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Journals Clinical Pharmacology and Ther...

Clinical Pharmacology and Therapeutics

https://read.qxmd.com/read/38864678/attaining-equity-of-access-to-research-perspective-on-research-in-pregnancy-and-breastfeeding-following-dolores-shockley-lecture-at-ascpt2024
#1
REVIEW
Catriona Waitt, Simon Peter Asiimwe, Francis Williams Ojara, Ritah Nakijoba, Aida N Kawuma, Barbara Castelnuovo
Everybody deserves access to evidence-based information to make decisions about their health. However, in many situations, clinical trial eligibility criteria mean that specific data do not exist for certain groups of individuals. These include pregnant and breastfeeding women, children, older people, those with hepatic and renal dysfunction, those with acute severe illness, and those with multiple co-morbidities and interacting medications. Resultantly, there may not be specific drug-dosing information for many patients who are treated in a clinical setting...
June 12, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38864600/identification-of-a-safe-and-tolerable-carbamazepine-dosing-paradigm-that-facilitates-effective-evaluation-of-cyp3a4-induction
#2
JOURNAL ARTICLE
Amita Datta-Mannan, Elaine Shanks, Eunice Yuen, Yan Jin, Jessica Rehmel, Stephen David Hall
Carbamazepine (CBZ) is the recommended alternative to rifampicin as a CYP3A4 inducer in drug-drug interaction studies. However, the traditional CBZ dosing paradigm can lead to several adverse events (AEs). This study tested a shorter CBZ dosing regimen using the CYP3A4-sensitive index substrate midazolam (MDZ). This was a fixed-sequence arm of an open-label, phase I study (NCT04840888). Healthy participants (n = 15) aged 18-63 years received oral doses of 1.2 mg MDZ alone (Day 1), CBZ b...
June 12, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38863261/advances-in-clinical-therapies-for-huntington-s-disease-and-the-promise-of-multi-targeted-functional-drugs-based-on-clinicaltrials-gov
#3
REVIEW
Chunhui Huang, Xiao Zheng, Sen Yan, Zaijun Zhang
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a triad of motor, cognitive, and psychiatric problems. Caused by CAG repeat expansion in the huntingtin gene (HTT), the disease involves a complex network of pathogenic mechanisms, including synaptic dysfunction, impaired autophagy, neuroinflammation, oxidative damage, mitochondrial dysfunction, and extrasynaptic excitotoxicity. Although current therapies targeting the pathogenesis of HD primarily aim to reduce mHTT levels by targeting HTT DNA, RNA, or proteins, these treatments only ameliorate downstream pathogenic effects...
June 11, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38863207/clinical-pharmacogenetics-implementation-consortium-guideline-for-cyp2b6-genotype-and-methadone-therapy
#4
REVIEW
Katherine M Robinson, Seenae Eum, Zeruesenay Desta, Rachel F Tyndale, Andrea Gaedigk, Richard C Crist, Cyrine E Haidar, Alan L Myers, Caroline F Samer, Andrew A Somogyi, Pablo Zubiaur, Otito F Iwuchukwu, Michelle Whirl-Carrillo, Teri E Klein, Kelly E Caudle, Roseann S Donnelly, Evan D Kharasch
Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP)...
June 11, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38863178/population-pharmacokinetic-and-exposure-response-modeling-to-inform-risankizumab-dose-selection-in-patients-with-ulcerative-colitis
#5
JOURNAL ARTICLE
Neha Thakre, Aline Goebel, Insa Winzenborg, Ahmed A Suleiman, Ronilda D'Cunha, Sven Mensing, Wei Liu, Yinuo Pang
Data from phase IIb/III and phase III studies were used to characterize the population pharmacokinetics of risankizumab and its exposure-response relationships for efficacy and safety in ulcerative colitis (UC) patients. A two-compartment model with first-order absorption and elimination accurately described risankizumab pharmacokinetics. Although certain covariates, namely, body weight, serum albumin, fecal calprotectin, sex, corticosteroid use, advanced therapy inadequate response, and pancolitis, were statistically correlated with risankizumab clearance, their impact on exposure was not clinically meaningful for efficacy or safety...
June 11, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38860726/corrigendum-comparative-effectiveness-of-bimekizumab-in-psoriatic-arthritis-a-model-based-meta-analysis-of-american-college-of-rheumatology-response-criteria
#6
(no author information available yet)
No abstract text is available yet for this article.
June 11, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38860403/thinking-three-dimensionally-a-self-and-externally-controlled-approach-to-screening-for-drug-drug-drug-interactions-among-high-risk-populations
#7
JOURNAL ARTICLE
Emily K Acton, Sean Hennessy, Michael A Gelfand, Charles E Leonard, Warren B Bilker, Di Shu, Allison W Willis, Scott E Kasner
The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2)...
