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We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

The DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

Background and Objectives: Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE ® NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL., Methods: Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling., Results: Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (t max ) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics., Conclusions: Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal impairment, or mild hepatic impairment. The risk of immunogenicity was low. These are the first published results of population pharmacokinetic modeling for epcoritamab., Competing Interests: Declarations. Funding: This study was funded by Genmab A/S and AbbVie. Conflict of interest: T.L., M.v.d.L., K.S., M.P., M.S., H.F., T.A., M.G., and S.X. are employees of Genmab. T.A. owns stock in Genmab. L.G. is an employee of QuantPharm LLC and is a paid consultant of Genmab. A.P. is an employee and stockholder of AbbVie. Availability of data and material: Deidentified individual participant data will not be available upon request for further analyses by external independent researchers. Aggregated clinical trial data from the trials are provided via publicly accessible study registries/databases as required by law. For more information, please contact clinicaltrials@genmab.com. Ethics approval: Both EPCORE NHL-1 and EPCORE NHL-3 protocols were approved by an institutional ethics committee before the start of the trials. The trials were conducted in compliance with the International Council for Harmonisation Good Clinical Practice E6(R2) guidelines, local guidelines (Japan Good Clinical Practice for EPCORE NHL-3), principles of the Declaration of Helsinki, and relevant regulatory requirements. Consent to participate: All patients reviewed and signed informed consent forms before enrollment. Consent for publication: Because of the nature of this study, consent to publish was waived. Author contributions: Conceptualization: T.L., A.P., M.G., and S.X. Methodology: T.L., L.G., and M.v.d.L. Formal analysis and investigation: T.L., L.G., M.v.d.L, M.S., and H.F. Writing, original draft preparation: T.L. and S.X. Funding acquisition: T.L. and M.G. Resources: K.S. and M.P. Supervision: T.L., M.G., and S.X. All authors participated in the critical review and revision of this manuscript and provided approval of the manuscript for submission. Code availability: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: This study explored employee health behavior changes and health care utilization after workplace genetic testing (wGT). Wellness-program-associated wGT seeks to improve employee health, but the related health implications are unknown., Methods: Employees of a large US health care system offering wGT (cancer, heart disease, and pharmacogenomics [PGx]) were sent electronic surveys. Self-reported data from those who received test results were analyzed. Descriptive statistics characterized responses, whereas logistic regression analyses explored correlates of responses to wGT., Results: 53.9% (n = 418/776) of respondents (88.3% female, mean age = 44 years) reported receiving wGT results. 12.0% (n = 48/399) received results indicating increased risk (IR) of cancer, 9.5% (n = 38/398) had IR of heart disease, and 31.4% (n = 125/398) received informative PGx results. IR results for cancer and/or heart disease (n = 67) were associated with health behavior changes (adjusted odds ratio: 3.23; 95% CI 1.75, 6.13; P < .001) and health care utilization (adjusted odds ratio: 8.60; 95% CI 4.43, 17.5; P < .001). Informative PGx results (n = 125) were associated with medication changes (PGx-informative: 15.2%; PGx-uninformative: 4.8%; P = .002)., Conclusion: This study explored employee responses to wGT, contributing to the understanding of the ethical and social implications of wGT. Receiving IR results from wGT may promote health behavior changes and health care utilization in employees., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Assessment of a patient's functional status prior to undergoing