المؤلفون: Akinyemi Oni‐Orisan, Nithya Srinivas, Krina Mehta, Jesmin Lohy Das, Thu T. Nguyen, Geoffrey H. Tison, Scott R. Bauer, Maria Burian, Ryan S. Funk, Richard A. Graham, Biomarkers and Translational Tools Community Working Group of the American Society for Clinical Pharmacology and Therapeutics

المصدر: Clinical and Translational Science, Vol 14, Iss 3, Pp 784-790 (2021)

مصطلحات موضوعية: Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270

الوصف: Abstract Although traditional approaches to biomarker discovery have elucidated key molecular markers that have improved drug selection (precision medicine), the discovery of biomarkers that inform optimal dose selection (precision dosing) continues to be a challenge in many therapeutic areas. Larger and more diverse study populations are necessary to discover additional biomarkers that provide the resolution needed for a more tailored dose. To generate and accommodate large datasets of drug response phenotypes, time‐ and cost‐efficient strategies are necessary. In particular, a multitude of technological advances that originated for purposes outside of biomedical research (electronic health records, direct‐to‐consumer genetic testing, social media, mobile devices, and machine learning) have made it easier to communicate, connect, and gather information from consumers. Although these technologies have been used with success in the health sciences for an array of purposes, these resources have not been fully capitalized on for precision dosing. This perspective will touch on how these innovations can be used as data sources, data collection tools, and data processing tools for drug‐response phenotypes with a unique focus on advancing biomarker‐driven precision dosing.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1752-8054Test; https://doaj.org/toc/1752-8062Test

الوصول الحر: https://doaj.org/article/a38a3cf9a98f4d94ab512a4c680c3614Test

المؤلفون: Nithya Srinivas, Sarah Beth Joseph, Kevin Robertson, Laura P. Kincer, Prema Menezes, Lourdes Adamson, Amanda P. Schauer, Kimberly H. Blake, Nicole White, Craig Sykes, Paul Luciw, Joseph J. Eron, Alan Forrest, Richard W. Price, Serena Spudich, Ronald Swanstrom, Angela D.M. Kashuba

المصدر: Clinical and Translational Science, Vol 12, Iss 3, Pp 302-311 (2019)

مصطلحات موضوعية: Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270

الوصف: Sparse data exist on the penetration of antiretrovirals into brain tissue. In this work, we present a framework to use efavirenz (EFV) pharmacokinetic (PK) data in plasma, cerebrospinal fluid (CSF), and brain tissue of eight rhesus macaques to predict brain tissue concentrations in HIV‐infected individuals. We then perform exposure‐response analysis with the model‐predicted EFV area under the concentration‐time curve (AUC) and neurocognitive scores collected from a group of 24 HIV‐infected participants. Adult rhesus macaques were dosed daily with 200 mg EFV (as part of a four‐drug regimen) for 10 days. Plasma was collected at 8 time points over 10 days and at necropsy, whereas CSF and brain tissue were collected at necropsy. In the clinical study, data were obtained from one paired plasma and CSF sample of participants prescribed EFV, and neuropsychological test evaluations were administered across 15 domains. PK modeling was performed using ADAPT version 5.0 Biomedical Simulation Resource, Los Angeles, CA) with the iterative two‐stage estimation method. An eight‐compartment model best described EFV distribution across the plasma, CSF, and brain tissue of rhesus macaques and humans. Model‐predicted median brain tissue concentrations in humans were 31 and 8,000 ng/mL, respectively. Model‐predicted brain tissue AUC was highly correlated with plasma AUC (γ = 0.99, P 0.05). This analysis provides an approach to estimate PK the brain tissue in order to perform PK/pharmacodynamic analyses at the target site.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1752-8054Test; https://doaj.org/toc/1752-8062Test

الوصول الحر: https://doaj.org/article/5ca79d0690d344ad8e6aa2ae8ce87005Test

المؤلفون: Madan Jagasia, Karl Staser, Michael Pratta, Gary J. Schiller, Jaebok Choi, Yi-Bin Chen, Peter Langmuir, Gabrielle Meyers, Miguel-Angel Perales, Haris Ali, Leah Gehrs, Ying Yan, H. Jean Khoury, Nithya Srinivas, John F. DiPersio, Mark A. Schroeder, Michael C. Arbushites

