for further facilitating tissue engineering by adjusting specific conditions of stem cells.

Sequential monitoring of PD-L1 on circulating stromal cells in blood predicts PFS in NSCLC patients undergoing immunotherapy after definitive chemoradiation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8534-8534
Author(s):  
Daniel L Adams ◽  
Alexander Augustyn ◽  
Jianzhong He ◽  
Yawei Qiao ◽  
Ting Xu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hazard Ratios ◽  
Fda Approval ◽  
Inflammatory State ◽  
Nsclc Patients ◽  
Tumor Biopsies ◽  
Relationship Of ◽  
The Relationship

8534 Background: Cancer Associated Macrophage-Like cells (CAMLs) are circulating stromal cells in the blood of patients (pts) with solid tumors that are phagocytic macrophages that may represent the inflammatory state of the tumor microenvironment. Previously, we demonstrated CAMLs ≥50µm after chemo-radiation therapy (CRT) in NSCLC is associated with worse progression free survival (PFS) and overall survival (OS). We also showed that PDL1 expression in CAMLs is dynamic & can change with CRT, difficult to assess with repeat biopsies, but possible with liquid biopsy. For this study we evaluated whether CAML properties can predict response to CRT with/without immunotherapy (IMT) agents in unresectable NSCLC. Methods: A single blind multi-year prospective study was undertaken to test the relationship of PDL1 expression and ≥50µm CAML size to PFS/OS in NSCLC, pre and post CRT with (n = 96) and without (n = 72) anti-PDL1/PD1 IMT. This included atezolizumab (prospective single arm NCT02525757) n = 39, durvalumab n = 52 or pembrolizumab n = 5 both after 2018 FDA approval. We recruited 168 pts with pathologically confirmed unresectable NSCLC prior to CRT. Blood samples 15 mL were taken at baseline (BL), CRT completion (T1), and ̃1 month after CRT (T2) (with n = 96 or without n = 72 IMT). Blood was filtered by CellSieve filtration and CAMLs quantified for size ( < 49 µm or ≥50 µm) and PDL1 expression to evaluate PFS and OS hazard ratios (HRs) by censored univariate and multivariate analysis at 24 months. Results: CAMLs were found in 90% of all samples, average 5.8 CAMLs/15mL. At BL, ≥50µm CAMLs did not predict PFS in CRT/IMT pts (HR 1.6, p = 0.220) nor CRT alone (HR 1.3, p = 0.593). However, after completion of CRT (T1) ≥50µm CAMLs predicted PFS in CRT/IMT pts (HR 2.7, p = 0.003) and CRT alone (HR 2.5, p = 0.015). In primary tumor biopsies, PDL1 expression > 1% did not predict CRT/IMT response (PFS HR 1.8, p = 0.262 & OS HR 2.3, p = 0.158). At BL, high CAML PDL1 did not predict PFS in CRT/IMT pts (HR 1.4, p = 0.427) nor CRT alone (HR 1.1, p = 0.982). Further, at CRT completion (T1), high CAML PDL1 only trended for better PFS in CRT/IMT pts (HR 1.7, p = 0.137), but not CRT alone (HR 1.1, p = 0.972). At T2, however, pts with continuously high CAML PDL1 had significantly better PFS with IMT (HR 3.2, p = 0.002) vs CRT alone (HR 1.4, p = 0.616). While ≥50µm CAMLs at BL did not predict 24 month progression, ≥50 µm CAMLs after CRT (with or without 1 cycle of anti-PDL1 IMT) was 84% accurate at predicting progression. Further subtyping and analysis is ongoing to evaluate OS and PDL1 in the CAML populations. Conclusions: Our data suggests that in unresectable NSCLC, ≥50 µm CAMLs after completion of CRT is prognostic regardless of IMT use. PDL1 expression in CAMLs also appears to predict for response to consolidated IMT after CRT. Additional studies are needed to validate these findings.

The Relationship Between Pharmacogenomics and Pharmacokinetics and Its Impact on Drug Choice and Dosing Regimens in Pediatrics

2018 ◽  
pp. 203-222
Author(s):  
Venkata K. Yellepeddi ◽  
Jessica K. Roberts ◽  
Leslie Escobar ◽  
Casey Sayre ◽  
Catherine M. Sherwin
Keyword(s):  
Drug Choice ◽  
Dosing Regimens ◽  
The Relationship

scholarly journals Pharmacodynamics of a Long-Acting Echinocandin, CD101, in a Neutropenic Invasive-Candidiasis Murine Model Using an Extended-Interval Dosing Design

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Brian VanScoy ◽  
Paul G. Ambrose ◽  
David R. Andes
Keyword(s):  
Invasive Candidiasis ◽  
Half Life ◽  
Intraperitoneal Administration ◽  
Time Curve ◽  
Content Type ◽  
Elimination Half ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Long Acting

ABSTRACT Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans, making it possible to design once-weekly dosing strategies. The present study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select Candida albicans (n = 4), C. glabrata (n = 3), and C. parapsilosis (n = 3) strains. The CD101 MIC ranged from 0.03 to 1 mg/liter. Plasma pharmacokinetic measurements were performed using uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 to 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days, at which time the organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC index) correlated well with efficacy (R 2, 0.74 to 0.93). The median stasis 24-h free-drug AUC/MIC targets were as follows: for C. albicans, 2.92; for C. glabrata, 0.07; and for C. parapsilosis, 2.61. The PK/PD targets for 1-log10 kill endpoint were 2- to 4-fold higher. Interestingly, the aforementioned PK/PD targets of CD101 were numerically lower for all three species than those of other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent in vivo pharmacodynamic activity.