cardiac surgery may be a useful marker for predicting outcomes when postoperative veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is required. In this short communication, we present retrospective data on 83 patients at a single center who required V-A ECMO after cardiac surgery. Our results did not show a statistically significant association between premorbid functional status and mortality, though age was predictive of mortality. Future studies should explore other markers of functional status and relationships with additional outcomes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PK of nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration-time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction-corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two-compartment model with time-varying clearance, zero-order infusion into the central compartment after i.v. dosing, and first-order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well-characterized using the combined s.c./i.v. population PK model. The model-based analysis facilitated a comprehensive benefit-risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation., (© 2023 Bristol-Myers Squibb. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: A patient-reported outcomes measure (PROM) is responsive if it is sensitive to clinical status changes. The minimal clinically important difference (MCID) is used to indicate meaningful change, helpful in designing studies and adding context to some study results, and is related to instrument responsiveness. Our purpose was to provide MCID estimates for the brief Michigan Hand Outcomes Questionnaire (bMHQ) and Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference (PI) in a hand and upper extremity surgery cohort within the context of varying patient-reported mental health., Methods: Data were analyzed from 1,262 adult patients who received surgical care at a single center between January 1, 2018, and December 31, 2019. Patients completed PROMIS PI, PROMIS Global Health (including global mental health [GMH] component), bMHQ, and a pain-focused anchor question before each clinic visit. Data were collected 8 ± 2 weeks before and after surgery. A distribution-based MCID then was calculated for the general patient population, lowest 10th percentile of GMH scores, and top 10th percentile of GMH scores., Results: Minimal clinically important difference estimates were 10.4 for the bMHQ and 4.3 for PROMIS PI. Analysis of MCID across different GMH score groups showed a mean score of 11.5 for bMHQ for the lowest 10th percentile of GMH, 9.6 for bMHQ for the top 10th percentile, 4.5 for PI for the lowest 10th percentile, and 4.9 for PI for the top 10th percentile., Conclusions: Analysis of subgroups stratified by preoperative patient-reported mental health condition found that preoperative mental health status, as indicated by GMH score, does not have a meaningful impact on responsiveness of bMHQ or PROMIS PI., Clinical Relevance: A patient's reported mental health condition does not meaningfully change how these common PRO instruments reflect the patient condition after hand and upper extremity surgery., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Aim: To analyze the predictive value of biochemical liver tests in patients with malignant melanoma, breast, colorectal or lung cancers at the time of diagnosis of liver metastases., Methods: A retrospective review of patients with the above-mentioned solid tumors at MedStar Georgetown University Hospital from 2016-2020., Results: The highest optimal cutoff according to sensitivity and specificity for the presence of liver metastases was for AST ≥1.5 × ULN for melanoma, lung, and breast cancers and ≥2 × ULN for colorectal cancer, ALT ≥1.25 × ULN for melanoma, breast and colorectal cancers and ≥1.5 × ULN for lung cancer, and ALP ≥1.5 × ULN for melanoma, breast and colorectal cancers., Conclusion: Using thresholds of liver enzymes above the ULN may improve the diagnostic accuracy for the presence of liver metastases., Competing Interests: Conflicts of interests disclosure The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties., (© 2023 The Authors.)