المصدر: Blood advances, vol 4, iss 8

مصطلحات موضوعية: Adult, medicine.medical_specialty, Adolescent, Anemia, medicine.medical_treatment, Clinical Trials and Supportive Activities, Graft vs Host Disease, Hematopoietic stem cell transplantation, Gastroenterology, law.invention, Rare Diseases, Randomized controlled trial, Adrenal Cortex Hormones, Stem Cell Research - Nonembryonic - Human, Clinical Research, law, hemic and lymphatic diseases, Internal medicine, Clinical endpoint, Humans, Medicine, Adverse effect, Protein Kinase Inhibitors, 6.2 Cellular and gene therapies, Transplantation, business.industry, Hematopoietic Stem Cell Transplantation, Evaluation of treatments and therapeutic interventions, Janus Kinase 1, Hematology, Stem Cell Research, medicine.disease, Clinical trial, Orphan Drug, surgical procedures, operative, Tolerability, 6.1 Pharmaceuticals, Steroids, business

الوصف: Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1–selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4387f96205dd71cf94603607ea441257Test
https://doi.org/10.1182/bloodadvances.2019001043Test

المؤلفون: Susan Petusky, Brad Yuska, Zhinyin Xun, Gongfu Zhou, Nithya Srinivas, April M. Barbour, Thomas Marbury, Naresh Punwani, Xuejun Chen, Noam Epstein, Swamy Yeleswaram

المصدر: Journal of Clinical Pharmacology

مصطلحات موضوعية: renal impairment, Adult, Male, medicine.medical_specialty, Acetonitriles, graft‐versus‐host disease, medicine.medical_treatment, itacitinib, Urology, Urine, Kidney, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Renal Dialysis, Dialysis Solutions, medicine, Humans, NON COVID RELATED ARTICLES, Pyrroles, Pharmacology (medical), Renal Insufficiency, Dosing, Adverse effect, Janus kinase inhibitor, Protein Kinase Inhibitors, Dialysis, Aged, Pharmacology, business.industry, Blood Proteins, Janus Kinase 1, Middle Aged, Confidence interval, Special Populations, Renal Elimination, Pyrimidines, Area Under Curve, 030220 oncology & carcinogenesis, dialysis, Pyrazoles, Female, Hemodialysis, business, pharmacokinetics, Protein Binding

الوصف: Itacitinib is a novel, selective, Janus kinase 1 inhibitor in development for treatment of graft‐versus‐host disease. The objective of this study was to assess pharmacokinetics and safety of 300‐mg itacitinib dosed in participants with normal renal function (n = 10), severe renal impairment (n = 8), and end‐stage renal disease (ESRD) on hemodialysis (n = 8). Serial plasma and urine samples (urine from normal and severe groups only) were collected before dosing until 72 hours after dosing. In the ESRD group, itacitinib was evaluated in 2 periods, when dosed before (period 1) and after (period 2) a hemodialysis session. Geometric mean ratios (90% confidence interval) in participants with severe renal impairment, ESRD period 1 and ESRD period 2 relative to participants with normal renal function were 1.65 (1.13‐2.39), 0.71 (0.49‐1.03), and 0.83 (0.57‐1.20) for maximum plasma drug concentration and 2.23 (1.56‐3.18), 0.81 (0.57‐1.16), and 0.95 (0.66‐1.35) for area under the plasma concentration–time curve from time zero to infinity. Itacitinib was well tolerated, and 3 grade 1 treatment‐emergent adverse events were reported over the course of the study. Given the magnitude of exposure changes in participants with severe renal impairment or ESRD and the historic risk‐benefit profile, no dose adjustment is recommended for itacitinib in patients with impaired renal function, although the final dosage recommendation will be based on cumulative pharmacokinetics and safety from this study and from the pivotal graft‐versus‐host disease trial. Additionally, itacitinib may be administered to patients undergoing dialysis regardless of the time of dialysis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ed82052940b518d1ca6844fcdc4e898bTest
https://doi.org/10.1002/jcph.1601Test