scholarly journals The Effect of Adjunctive Mangosteen Pericarp on Cognition in People With Schizophrenia: Secondary Analysis of a Randomized Controlled Trial

2021 ◽  
Vol 12 ◽  
Author(s):  
Wolfgang Marx ◽  
David R. Skvarc ◽  
Mohammadreza Mohebbi ◽  
Adam J. Walker ◽  
Alcy Meehan ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Visual Learning ◽  
Secondary Analysis ◽  
Cognitive Outcomes ◽  
Garcinia Mangostana ◽  
Cognitive Domains ◽  
Optimal Dosing ◽  
Dosing Strategies ◽  
The Relationship

Background: Cognitive impairment is prevalent and often highly burdensome in people with schizophrenia. The aim of this study was to investigate if mangosteen (Garcinia mangostana Linn.) pericarp extract may be an effective intervention to improve cognitive performance in this population.Methods: This was a secondary analysis of a larger randomized placebo-controlled trial that investigated a 24-weeks intervention of mangosteen pericarp extract supplementation in people diagnosed with schizophrenia. A subset of n = 114 participants with completed cognitive outcomes at follow up were included in this analysis. Using the Cogstate Brief Battery, the following cognitive outcomes were assessed: psychomotor function, attention, visual learning and memory (visual and working). Subgroup analyses investigated whether baseline clinical parameters (baseline cognitive functioning, illness severity and duration, depressive symptoms) moderated the relationship between mangosteen pericarp extract intervention and change in cognitive outcomes.Results: There were no significant between-group changes in any cognitive outcomes assessed. Subgroup analysis based on baseline cognition and clinical characteristics did not reveal any significant between-group difference in change.Conclusions: Mangosteen pericarp extract did not affect cognitive outcomes in people with schizophrenia. Further investigation regarding optimal dosing strategies for mangosteen interventions and the testing of additional cognitive domains may be warranted.Trial Registration:ANZCTR.org.au identifier: ACTRN12616000859482, registered 30 June 3 2016.

Patient Perceptions of FDA Approval: Gaps in Education or Variation in Values?

2021 ◽  
pp. 10.1212/CPJ.0000000000001034
Author(s):  
Paul J. Ford ◽  
Robert J. Fox ◽  
Mary Beth Mercer ◽  
Stacey S. Cofield
Keyword(s):  
Drug Approval ◽  
Patient Perceptions ◽  
Approval Process ◽  
Inclusion Criteria ◽  
Web Based ◽  
Risks And Benefits ◽  
Disease Modifying Therapies ◽  
Fda Approval ◽  
Disease Modifying

Abstract:Objective:To assess perceptions and opinions about the FDA approval process for disease modifying therapies (DMT) in people living with multiple sclerosis (MS).Methods:People living with MS were invited to complete a web-based survey of their perceptions of the FDA role and process for approval of MS medications. The survey asked about the role of the FDA, factors involved in the approval process, which voices should represent those with MS in deliberations about drug approval, and the level of comfort with uncertain safety of newly-approved therapies.Results:3533 respondents met inclusion criteria for data analysis. Most respondents appeared to understand the role of the FDA, although only half understood a fundamental FDA role: balancing the risks and benefits when considering drug approval. Significant differences were observed in many areas between those who have and have not tried DMTs. Comfort with uncertainty was associated with several factors relating to side effects and benefits thought important for the FDA to consider. Most respondents reported that people who participated in the medication’s clinical trial were particularly able to represent people living with MS.Conclusion:Perceptions regarding the FDA and views of who should represent people living with MS varied between those who have and have not tried DMT. There is variability in personal values that should be recognized and taken into account when considering regulatory responsibilities. Interventions are needed to address educational gaps regarding the mission and trustworthiness of the FDA as an oversight body.

The Twenty-Five-Year FDA Approval Controversy

2017 ◽  
Author(s):  
William Green
Keyword(s):  
Population Control ◽  
Obstetrics And Gynecology ◽  
Marketing Approval ◽  
Approval Process ◽  
Control Programs ◽  
Drug Risk ◽  
Fda Approval ◽  
Political Controversy ◽  
Long Acting ◽  
Risk Acceptability

Judith Weisz's story of the politics of drug risk management shifts its focus to Depo-Provera's lengthy FDA marketing approval process. Here her story explores the scientific and political controversy over the FDA's assessment of the drug's risk and its policy judgments about the risk acceptability of its marketing approval. The controversy was dominated by the fear that the drug could cause breast, endometrial, and cervical cancer, and by Depo-Provera's uniqueness as a long-acting contraceptive and its use in international population control programs. The controversy began when the FDA relied on its Obstetrics and Gynecology Advisory Committee to grant the drug limited marketing approval in 1974, which it withdrew after congressional criticism, and then, following an intra-agency review, disapproved the drug for general contraceptive marketing which, once again, brought congressional scrutiny because of its impact on international family planning programs. An FDA Public Board of Inquiry, convened at Upjohn's request and chaired by Judith Weisz, conducted an intensive scientific assessment of the drug's animal and human studies at its 1983 hearings and then made a recommendation, accepted by the FDA in 1986, to disapprove the drug for general contraceptive marketing.

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