Introduction: The primary objective of this study was to examine patient portal usage from pre- to post-onset of the COVID-19 pandemic to determine what impact the pandemic had on portal usage by patient sub-populations. The second study objective was to assess differences in portal usage by chronic disorders from pre- to post-onset of the pandemic., Methods: Patient portal data were extracted and analyzed from a non-profit healthcare system in the Mid-Atlantic region. A total of 153,628 unique patients with patient portal account were included in this study. We assessed patient portal usage from pre-onset (March 2019-February 2020) to post-onset of the COVID-19 pandemic (March 2020-February 2021). We examined usage by patient sub-populations (age, sex, race, ethnicity), comorbid conditions, and health insurance type., Results: Differences were seen in specific patient portal actions. Increases were seen in immunization views (0.43, 95% CI: 0.39, 0.46) and health record views (0.43, 95% CI: 0.40, 0.46) from post-onset compared to pre-onset. A decrease was noted in prescription renewal (medication) views (-0.07, 95% CI -0.09, -0.05) from pre- to post-onset There was a decrease in both immunization views and health record views among Black patients (-0.07, 95% CI: -0.11, -0.03) in comparison to White patients, but an increase in prescription renewal (medication) views (0.07, 95%CI 0.04, 0.09) amongst Black patients compared to White patients., Conclusions: Patient portals are integral to patient care, allowing patients to actively engage in their care and communicate with their healthcare team about ongoing health needs. However, prior disparities in patient portal access have been exacerbated by the COVID-19 pandemic and solutions to address these disparities are urgently needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: The objectives of this study were to (1) examine demographic differences between patient portal users and nonusers; and (2) examine health literacy, patient self-efficacy, and technology usage and attitudes between patient portal users and nonusers., Methods: Data were collected from Amazon Mechanical Turk (MTurk) workers from December 2021 to January 2022. MTurk workers completed an online survey, which asked about their health, access to technology, health literacy, patient self-efficacy, media and technology attitudes, and patient portal use for those with an account. A total of 489 MTurk workers completed the survey. Data were analyzed using latent class analysis (LCA) and multivariate logistic regression models., Results: Latent class analysis models revealed some qualitative differences between users and nonusers of patient portals in relation to neighborhood type, education, income, disability status, comorbidity of any type, insurance type, and the presence or absence of primary care providers. These results were partially confirmed by logistic regression models, which showed that participants with insurance, a primary care provider, or a disability or comorbid condition were more likely to have a patient portal account., Conclusions: Our study findings suggest that access to health care, along with ongoing patient health needs, influence the usage of patient portal platforms. Patients with health insurance have the opportunity to access health care services, including establishing a relationship with a primary care provider. This relationship can be critical to a patient ever creating a patient portal account and actively engaging in their care, including communicating with their care team., Competing Interests: The authors have no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although esophageal candidiasis (EC) may manifest in immunocompetent individuals, there is a lack of consensus in the current literature about predisposing conditions that increase the risk of infection., Aim: To determine the prevalence of EC in patients without human immunodeficiency virus (HIV) and identify risk factors for infection., Methods: We retrospectively reviewed inpatient and outpatient encounters from 5 regional hospitals within the United States (US) from 2015 to 2020. International Classification of Diseases, Ninth and Tenth Revisions were used to identify patients with endoscopic biopsies of the esophagus and EC. Patients with HIV were excluded. Adults with EC were compared to age, gender, and encounter-matched controls without EC. Patient demographics, symptoms, diagnoses, medications, and laboratory data were obtained from chart extraction. Differences in medians for continuous variables were compared using the Kruskal-Wallis test and categorical variables using chi-square analyses. Multivariable logistic regression was used to identify independent risk factors for EC, after adjusting for potential