Efflux transporters in drug disposition during pregnancy.

Evidence-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. In this review, as Dr. Qingcheng Mao's former and current lab members, we summarize the collective contributions of Dr. Mao, who lost his life to cancer, focusing on the role of drug transporters in drug disposition during pregnancy. Dr. Mao and his team initiated their research by characterizing the structure of Breast Cancer Resistance Protein [BCRP, ATP-Binding Cassette (ABC) G2]. Subsequently, they have made significant contributions to the understanding of the role of BCRP and other transporters, particularly P-glycoprotein (P-gp/ABCB1), in the exposure of pregnant women and their fetuses to various drugs, including nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol, and their metabolites. This review also highlights the gestation- and pregnancy-dependent transporter expression at the blood-brain and blood-placenta barriers in mice. Significance Statement Dr. Qingcheng Mao and his team have made significant contributions to the investigation of the role of efflux transporters, especially P-glycoprotein and breast cancer resistance protein, in maternal-fetal exposure to many xenobiotics: nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol and their metabolites. Studies of individual compounds and the expression of transporters during gestation and pregnancy have improved the understanding of maternal-fetal pharmacokinetics.

Translational PK/PD framework for antibody-drug conjugates to inform drug discovery and development.

(171/200)ADCs 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. ADC development is a multidisciplinary endeavor requiring a strategic integration of nonclinical safety, pharmacology, and PK/PD modeling to translate from bench to bedside successfully.The ADC development underscores the necessity for a robust scientific foundation, leveraging advanced analytical and modeling tools to predict human responses and optimize therapeutic outcomes.This review aims to provide an ADC translational PK/PD framework by discussing unique aspects of ADC nonclinical to clinical PK translation, starting dose determination, and leveraging PK/PD modeling for human efficacious dose prediction and potential safety mitigation.

Population pharmacokinetics and exposure-response analyses of polatuzumab vedotin in patients with previously untreated DLBCL from the POLARIX study.

Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.

Clinical pharmacology strategies to accelerate the development of polatuzumab vedotin and summary of key findings.

The 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. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.

Enhanced Thermal Boundary Conductance across GaN/SiC Interfaces with AlN Transition Layers.

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. Our findings reveal that the addition of an AlN transition layer leads to a notable increase in the TBC of the GaN/SiC interface, particularly at elevated temperatures. Structural characterization techniques are employed to understand the influence of the AlN transition layer on the crystalline quality of the GaN layer and its potential effects on interfacial thermal transport. To gain further insights into the trend of TBC, we conduct molecular dynamics simulations using high-fidelity deep learning-based interatomic potentials, which reproduce the experimentally observed enhancement in TBC even for atomically perfect interfaces. These results suggest that the enhanced TBC facilitated by the AlN intermediate layer could result from a combination of improved crystalline quality at the interface and the "phonon bridge" effect provided by AlN that enhances the overlap between the vibrational spectra of GaN and SiC.

Ethnic sensitivity assessment: Polatuzumab vedotin pharmacokinetics in Asian and non-Asian patients with previously untreated diffuse large B-cell lymphoma in POLARIX.

This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non-Asian patients with previously untreated diffuse large B-cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non-Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody-conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non-Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%-7.0% and 17.3%-19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non-Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety.

PK/PD and Bioanalytical Considerations of AAV-Based Gene Therapies: an IQ Consortium Industry Position Paper.

Interest 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). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.Traditional PK concepts are generally not applicable to AAV-based therapies due to the inherent complexity of a transgene-carrying viral vector, and the multiple steps and analytes involved in cell transduction and transgene-derived protein expression. Therefore, we explain PK concepts of biodistribution of AAV-based therapies and place key terminologies related to drug exposure and PD in the proper context. Factors affecting biodistribution are presented in detail, and guidelines are provided to design nonclinical studies to enable a stage-gated progression to Phase 1 testing. The nonclinical and clinical utility of transgene DNA, mRNA, and protein analytes are discussed with bioanalytical strategies to measure these analytes. The pros and cons of qPCR vs. ddPCR technologies for DNA/RNA measurement and qualitative vs. quantitative methods for transgene-derived protein are also presented. Last, best practices and recommendations for use of clinical and nonclinical data to project human dose and response are discussed. Together, the manuscript provides a holistic framework to discuss evolving concepts of PK/PD modeling, bioanalytical technologies, and clinical dose selection in gene therapy.

Best Practices and Considerations for Clinical Pharmacology and Pharmacometric Aspects for Optimal Development of CAR-T and TCR-T Cell Therapies: An Industry Perspective.

With 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. There are unique clinical pharmacology, pharmacometric, bioanalytical, and immunogenicity considerations and challenges in the development of these CAR-T and TCR-T cell therapies. Hence, to help accelerate the development of these life-saving therapies for the patients with cancer, experts in this field came together under the umbrella of International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) to form a joint working group between the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). In this white paper, we present the IQ consortium perspective on the best practices and considerations for clinical pharmacology and pharmacometric aspects toward the optimal development of CAR-T and TCR-T cell therapies.

Borazine Promoted Growth of Highly Oriented Thin Films.