المؤلفون: Amer M. Zeidan, Rachel J. Cook, Rodolfo Bordoni, James R. Berenson, William J. Edenfield, Sanjay Mohan, Gongfu Zhou, Ekaterine Asatiani, Nithya Srinivas, Michael R. Savona

المصدر: Clinical lymphoma, myelomaleukemia. 22(7)

مصطلحات موضوعية: Cancer Research, Acetonitriles, Hematology, Janus Kinase 1, Leukemia, Myeloid, Acute, Pyrimidines, Oncology, Hematologic Neoplasms, Myelodysplastic Syndromes, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Humans, Janus Kinase Inhibitors, Pyrazoles, Pyrroles

الوصف: The Janus kinase (JAK)/signal transducers and activators of transcription pathway has been implicated in the pathogenesis and progression of various hematologic malignancies. JAK1-regulated cytokines stimulate proliferation and growth of malignant cells and resistance to certain therapies.This phase 1/2 study evaluated 2 oral, novel JAK1 inhibitors (INCB052793 and itacitinib) in advanced hematologic malignancies. Phase 1a assessed dose escalation and expansion of INCB052793 monotherapy. Phase 1b evaluated INCB052793 plus standard therapy in relapsed/refractory multiple myeloma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). Phase 2 evaluated INCB052793 or itacitinib plus azacitidine in DNA methyltransferase inhibitor (DNMTi)-refractory AML or MDS. Primary endpoints included safety and tolerability for phase 1, and objective response rate for phase 2.Fifty-eight patients were enrolled, all received study treatment and discontinued either treatment or participation in the study. The most common reasons for treatment discontinuation were progressive disease (35.4% and 50.0%) and adverse events (22.9% and 20.0%) for INCB052793 and itacitinib plus azacitidine, respectively. In phase 1, 12 of 39 patients (31%) achieved an objective response; 35 mg once daily was selected as the phase 2 dose. Two patients with DNMTi-refractory disease had an objective response in phase 2. The study was terminated for lack of efficacy.Inhibition of JAK1 with INCB052793 (monotherapy or combination therapy) or itacitinib plus azacitidine did not demonstrate clinically meaningful responses in these patients with hematopoietic malignancies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::72a596a4e7e09dc03674d62c394704e3Test
https://pubmed.ncbi.nlm.nih.gov/35260349Test

المؤلفون: Thu T. Nguyen, Ryan S. Funk, Krina Mehta, Scott R. Bauer, Jesmin Lohy Das, Nithya Srinivas, Akinyemi Oni-Orisan, Richard A Graham, Therapeutics, Geoffrey H. Tison, Maria Burian

المصدر: Clinical and Translational Science
Clinical and translational science, vol 14, iss 3
Clinical and Translational Science, Vol 14, Iss 3, Pp 784-790 (2021)

مصطلحات موضوعية: 030213 general clinical medicine, Computer science, Oncology and Carcinogenesis, Datasets as Topic, RM1-950, Cardiorespiratory Medicine and Haematology, 030226 pharmacology & pharmacy, General Biochemistry, Genetics and Molecular Biology, Machine Learning, 03 medical and health sciences, 0302 clinical medicine, medicine, Electronic Health Records, Humans, Dosing, General Pharmacology, Toxicology and Pharmaceutics, Biomarker discovery, Precision Medicine, General Clinical Medicine, Selection (genetic algorithm), Genetic testing, Data collection, Biomarkers and Translational Tools Community Working Group of the American Society for Clinical Pharmacology and Therapeutics, Other Medical and Health Sciences, medicine.diagnostic_test, Dose-Response Relationship, Drug, General Neuroscience, General Medicine, Precision medicine, Data science, ComputingMethodologies_PATTERNRECOGNITION, Treatment Outcome, Biomarker (medicine), Therapeutics. Pharmacology, Position Paper, Public aspects of medicine, RA1-1270, Mobile device, Biomarkers