confounding factors., Results: Of the 1969 patients who had endoscopic biopsies of the esophagus performed from 2015 to 2020, 295 patients had the diagnosis of EC. 177 of 1969 patients (8.99%) had pathology confirming the diagnosis of EC and were included in the study for data collection and further analysis. In comparison to controls, patients with EC had significantly higher rates of gastroesophageal reflux disease (40.10% vs 27.50%; P = 0.006), prior organ transplant (10.70% vs 2%; P < 0.001), immunosuppressive medication (18.10% vs 8.10%; P = 0.002), proton pump inhibitor (48% vs 30%; P < 0.001), corticosteroid (35% vs 17%; P < 0.001), Tylenol (25.40% vs 16.20%; P = 0.019), and aspirin use (39% vs 27.50%; P = 0.013). On multivariable logistic regression analysis, patients with a prior organ transplant had increased odds of EC (OR = 5.81; P = 0.009), as did patients taking a proton pump inhibitor (OR = 1.66; P = 0.03) or corticosteroids (OR = 2.05; P = 0.007). Patients with gastroesophageal reflux disease or medication use, including immunosuppressive medications, Tylenol, and aspirin, did not have a significantly increased odds of EC., Conclusion: Prevalence of EC in non-HIV patients was approximately 9% in the US from 2015-2020. Prior organ transplant, proton pump inhibitors, and corticosteroids were identified as independent risk factors for EC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background & Objectives: Screening for hepatitis C virus is the first critical decision point for preventing morbidity and mortality from HCV cirrhosis and hepatocellular carcinoma and will ultimately contribute to global elimination of a curable disease. This study aims to portray the changes over time in HCV screening rates and the screened population characteristics following the 2020 implementation of an electronic health record (EHR) alert for universal screening in the outpatient setting in a large healthcare system in the US mid-Atlantic region., Methods: Data was abstracted from the EHR on all outpatients from 1/1/2017 through 10/31/2021, including individual demographics and their HCV antibody (Ab) screening dates. For a limited period centered on the implementation of the HCV alert, mixed effects multivariable regression analyses were performed to compare the timeline and characteristics of those screened and un-screened. The final models included socio-demographic covariates of interest, time period (pre/post) and an interaction term between time period and sex. We also examined a model with time as a monthly variable to look at the potential impact of COVID-19 on screening for HCV., Results: Absolute number of screens and screening rate increased by 103% and 62%, respectively, after adopting the universal EHR alert. Patients with Medicaid were more likely to be screened than private insurance (ORadj 1.10, 95% CI: 1.05, 1.15), while those with Medicare were less likely (ORadj 0.62, 95% CI: 0.62, 0.65); and Black (ORadj 1.59, 95% CI: 1.53, 1.64) race more than White., Conclusions: Implementation of universal EHR alerts could prove to be a critical next step in HCV elimination. Those with Medicare and Medicaid insurance were not screened proportionately to the national prevalence of HCV in these populations. Our findings support increased screening and re-testing efforts for those at high risk of HCV., Competing Interests: Dawn Fishbein, MD receives grant funding for this research from Gilead Sciences, Inc through her employer. She has stock ownership in Abbvie and Merck is a discretionary portfolio with a value less than $10,000. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Hack et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objectives: To explore the incidence of adverse events after bilateral same-day intravitreal 0.7-mg dexamethasone implant (SDIDI) injections., Materials and Methods: We performed an IRB approved, single-center, retrospective review of patients receiving bilateral SDIDI injections from January 1, 2016 to October 31, 2021 and reviewed adverse events that occurred within 3 months of injection., Results: A total of 206 bilateral (412 eyes) SDIDI injections were performed in 59 patients. Ocular hypertension or the addition of intraocular pressure (IOP) lowering drops occurred in 121 (29.4%) eyes after IDI. Two (0.5%) eyes required glaucoma drainage surgeries. Of the 117 phakic eyes, 32 (27.4%) had progression of cataract or cataract extraction. There were two (0.5%) episodes of vitreous hemorrhage and one (0.2%) retinal tear with retinal detachment. There were no cases of endophthalmitis., Conclusion: Serious complication rates after bilateral same-day IDI injections appears low. Increased IOP that requires intervention can occur. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:612-618.] .