June 11, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38860384/comprehensive-evaluation-of-oatp-and-bcrp-mediated-drug-drug-interactions-of-methotrexate-using-physiologically-based-pharmacokinetic-modeling
#8
JOURNAL ARTICLE
Sejung Hwang, Yujin Lee, Yeonseo Jang, Joo-Youn Cho, Seonghae Yoon, Jae-Yong Chung
Methotrexate (MTX) is an antifolate agent widely used for treating conditions such as rheumatoid arthritis and hematologic cancer. This study aimed to quantitatively interpret the drug-drug interactions (DDIs) of MTX mediated by drug transporters using physiologically-based pharmacokinetic (PBPK) modeling. An open-label, randomized, 4-treatment, 6-sequence, 4-period crossover study was conducted to investigate the effects of rifampicin (RFP), an inhibitor of organic anionic transporting peptides (OATP) 1B1/3, and febuxostat (FBX), an inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics of MTX in healthy volunteers...
June 11, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38859656/pharmacogenetics-of-efavirenz-exposure-in-cervicovaginal-fluid-during-pregnancy-and-postpartum
#9
JOURNAL ARTICLE
Oluwasegun Eniayewu, Uche Azuka, Jonah Ogah, Ebunoluwa Adejuyigbe, Oluseye Bolaji, Adeniyi Olagunju
In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy. Women receiving efavirenz-containing antiretroviral therapy were recruited from two hospitals in Nigeria during 2017-2020. Sparse CVF and plasma samples were obtained during pregnancy to assess the possible association between drug concentration and CYP2B6 polymorphisms (stage I). Participants were stratified into three CYP2B6 516G>T (rs3745274) genotype groups and re-enrolled for intensive pharmacokinetic sampling (stage II)...
June 10, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38847597/beyond-mabel-an-integrative-approach-to-first-in-human-dose-selection-of-immunomodulators-by-the-health-and-environmental-sciences-institute-hesi-immuno-safety-technical-committee-itc
#10
REVIEW
Mineo Matsumoto, Joseph Ryan Polli, Suresh K Swaminathan, Kaushik Datta, Cris Kampershroer, Marie C Fortin, Smita Salian-Mehta, Rutwij Dave, Zheng Yang, Payal Arora, Masanori Hiura, Mizuho Suzuki, Frank R Brennan, Jean Sathish
Administration of a new drug candidate in a first-in-human (FIH) clinical trial is a particularly challenging phase in drug development and is especially true for immunomodulators, which are a diverse and complex class of drugs with a broad range of mechanisms of action and associated safety risks. Risk is generally greater for immunostimulators, in which safety concerns are associated with acute toxicity, compared to immunosuppressors, where the risks are related to chronic effects. Current methodologies for FIH dose selection for immunostimulators are focused primarily on identifying the minimum anticipated biological effect level (MABEL), which has often resulted in sub-therapeutic doses, leading to long and costly escalation phases...
June 7, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38847591/clinical-pharmacology-of-glucagon
#11
REVIEW
Mohamad M Kronfol, Edwin C Chow, S W Johnny Lau, Mohamed I Nounou, Jayabharathi Vaidyanathan, Shirley K Seo
Glucagon was discovered about a hundred years ago and its role in health and disease is under continuous investigation. Glucagon is a counter regulatory hormone secreted by alpha cells of the pancreas in response to multiple stimuli. Although some of glucagon's actions and its clinical application have been described, clinical experience with glucagon has been historically overshadowed by that of insulin. To date, the role of glucagon's actions in pharmacotherapy has been under explored. Glucagon plays a considerable role as a hormonal regulator via its known actions on the liver...
June 7, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38842030/medications-and-acute-hemolysis-in-g6pd-deficient-patients-a-real-world-study
#12
JOURNAL ARTICLE
Naomi Gronich, Bar Rosh, Nili Stein, Walid Saliba
Many drug labels contain precautions of use in G6PD-deficient patients due to hemolytic concerns, but much of this is based on scarce clinical, epidemiological, or structural data. In this real-world study, we aimed to examine if the administration of presumably risky medications for G6PD-deficient patients was followed by hemolysis. The study is based on data from Clalit Health Services database that provides inclusive health care for more than half of the Israeli population (~ 4.7 million). Within the database, we identified all G6PD-deficient patients by G6PD <6 U/g Hb...
June 6, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38837390/mapping-the-pharmacogenetic-landscape-in-a-ugandan-population-implications-for-personalized-medicine-in-an-underrepresented-population
#13
JOURNAL ARTICLE
Sumudu Rangika Samarasinghe, Seung-Been Lee, Manuel Corpas, Segun Fatumo, Henk-Jan Guchelaar, Shivashankar H Nagaraj
Africans are extremely underrepresented in global genomic research. African populations face high burdens of communicable and non-communicable diseases and experience widespread polypharmacy. As population-specific genetic studies are crucial to understanding unique genetic profiles and optimizing treatments to reduce medication-related complications in this diverse population, the present study aims to characterize the pharmacogenomics profile of a rural Ugandan population. We analyzed low-pass whole genome sequencing data from 1998 Ugandans to investigate 18 clinically actionable pharmacogenes in this population...