We report on a phenomenon, where thin films sputter-deposited on single-crystalline Al2O3(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 Al2O3(0001) under the same conditions. We observed this phenomenon in face-centered cubic Pd, body-centered cubic Mo, and trigonal Ta2C thin films grown on Al2O3(0001). Interestingly, intermittent exposure to borazine during the growth of Ta2C thin films on Ta2C yields better crystallinity than direct deposition of monolithic Ta2C. We attribute these rather unusual results to a combination of both enhanced adatom mobilities on, and epitaxial registry with, surfaces exposed to borazine during the deposition. We expect that our approach can potentially help improve the crystalline quality of thin films deposited on a variety of substrates.

Pharmacokinetics of biologics in gastric cancer.

Gastric 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. Achieving optimal exposure for patients with GC is an important factor in balancing risk and optimizing therapeutic benefit and thus maximizing chance of positive outcomes for pivotal trials. Therefore, in this review, we summarize the PK disposition of several molecules (e.g., anti-HER2, anti-VEGF, and anti-PD1) evaluated in GC and showed a consistent trend of lower drug exposure as compared to other solid tumors. We hypothesize that two possible mechanisms: (1) hyper-catabolism of endogenous and exogenous proteins due to cancer cachexia; and (2) gastric protein leakage due to local inflammation at the gastrointestinal tract may explain or partially explain the increase of clearance in patients with GC. Last, the potential implications of such findings on dose selection to optimize the benefit: risk profile for biologics in GC are also discussed.

Clinical Pharmacology Considerations on Recombinant Adeno-Associated Virus-Based Gene Therapy.

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. The main topics covered are biodistribution and shedding, dose-exposure-response relationship, safety, immune and stress response, and clinical dose selection strategies. We highlight how the cumulative knowledge of AAV gene therapy could help with guiding clinical trial design and assessing and mitigating risks, as well as planning and executing pharmacokinetic/pharmacodynamic /safety data analyses. In addition, we discuss the major gaps and areas of growth in clinical pharmacology understanding of recombinant AAV. These include the mechanisms of the durability of treatment response and variability in biodistribution, transduction, and immunogenicity, as well as a potential influence on AAV's safety and efficacy profiles by drug product characteristics and patient intrinsic/extrinsic factors.

COVID-19 Vaccination Perceptions Among Young Adults of Color in the San Francisco Bay Area.

Background: COVID-19 vaccination rates among U.S. young adults, particularly in communities of color, remain lower than other age groups. We conducted a qualitative, community-based participatory study to explore beliefs and attitudes about COVID-19 vaccines among young adults in Black/African American, Latinx, and Asian American or Pacific Islander (AAPI) communities in the San Francisco Bay Area. Methods: We conducted six focus groups between June and August 2021. Participants were recruited by partnering with community-based organizations in the San Francisco Bay Area. Focus groups included Black/African American (N=13), Latinx (N=20), and AAPI (N=12) participants between 18 and 30 years of age. Emerging themes were identified using a modified Grounded Theory approach. Results: Prominent themes among all three racial-ethnic groups included mistrust in medical and government institutions, strong conviction about self-agency in health decision-making, and exposure to a thicket of contradictory information and misinformation in social media. Social benefit and a sense of familial and societal responsibility were often mentioned as reasons to get vaccinated. Young adult mistrust had a generational flavor fueled by anger about increasing inequity, the profit-orientation of pharmaceutical companies and health institutions, society's failure to rectify injustice, and pessimism about life prospects. Conclusion: Factors influencing vaccine readiness among Black/African American, Latinx, and AAPI young adults have a distinct generational and life-course texture. Outreach efforts should appeal to young adults' interest in family and social responsibility and the social benefits of vaccination, while being cognizant of the friction mandates pose for young adults' sense of self-agency. Efforts will be most effective coming from trusted messengers with a proven commitment to communities of color and health equity.

COVID-19 vaccination readiness among multiple racial and ethnic groups in the San Francisco Bay Area: A qualitative analysis.

BACKGROUND: 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. Focus groups (N = 10) and in-depth interviews (N = 25) were conducted among Black/African Americans (N = 35), Latinx (N = 40), and Chinese Americans (n = 34) in English, Spanish, Cantonese, or Mandarin. Themes were identified using grounded field theory, and included misinformation, mistrust of government and health institutions, and linguistic and other barriers to vaccine access. All three racial/ethnic groups had experiences with vaccine misinformation and information overload. Many African American and Latinx participants cited structural and interpersonal racism, and anti-immigrant discrimination, as factors reducing their trust in government and public health disseminated information and their willingness to be vaccinated. Participants expressed trust in community-based organizations, including faith-based organizations and community-run clinics. Participants often experienced barriers to vaccine access, such as transportation to drive-in sites, with Latinx and Chinese American groups also frequently citing language barriers. CONCLUSIONS: Vaccine outreach strategies must acknowledge how longstanding systemic, institutional, and structural racism contributes to mistrust in government and health institutions and engage with and support trusted messengers from the community to eliminate cultural, linguistic, and other barriers to vaccine access.

Experimental evidence of auxeticity in ion implanted single crystal calcite.