Introduction: Fucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1., Methods: CA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival., Results: Patients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%-57.7%]) than with monotherapy (4% [0.8%-11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively., Conclusions: BMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880)., (© 2022 by the International Association for the Study of Lung Cancer.)

Purpose: Genetic variants may influence the pharmacokinetics and pharmacodynamics (PKPD) of cyclophosphamide (CY). CY plays a critical role in conditioning chemotherapy for hematopoietic cell transplantation (HCT), but its use is limited by toxicity. We explored the effect of genetic variants, potentially affecting PKPD of CY, and outcomes after HCT., Methods: This observational pharmacogenomic study included 85 adults with hematologic malignancies who received reduced intensity conditioning with CY, fludarabine, and total body irradiation. We collected recipient DNA prior to HCT and evaluated 97 candidate variants in 66 genes and 3 metabolism phenotypes potentially involved in PKPD pathways of CY. In multivariable analysis we investigated the association between the genotypes and four clinical outcomes: Day 180 non-relapse mortality (NRM) and day 180 overall survival (OS), acute graft-versus-host-disease (aGVHD) grades 2-4, and engraftment. p values were not adjusted for multiple testing., Results: The median recipient age was 63 years (range 21-75). Acute myeloid leukemia was the most common diagnosis (34%; n = 29). In multivariable analysis adjusted for exposure to phosphoramide mustard, the final active metabolite of CY, we identified 6 variants in 6 genes associated with at least one of the clinical outcomes. An ABCC4 variant (rs9561778) was associated with poor Day 180 NRM (p < 0.01), MUTYH variant (rs3219484) with higher Day 180 NRM and aGVHD (both p < 0.01), and SYNE1 variant (rs4331993) with better Day 180 OS and engraftment (both p ≤ 0.01)., Conclusion: The present study suggests that genetic variants influencing the PKPD of CY may help identify patients at risk for inferior outcomes after HCT using CY-based reduced-intensity conditioning., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Consumer interest in genetic and genomic testing is growing rapidly, with more than 26 million Americans having purchased direct-to-consumer genetic testing services. Capitalizing on the increasing comfort of consumers with genetic testing outside the clinical environment, commercial vendors are expanding their customer base by marketing genetic and genomic testing services, including testing for pharmacogenomic and pathogenic variants, to employers for inclusion in workplace wellness programs. We describe the appeal of voluntary workplace genomic testing (wGT) to employers and employees, how the ethical, legal, and social implications literature has approached the issue of genetic testing in the workplace in the past, and outline the relevant legal landscape. Given that we are in the early stages of development of the wGT market, now is the time to identify the critical interests and concerns of employees and employers, so that governance can develop and evolve along with the wGT market, rather than behind it, and be based on data, rather than speculative hopes and fears., (© 2022. The Author(s).)