الوصف: Although traditional approaches to biomarker discovery have elucidated key molecular markers that have improved drug selection (precision medicine), the discovery of biomarkers that inform optimal dose selection (precision dosing) continues to be a challenge in many therapeutic areas. Larger and more diverse study populations are necessary to discover additional biomarkers that provide the resolution needed for a more tailored dose. To generate and accommodate large datasets of drug response phenotypes, time‐ and cost‐efficient strategies are necessary. In particular, a multitude of technological advances that originated for purposes outside of biomedical research (electronic health records, direct‐to‐consumer genetic testing, social media, mobile devices, and machine learning) have made it easier to communicate, connect, and gather information from consumers. Although these technologies have been used with success in the health sciences for an array of purposes, these resources have not been fully capitalized on for precision dosing. This perspective will touch on how these innovations can be used as data sources, data collection tools, and data processing tools for drug‐response phenotypes with a unique focus on advancing biomarker‐driven precision dosing.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7c83bb8ef325bce0407b760633d03c56Test
https://pubmed.ncbi.nlm.nih.gov/33421282Test

المؤلفون: Erin M. Burgunder, Lourdes Adamson, Craig Sykes, Kimberly Blake, Ramesh Akkina, Martina Kovarova, Aaron S. Devanathan, Nithya Srinivas, Nicole White, J. Victor Garcia, Jason R. Pirone, Paul A. Luciw, Angela D. M. Kashuba, Leila Remling-Mulder, Amanda P. Schauer, Elias P. Rosen

المصدر: Antimicrob Agents Chemother

مصطلحات موضوعية: Tissue concentrations, Anti-HIV Agents, Atazanavir Sulfate, Human immunodeficiency virus (HIV), HIV Infections, In Vitro Techniques, medicine.disease_cause, Maraviroc, 03 medical and health sciences, Mice, Pharmacokinetics, immune system diseases, Raltegravir Potassium, medicine, Animals, Emtricitabine, Humans, Pharmacology (medical), Dosing, Hiv treatment, Tenofovir, 030304 developmental biology, Pharmacology, 0303 health sciences, 030306 microbiology, business.industry, virus diseases, Penetration (firestop), Infectious Diseases, Anti-Retroviral Agents, Immunology, Female, business

الوصف: For HIV cure strategies like "kick and kill" to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of six ARVs in three preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some, but not all, ARVs. These results have implications for interpreting HIV treatment, prevention, or cure interventions between preclinical and clinical models.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a624af0134b107057c8fec400d2996a6Test
https://europepmc.org/articles/PMC7187610Test/

المؤلفون: Nicholas J. Shaheen, Angela D. M. Kashuba, Craig Sykes, Nithya Srinivas, Nicole White, Kaitlyn A. Maffuid, Julie A. E. Nelson, Daniel Gonzalez, Ryan D. Madanick, Heather M.A. Prince, Mackenzie L. Cottrell, Evan S. Dellon

المصدر: Antimicrob Agents Chemother

مصطلحات موضوعية: Oncology, Drug, CD4-Positive T-Lymphocytes, medicine.medical_specialty, Tenofovir, Anti-HIV Agents, media_common.quotation_subject, Population, Human immunodeficiency virus (HIV), HIV Infections, 030312 virology, Emtricitabine, medicine.disease_cause, Reproductive Tract Infections, Cohort Studies, Maraviroc, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Pharmacology (medical), Computer Simulation, 030212 general & internal medicine, Dosing, education, media_common, Demography, Pharmacology, 0303 health sciences, education.field_of_study, business.industry, Infectious Diseases, Treatment Outcome, chemistry, Drug Therapy, Combination, Female, Pre-Exposure Prophylaxis, business, Exposure data, medicine.drug

الوصف: Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated in vitro, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24 healthy women. The 90% effective concentrations (EC(90)) of maraviroc (alone and combined with tenofovir and emtricitabine) for protection against HIV were identified in CD4(+) T cells. Monte Carlo simulations were performed to identify dosing strategies to protect colorectal and female genital tract (FGT) tissues from HIV infection. Colorectal maraviroc concentrations were 350-fold higher than in the FGT. Under steady-state conditions, our model predicted that one 300-mg dose/week was sufficient to protect colorectal tissue from HIV in 99% of the population, while 300 mg daily would protect the FGT in only 63% of the population. FGT protection increased to >90% when maraviroc was used in combination with tenofovir (5 doses/week) or emtricitabine (3 doses/week). Poor adherence resulted in a drastic decrease in efficacy in the FGT but not colorectal tissue. However, greater forgiveness was seen when maraviroc was combined with tenofovir or emtricitabine, suggesting that maraviroc should not be used alone as PrEP.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::42ff1ac24f29b95f4ddc47a42073ba37Test
https://pubmed.ncbi.nlm.nih.gov/31740561Test