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 × 1014 cm-2. 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]. Materials with a positive Poisson's ratio experience lattice expansion normal to the substrate surface when ion implanted, whereas lattice contraction normal to the surface is evidence of auxetic behavior. Triple-axis X-ray diffraction measurements confirmed the auxetic strain state of the implanted calcite substrates. Reciprocal space maps for the symmetric 3030 and asymmetric 1450 reflections revealed that the implanted region was fully strained (pseudomorphic) to the bulk of the substrate, as is typical with implanted single crystals. A symmetric (3030) ω:2θ line scan was used with X-ray dynamical diffraction simulations to model the strain profile and extract the variation of compressive strain as a function of depth normal to the substrate surface. SRIM calculations were performed to obtain a displacement-per-atom profile and implanted Ar+ concentration profile. It was found that the strain profile matches the displacement-per-atom profile. This study demonstrated the use of ion implantation and X-ray diffraction methods to probe mechanical properties of materials and to test predictions such as the auxeticity.

Clinical Pharmacology Perspectives for Adoptive Cell Therapies in Oncology.

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. As ACT is comprised of alive, polyfunctional, and heterogeneous immune cells, its overall physicochemical and pharmacological property is vastly different from other platforms/modalities, such as small molecule and protein therapeutics. In this review, we first describe the unique kinetics of T cells and the appropriate bioanalytical strategies to characterize cellular kinetics. We then assess the distinct aspects of clinical pharmacology for ACTs in comparison to traditional small molecule and protein therapeutics. Additionally, we provide a review for the five FDA-approved CAR T-cell therapies and summarize their properties, cellular kinetic characteristics, dose-exposure-response relationship, and potential baseline factors/variables in product, patient, and regimen that may affect the safety and efficacy. Finally, we probe into existing empirical and mechanistic quantitative techniques to understand how various modeling and simulation approaches can support clinical pharmacology strategy and propose key considerations to be incorporated and explored in future models.

Experimental observation of localized interfacial phonon modes.

Interfaces 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. However, experimental validation is still lacking. Through a combination of Raman spectroscopy and high-energy-resolution electron energy-loss spectroscopy in a scanning transmission electron microscope, we report the experimental observation of localized interfacial phonon modes at ~12 THz at a high-quality epitaxial Si-Ge interface. These modes are further confirmed using molecular dynamics simulations with a high-fidelity neural network interatomic potential, which also yield thermal boundary conductance agreeing well with that measured in time-domain thermoreflectance experiments. Simulations find that the interfacial phonon modes have an obvious contribution to the total thermal boundary conductance. Our findings significantly contribute to the understanding of interfacial thermal transport physics and have impact on engineering thermal boundary conductance at interfaces in applications such as electronics thermal management and thermoelectric energy conversion.

Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study.

PURPOSE: 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). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS: Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10-6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION: Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi-treated patients remaining in remission.

The impact of hepatic and renal function on panitumumab exposures in patients with metastatic RAS wild-type colorectal cancer.

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. METHODS: From three multicenter, open-label, phase 2 and phase 3 studies, 349 and 351 patients were included in hepatic and renal function subgroup analyses, respectively. Patients who received IV panitumumab and serum exposures were compared to patients with varying degrees of hepatic and renal organ dysfunction. RESULTS: The Cmax and Ctrough values for patients with mild (n = 119) and moderate (n = 4) hepatic impairment were within the range of serum concentrations of panitumumab for the normal hepatic function subgroup. The distributions of serum concentration of panitumumab in patients with mild (n = 85) or moderate (n = 19) renal impairment were similar to the serum concentrations of panitumumab in the normal renal function subgroup. Population pharmacokinetic modeling and covariate analysis results were also consistent with lack of any significant effect of renal or hepatic impairment on the pharmacokinetics of panitumumab. Additionally, real-world evidence from case studies of patients with mCRC and severe hepatic or renal impairment, which is a rare patient population to study, indicated lack of clinically relevant differences in exposure of panitumumab compared with patients with mCRC and normal hepatic or renal function. CONCLUSIONS: Mild-to-moderate hepatic or renal dysfunction had no clinically meaningful impact on the pharmacokinetics of panitumumab in patients with mCRC. No dose adjustments for panitumumab are warranted in patients with mCRC with mild-to-moderate hepatic or renal dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov; NCT00083616, NCT00089635, NCT00113763.

Surface Reconstruction of Halide Perovskites During Post-treatment.

Postfabrication surface treatment strategies have been instrumental to the stability and performance improvements of halide perovskite photovoltaics in recent years. However, a consensus understanding of the complex reconstruction processes occurring at the surface is still lacking. Here, we combined complementary surface-sensitive and depth-resolved techniques to investigate the mechanistic reconstruction of the perovskite surface at the microscale level. We observed a reconstruction toward a more PbI2-rich top surface induced by the commonly used solvent isopropyl alcohol (IPA). We discuss several implications of this reconstruction on the surface thermodynamics and energetics. Particularly, our observations suggest that IPA assists in the adsorption process of organic ammonium salts to the surface to enhance their defect passivation effects.