Purpose: Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM., Methods: A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily C avg ) for multi-variable time-to-event exposure-response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM., Results: Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment (V max ) and non-renewable target-mediated elimination from the peripheral compartment (K int ). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and K int , respectively, versus Ld; steady-state exposures were similar. V max increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily C avg were 0.9983 (0.9969-0.9997) and 0.9981 (0.9964-0.9998) for PFS and grade 3 + AEs, respectively., Conclusions: The PPK model adequately described the data and was appropriate for determining exposures for exposure-response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily C avg prolonged PFS without increasing grade 3 + AEs., (© 2021. The Author(s).)

Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients. The optimal exposure of these agents remains to be determined. We aimed to delineate the exposure-outcome associations of Flu and Cy separately and then both combined on HCT outcomes. This is a single-center, observational, pharmacokinetic (PK)-pharmacodynamic (PD) study of Flu and Cy in HCT recipients age ≥18 years who received Cy (50 mg/kg in a single dose), Flu (150 to 200 mg/m 2 given as 5 daily doses), and total body irradiation (TBI; 200 cGy). We measured trough concentrations of 9-β-D-arabinosyl-2-fluoradenine (F-ara-A), an active metabolite of Flu, on days -5 and -4 (F-ara-A Day-5 and F-ara-A Day-4 , respectively), and measured phosphoramide mustard (PM), the final active metabolite of Cy, and estimated the area under the curve (AUC). The 89 enrolled patients had a nonrelapse mortality (NRM) of 9% (95% confidence interval [CI], 3% to 15%) at day +100 and 15% (95% CI, 7% to 22%) at day +180, and an overall survival (OS) of 73% (95% CI, 63% to 81%) at day +180. In multivariate analysis, higher PM area under the curve (AUC) for 0 to 8 hours (PM AUC 0-8 hr ) was an independent predictor of worse NRM (P < .01 at both day +100 and day +180) and worse day +180 OS (P < .01), but no associations were identified for F-ara-A trough levels. We observed lower day +100 NRM in those with both high F-ara-A Day-4 trough levels (≥40 ng/mL; >25th percentile) and low PM AUC 0-8 hr (<34,235 hr ng/mL; <75th percentile), compared with high exposures to both agents (hazard ratio, 0.06; 95% CI, 0.01 to 0.48). No patients with low F-ara-A Day-4 (<40 ng/mL; <25th percentile) had NRM by day +100, regardless of PM AUC. The interpatient PK variability was large in F-ara-A Day-4 trough and PM AUC 0-8 hr (29-fold and 5.0-fold, respectively). Flu exposure alone was not strongly associated with NRM or OS in this reduced Flu dose regimen; however, high exposure to both Flu and Cy was associated with a >16-fold higher NRM. These results warrant further investigation to optimize reduced-intensity regimens based on better PK-PD understanding and possible adaptation to predictable factors influencing drug clearance., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Nivolumab monotherapy is approved as adjuvant treatment for melanoma based on results from the pivotal CheckMate 238 trial. We present a model-based, benefit-risk assessment of nivolumab in adjuvant melanoma supporting a posology change from a weight-based to a less frequent, flat-dosing regimen. The exposure-response (E-R) relationship for efficacy was evaluated using recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) end points from the CheckMate 238 trial. The E-R for safety was evaluated using data from 14 studies across a broad range of doses in several tumor types using grade 3+ adverse event (AE) and grade 2+ immune-mediated AE (IMAE) end points. Nivolumab trough exposures were not significant predictors of RFS or DMFS. Covariates significantly associated with increased risk of disease recurrence or death were programmed death ligand 1 (PD-L1; less than 5% cutoff), lower baseline lactate dehydrogenase, and higher age. Covariates associated with increased risk of distant metastasis or death were PD-L1 (less than 5% cutoff) and higher age. Higher nivolumab maximum concentration after first dose (Cmax1) was significantly associated with grade 2+ IMAEs, but not grade 3+ AEs. The risk of grade 3+ AEs was significantly lower in adjuvant versus advanced melanoma. Eastern Cooperative Oncology Group Performance Status higher than zero was associated with higher incidences of grade 2+ IMAEs and grade 3+ AEs. Female patients had significantly higher incidences of grade 2+ IMAEs than male patients. Nivolumab monotherapy in adjuvant melanoma demonstrated a relatively flat E-R relationship over the range of exposures produced by 3 mg/kg every 2 weeks and predicted a comparable benefit-risk profile to flat-dosing regimens., (© 2021 Bristol Myers Squibb Co. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Employers have begun to offer voluntary workplace genomic testing (wGT) as part of employee wellness benefit programs, but few empirical studies have examined the ethical, legal, and social implications (ELSI) of wGT. To better understand employee perspectives on wGT, employees were surveyed at a large biomedical research institution. Survey respondents were presented with three hypothetical scenarios for accessing health-related genomic testing: via (1) their doctor; (2) their workplace; and 3) a commercial direct-to-consumer (DTC) genetic testing company. Overall, 594 employees (28%) responded to the survey. Respondents indicated a preference for genomic testing in the workplace setting (70%; 95% CI 66-74%), followed by doctor's office (54%; 95% CI 50-58%), and DTC testing (20%; 95% CI 17-24%). Prior to participating in wGT, respondents wanted to know about confidentiality of test results (79%), existence of relevant laws and policies (70%), and privacy protection (64%). Across scenarios, 92% of respondents preferred to view the test results with a genetic counselor. These preliminary results suggest that many employees are interested and even prefer genetic testing in the workplace and would prefer testing with support from genetic health professionals. Confirmation in more diverse employer settings will be needed to generalize such findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sanghavi, Feero, Mathews, Prince, Price, Liu, Brothers, Roberts and Lee.)

