The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs).
View Article and Find Full Text PDFEvidence-based dose selection of drugs in pregnant women has been lacking due to challenges in studying maternal-fetal pharmacokinetics. Hence, many drugs are administered off-label during pregnancy based on data obtained from non-pregnant women. During pregnancy, drug transporters play an important role in drug disposition along with known gestational age-dependent changes in physiology and drug-metabolizing enzymes.
View Article and Find Full Text PDFADCs represent a transformative class of medicine that combines the specificity of monoclonal antibodies with the potency of highly cytotoxic agents through linkers, aiming to enhance the therapeutic index of cytotoxic drugs. Given the complex molecular structures of ADCs, combining the molecular characteristics of small-molecule drugs and those of large-molecule biotherapeutics, there are several unique considerations when designing nonclinical-to-clinical PK/PD translation strategies.This complexity also demands a thorough understanding of the ADC's components - antibody, linker, and payload - to the overall toxicological, PK/PD, and efficacy profile.
View Article and Find Full Text PDFACS Appl Mater Interfaces
February 2024
Heat dissipation plays a crucial role in the performance and reliability of high-power GaN-based electronics. While AlN transition layers are commonly employed in the heteroepitaxial growth of GaN-on-SiC substrates, concerns have been raised about their impact on thermal transport across GaN/SiC interfaces. In this study, we present experimental measurements of the thermal boundary conductance (TBC) across GaN/SiC interfaces with varying thicknesses of the AlN transition layer (ranging from 0 to 73 nm) at different temperatures.
View Article and Find Full Text PDFThe favorable benefit-risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody-drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches.
View Article and Find Full Text PDFInterest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ).
View Article and Find Full Text PDFWith the promise of a potentially "single dose curative" paradigm, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies. Both CAR-T and TCR-T cell therapies have also made great progress toward the successful treatment of solid tumor indications. The field is rapidly evolving with recent advancements including the clinical development of "off-the-shelf" allogeneic CAR-T therapies that can overcome the long and difficult "vein-to-vein" wait time seen with autologous CAR-T therapies.
View Article and Find Full Text PDFWe report on a phenomenon, where thin films sputter-deposited on single-crystalline AlO(0001) substrates exposed to borazine─a precursor commonly used for the synthesis of hexagonal boron nitride layers─are more highly oriented than those grown on bare AlO(0001) under the same conditions. We observed this phenomenon in face-centered cubic Pd, body-centered cubic Mo, and trigonal TaC thin films grown on AlO(0001). Interestingly, intermittent exposure to borazine during the growth of TaC thin films on TaC yields better crystallinity than direct deposition of monolithic TaC.
View Article and Find Full Text PDFGastric cancer (GC) remains one of the leading causes of cancer death worldwide despite improvements in therapeutic options. Several biologics have been investigated in patients with GC, including those approved in other solid tumors; however, the success rate of the pivotal trials that investigated these biologic molecules in GC remains low. Elevation in total clearance and a decrease in systemic pharmacokinetic (PK) exposure in GC compared with other indications have been observed in these biologics across different pathways.
View Article and Find Full Text PDFJ Clin Pharmacol
December 2022
Recombinant adeno-associated virus (AAV) is currently the most widely used platform for in vivo gene therapy. Clinical pharmacology is a central field for AAV gene therapy, represented by the pillars of pharmacokinetics, pharmacodynamics/efficacy, and safety. In this review, we provide a comprehensive summary of clinical pharmacology considerations for recombinant AAV.
View Article and Find Full Text PDFBackground: COVID-19 vaccination rates are lower among historically marginalized populations, including Black/African American and Latinx populations, threatening to contribute to already high COVID-19 morbidity and mortality disparities for these groups. We conducted a community-based participatory research study using qualitative methods to explore knowledge and beliefs about COVID-19 vaccination among Black/African American, Latinx, and Chinese American residents of the San Francisco Bay Area and assess their views on vaccination outreach and delivery strategies.
Methods And Findings: Data were collected from January 14, 2021, to February 24, 2021, with adult residents (N = 109 [Female: N = 76; 70%]) in San Francisco.
We report initial experimental evidence of auxeticity in calcite by ion implanting (1010) oriented single crystalline calcite with Ar at room temperature using an ion energy of 400 keV and a dose of 1 × 10 cm. Lattice compression normal to the substrate surface was observed, which is an atypical result for ion implanted materials. The auxetic behavior is consistent with predictions that indicate auxeticity had been predicted along two crystallographic directions including [1010].
View Article and Find Full Text PDFClin Pharmacol Ther
November 2022
Adoptive cell therapies (ACTs) have shown transformative efficacy in oncology with five US Food and Drug Administration (FDA) approvals for chimeric antigen receptor (CAR) T-cell therapies in hematological malignancies, and promising activity for T cell receptor T-cell therapies in both liquid and solid tumors. Clinical pharmacology can play a pivotal role in optimizing ACTs, aided by modeling and simulation toolboxes and deep understanding of the underlying biological and immunological processes. Close collaboration and multilevel data integration across functions, including chemistry, manufacturing, and control, biomarkers, bioanalytical, and clinical science and safety teams will be critical to ACT development.
View Article and Find Full Text PDFInterfaces impede heat flow in micro/nanostructured systems. Conventional theories for interfacial thermal transport were derived based on bulk phonon properties of the materials making up the interface without explicitly considering the atomistic interfacial details, which are found critical to correctly describing thermal boundary conductance. Recent theoretical studies predicted the existence of localized phonon modes at the interface which can play an important role in understanding interfacial thermal transport.
View Article and Find Full Text PDFPurpose: The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study.
Patients And Methods: Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi).
Purpose: Panitumumab is a human monoclonal antibody targeting the epidermal growth factor receptor for the treatment of wild-type RAS metastatic colorectal cancer (mCRC). Currently, no dedicated clinical studies have evaluated the effect of organ impairment on the pharmacokinetics of panitumumab. Here, we present data from late phase studies of panitumumab in patients with mCRC and analyses of the effect of hepatic or renal impairment on the exposure of panitumumab.
View Article and Find Full Text PDFHigh thermal conductivity materials show promise for thermal mitigation and heat removal in devices. However, shrinking the length scales of these materials often leads to significant reductions in thermal conductivities, thus invalidating their applicability to functional devices. In this work, we report on high in-plane thermal conductivities of 3.
View Article and Find Full Text PDFAntibody-drug conjugates (ADCs) combine the specificity of an antibody with the cytotoxicity of a chemical agent. They represent a rapidly evolving area of oncology drug development and hold significant promise. There are currently nine ADCs on the market, more than half of which gained US Food and Drug Administration approval more recently, since 2019.
View Article and Find Full Text PDFPurpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy.
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