المؤلفون: Nicole White, Nithya Srinivas, Craig Sykes, William M. Gilliland, Leila Remling-Mulder, Gabriela De la Cruz, Elias P. Rosen, Lourdes Adamson, J. Victor Garcia, Ramesh Akkina, Angela D. M. Kashuba, Martina Kovarova, Paul A. Luciw, Amanda P. Schauer

المصدر: Xenobiotica

مصطلحات موضوعية: Cyclopropanes, Male, Pathology, medicine.medical_specialty, Efavirenz, Anti-HIV Agents, Health, Toxicology and Mutagenesis, Human immunodeficiency virus (HIV), Drug Evaluation, Preclinical, HIV Infections, Brain tissue, Toxicology, medicine.disease_cause, 030226 pharmacology & pharmacy, Biochemistry, Mass spectrometry imaging, Article, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cerebrospinal fluid, medicine, Animals, Humans, Pharmacology, business.industry, Brain, General Medicine, Macaca mulatta, Benzoxazines, chemistry, 030220 oncology & carcinogenesis, Alkynes, HIV-1, Female, business

الوصف: 1. Antiretroviral concentrations in cerebrospinal fluid (CSF) are used as surrogate for brain tissue, although sparse data support this. We quantified antiretrovirals in brain tissue across preclinical models, compared them to CSF, and calculated 90% inhibitory quotients (IQ90) for nonhuman primate (NHP) brain tissue. Spatial distribution of efavirenz was performed by mass-spectrometry imaging (MSI). 2. HIV or RT-SHIV-infected and uninfected animals from two humanized mouse models (hemopoietic-stem cell/RAG2-, n = 36; bone marrow-liver-thymus/BLT, n =13) and an NHP model (rhesus macaque, n =18) were dosed with six antiretrovirals. Brain tissue, CSF (NHPs), and plasma were collected at necropsy. Drug concentrations were measured by LC-MS/MS. Rapid equilibrium dialysis determined protein binding in NHP brain. 3. Brain tissue penetration of most antiretrovirals were >10-fold lower (p 13-fold lower (p r = 0.91, p = 0.001). Despite 97% brain tissue protein binding, efavirenz achieved IQ90>1 in all animals and 2-fold greater white versus gray matter concentration. 4. Brain tissue penetration varied across animal models for all antiretrovirals except raltegravir, and extrapolating brain tissue concentrations between models should be avoided. With the exception of efavirenz, CSF is not a surrogate for brain tissue concentrations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b6bf5de8a180383d76aa100f1d1714a4Test
https://europepmc.org/articles/PMC6579712Test/

المؤلفون: Nithya Srinivas, Angela D. M. Kashuba, Kaitlyn A. Maffuid

المصدر: Clinical pharmacokinetics. 57(9)

مصطلحات موضوعية: Intracellular Fluid, Psychosis, Central nervous system, Disease, Bioinformatics, 030226 pharmacology & pharmacy, Models, Biological, Article, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Pharmacokinetics, Drug Development, Medicine, Animals, Humans, Pharmacology (medical), Computer Simulation, Tissue Distribution, Pharmacology, business.industry, Brain, Extracellular Fluid, medicine.disease, Clinical trial, medicine.anatomical_structure, Drug development, Pharmacodynamics, business, 030217 neurology & neurosurgery, Biomarkers, Central Nervous System Agents

الوصف: Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS-therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PKPD) such as lack of efficacy or improper selection of initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PKPD from animal models as well as choose the appropriate dose. In this review, we summarize available literature from human studies on the pharmacokinetics and pharmacodynamics in brain tissue, cerebrospinal fluid and interstitial fluid for drugs used in the treatment of psychosis, Alzheimer’s disease and neuro-HIV and address critical questions in the field. We also explore newer methods to characterize pharmacokinetic/pharmacodynamic relationships that may lead to more efficient dose selection in CNS drug development.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::66ec20e1467f82a0b2d9fbe025bc7295Test
https://pubmed.ncbi.nlm.nih.gov/29464550Test