Ipilimumab is a fully human monoclonal antibody approved for the treatment of melanoma as monotherapy and for the treatment of melanoma, renal cell carcinoma, and colorectal cancer in combination with nivolumab. Ipilimumab time-varying clearance (CL) was assessed by a population pharmacokinetics (PPK) model developed using statistically significant covariates identified in a previous PPK analysis plus additional covariates. Data from 3,411 patients who received ipilimumab 0.3-10 mg/kg alone or in combination with nivolumab in 16 clinical trials were analyzed. Ipilimumab CL decreased over time; the change in CL was greater in patients treated with nivolumab combination than ipilimumab alone and in responders vs. nonresponders. Time-varying covariates including body weight, lactate dehydrogenase, albumin, and performance status were evaluated on change in ipilimumab CL. In addition, ipilimumab CL was similar across different tumor types, nivolumab dosing regimens, and lines of therapy. These data suggest an association of ipilimumab CL with disease severity., (© 2019 Bristol-Myers Squibb. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Nivolumab is a fully human monoclonal antibody that inhibits programmed cell death-1 activation. To assess covariate effects on nivolumab clearance (CL), a population pharmacokinetics model was developed using data from 6,468 patients with colorectal cancer, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, or small cell lung cancer who received nivolumab as monotherapy or in combination with ipilimumab or chemotherapy across 25 clinical studies. Nivolumab CL was similar across the tumor types examined; CL was higher for ipilimumab 1 mg/kg every 6 weeks (by 17%) and 3 mg/kg every 3 weeks (by 29%) vs. nivolumab monotherapy. Nivolumab CL over time was partially explained by time-varying covariates. A greater decrease in nivolumab time-varying CL was associated with increased albumin and body weight and a responder status. Our findings support the observed association between nivolumab CL and disease severity., (© 2019 Bristol-Myers Squibb. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The use of live video consultations in genetics has been shown to improve patient access with high satisfaction; however, little is known about the current landscape of clinical telehealth models in the field of genetics (i.e., telegenetics). This survey aimed to address that gap across seven states and the District of Columbia. Among 51 self-defined telegenetics programs responding to an online survey, 32 currently utilized live videoconferencing as at least one of their technologies (i.e., were "video-capable"). Analysis of this subgroup revealed that medical institutions were the most common program setting, and prenatal and cancer services were the most common sub-specialty. Forty-seven percent of these programs reported billing insurance for patient care. When exploring measures of patient access among these programs, 56% had a wait time of under 2 weeks, 25% saw more than 50 patients per month, 50% estimated their geographic reach at over 200 miles, and 59% were able to provide remote telegenetics consultations to patients' homes. Professional licensure was reported as the biggest barrier, and patient access and convenience were reported as the largest benefit and success. Among the 19 remaining programs, eight currently active programs exclusively used telephone technology; these were less likely to have a geneticist (p = 0.01), had a shorter wait time (p = 0.04), and had been established for a longer time (p = 0.02) when compared to video-capable programs. Further, two currently active programs indicated the use of store-and-forward telehealth. Finally, nine programs were currently planning their programs, with a focus on video-capable technologies and more varied patient specialties. We observed a diverse landscape of telehealth models being utilized to provide genetic services, and the data demonstrated that these programs are focused on enhancing patient access. Our query about telegenetics drew responses from programs that were not using live videoconferencing technology models, which prompts further exploration, and challenges us to develop consensus around the meaning of "telegenetics." Similarly, our data suggest a need for continued research to assess the equivalency, accessibility, and role of telephone consultations across genetic services. While a multitude of policy factors influence which service delivery models are utilized, further research on these varied approaches, and their associated patient outcomes, is also needed to inform program development., (© 2019 National Society of Genetic Counselors.)

Discussion of family health history (FH) has the potential to be a communication tool within families and with health providers to stimulate health promotion related to many chronic conditions, including those with genetic implications for prevention, screening, diagnosis, treatment. Diverse communities with disparities in health outcomes may require different approaches to engage individuals and families in the evolving areas of genetic risk communication, assessment, and services. This work was a partnership of a local urban agency and academic genetics professionals to increase understanding of community concerns and preferences related to FH and genetic awareness. Thirty community stakeholders in the East Baltimore area participated in structured interviews conducted by community members. We identified key themes on family health history FH, risk assessment, and genetic services. Forty-three percent (18/27) of community stakeholders thought families in East Baltimore did not discuss family health history FH with doctors. Stakeholders recognized the benefits and challenges of potential actions based on genetic risk assessment and the multiple competing priorities of families. FH awareness with community engagement and genetics education were the major needs identified by the participants. Research undertaken in active collaboration with community partners can provide enhanced consumer perspectives on the importance of family health history and its potential connections to health promotion and prevention activities.

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

Purpose: We investigated the safety, pharmacokinetics, and efficacy of gemcitabine administered via bronchial artery infusion (BAI) and IV infusion in advanced NSCLC patients., Methods: Patients were eligible if they had received at least two prior cytotoxic chemotherapy regimens. Gemcitabine was administered via BAI as 600 mg/m 2 on day one of cycle one, followed by IV as 1000 mg/m 2 on day eight of cycle one, and IV on days one and eight of all subsequent cycles. Pharmacokinetics for gemcitabine and dFdU metabolite in plasma, and dFdCTP active metabolite in peripheral blood mononuclear cells (PBMC) were evaluated. Intensive pharmacokinetic sampling was performed after BAI and IV infusions during cycle one., Results: Three male patients (age range 59-68 years) were evaluated. All patients responded with stable disease or better. One PR was observed after cycle three, and the remaining had SD. C max (mean ± SD) following BAI for gemcitabine, dFdCTP, and dFdU were 7.71 ± 0.13, 66.5 ± 40.6, and 38 ± 6.27 µM and following IV infusion, 17 ± 2.36, 50.8 ± 3.61, and 83.2 ± 12.3 µM, respectively. The AUCinf (mean ± SD) following BAI for gemcitabine, dFdCTP, and dFdU were 6.89 ± 1.2, 791.1 ± 551.2, and 829.9 ± 217.8 µM h and following IV infusion, 12.5 ± 3.13, 584 ± 86.6, and 1394.64 ± 682.2 µM h, respectively. The AUC and Cmax of dFdCTP after BAI were higher than IV. The median OS was 6.27 months. No grade 3 or 4 toxicity was observed. The most common side effects were all grade ≤ 2 involving nausea, vomiting, rigor, thrombocytopenia, and anemia., Conclusions: Systemic exposure to dFdCTP was higher after BAI than IV in two out of three patients.

Metastasis to the thyroid gland is rare; furthermore, intrathyroid metastasis from head and neck squamous cell carcinoma (SCC) is very unusual, with only nine previously documented cases four from intrathyroid metastasis from nasopharyngeal carcinoma, two from oral cavity, one each from oropharynx, larynx, and parotid. The reported case series are unique in nature and illustrates the role of fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) and ultrasound-guided biopsy in diagnosing clinically occult isolated intrathyroidal metastasis, which helps in the best management for an isolated intrathyroid metastases. This study details the cases of three patients who were diagnosed with intrathyroidal metastasis from SCC of the tongue by PET-CT, followed by USG-guided biopsy, who were treated with either surgery and or chemotherapy. Although intrathyroidal metastasis is an uncommon occurrence and signifies poor prognosis, early detection of an isolated intrathyroidal metastasis on imaging in an appropriately selected patients, radical surgery, and/or chemotherapy improve local control and quality of patient's life., Competing Interests: There are no conflicts of interest.

The rapidly increasing number of therapeutic biologics in development has led to a growing recognition of the need for improvements in immunogenicity assessment. Published data are often inadequate to assess the impact of an antidrug antibody (ADA) on pharmacokinetics, safety, and efficacy, and enable a fully informed decision about patient management in the event of ADA development. The recent introduction of detailed regulatory guidance for industry should help address many past inadequacies in immunogenicity assessment. Nonetheless, careful analysis of gathered data and clear reporting of results are critical to a full understanding of the clinical relevance of ADAs, but have not been widely considered in published literature to date. Here, we review visualization and modeling of immunogenicity data. We present several relatively simple visualization techniques that can provide preliminary information about the kinetics and magnitude of ADA responses, and their impact on pharmacokinetics and clinical endpoints for a given therapeutic protein. We focus on individual sample- and patient-level data, which can be used to build a picture of any trends, thereby guiding analysis of the overall study population. We also discuss methods for modeling ADA data to investigate the impact of immunogenicity on pharmacokinetics, efficacy, and safety.

Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches., (© 2017, The American College of Clinical Pharmacology.)

Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of nonrelapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft versus host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort, the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) <8.50 L/h (P < 0.01) and area under the curve (AUCpred) >6.00 μg × h/mL (P = 0.01). A lower Clpred was also associated with more NRM at month 6 (P = 0.01) and trended toward significance at 12 months (P = 0.05). In multivariate analysis, low fludarabine clearance trended toward higher risk of acute GVHD (P = 0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing especially in overweight individuals and those with altered kidney function., Competing Interests: All authors have read the journal's authorship agreement and policy on disclosure of conflict of interest. None of the authors have any conflicts of interest and all authors approved this publication., (Copyright © 2016 Elsevier Inc. All rights reserved.)