June 4, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38825990/clinical-pharmacology-strategies-for-bispecific-antibody-development-learnings-from-fda-approved-bispecific-antibodies-in-oncology
#14
REVIEW
KyoungSoo Lim, Xu Sue Zhu, Diansong Zhou, Song Ren, Alex Phipps
Bispecific antibodies, by enabling the targeting of more than one disease-associated antigen or engaging immune effector cells, have both advantages and challenges compared with a combination of two different biological products. As of December 2023, there are 11 U.S. Food and Drug Administration-approved BsAb products on the market. Among these, 9 have been approved for oncology indications, and 8 of these are CD3 T-cell engagers. Clinical pharmacology strategies, including dose-related strategies, are critical for bispecific antibody development...
June 2, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38822554/discovery-and-model-informed-drug-development-of-a-controlled-release-formulation-of-nonracemic-amisulpride-that-reduces-plasma-exposure-but-achieves-pharmacodynamic-bioequivalence-in-the-brain
#15
JOURNAL ARTICLE
Seth C Hopkins, Siriporn Toongsuwan, Taryn J Corriveau, Takao Watanabe, Yuki Tsushima, Takumi Asada, Robert Lew, Lei Shi, Vanessa Zann, Thomas J Snowden, Piet H van der Graaf, Borje Darpo, Graham E Searle, Eugenii A Rabiner, Ian Wilding, Steven T Szabo, Gerald R Galluppi, Kenneth S Koblan
Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects...
May 31, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38818726/direct-comparison-of-the-effectiveness-and-safety-among-direct-oral-anticoagulants-and-warfarin-in-japanese-patients-nationwide-cohort-study-in-japan
#16
JOURNAL ARTICLE
Saki Katayama, Yuka Aoki, Ayu Akita, Rino Satake, Masahiro Tohkin
Direct oral anticoagulant drugs (DOACs) are available in addition to warfarin for the treatment of patients with non-valvular atrial fibrillation (NVAF). Anticoagulants are useful for practical pharmacotherapy in Asian populations, but their responses are different from those in Caucasian populations. Therefore, we aimed to identify the most useful anticoagulant using a nationwide insurance claims database in Japan. We extracted information on patients with NVAF treated with DOACs or warfarin for the first time between September 2015 and February 2018 to conduct a retrospective observational cohort study using the claims database of Japan...
May 31, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38803056/risk-versus-benefit-of-tyrosine-kinase-inhibitors-for-hepatocellular-carcinoma-a%C3%A2-systematic-review-and-meta-analysis-of-randomized-controlled-trials
#17
REVIEW
Tania Payo-Serafín, Carolina Méndez-Blanco, Paula Fernández-Palanca, Jennifer Martínez-Geijo, María Reviejo, Juan José Ortiz-de-Urbina, Javier González-Gallego, Jose J G Marin, José L Mauriz, Beatriz San-Miguel
Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16...
May 27, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38797995/integrating-clinical-variability-into-pbpk-models-for-virtual-bioequivalence-of-single-and-multiple-doses-of-tofacitinib-modified-release-dosage-form
#18
JOURNAL ARTICLE
Vivek Purohit, Kazuko Sagawa, Hao-Jui Hsu, Joseph Kushner, Martin E Dowty, Susanna Tse, Jian Lin, Andrew Blanchard, Arnab Mukherjee, Vu Le, Cheng Chang
Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate-release (IR) tablets, modified-release (MR) tablets, and IR solution. A once daily MR microsphere formulation was developed for use in pediatric patients. Demonstration of bioequivalence (BE) between the 10 mg once daily (q.d.) MR microsphere formulation and 5 mg twice daily (b...
May 26, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38797987/use-of-cyp2d6-inhibitors-with-cyp2d6-opioids-association-with-emergency-department-visits-for-pain
#19
JOURNAL ARTICLE
Noor Ahmed Nahid, Caitrin W McDonough, Yu-Jung Jenny Wei, Emily J Cicali, Yan Gong, Roger B Fillingim, Julie A Johnson
Hydrocodone, tramadol, codeine, and oxycodone are commonly prescribed opioids that rely on activation by cytochrome P450 2D6 (CYP2D6). CYP2D6 inhibitors can significantly decrease CYP2D6 activity, leading to reduced generation of active metabolites, and impairing pain control. To understand this impact, we assessed emergency department (ED) visits in patients initiating these CYP2D6-dependent opioids while on CYP2D6-inhibitor antidepressants vs. antidepressants that do not inhibit CYP2D6. This retrospective cohort study included adult patients prescribed CYP2D6-dependent opioids utilizing electronic health records data from the University of Florida Health (2015-2021)...
May 26, 2024: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/38797892/mirikizumab-exposure-response-relationships-in-patients-with-moderately-to-severely-active-ulcerative-colitis-in-randomized-phase-ii-and-iii-studies
#20
JOURNAL ARTICLE
Stuart Friedrich, Laiyi Chua, David H Adams, Wallace Crandall, Xin Cindy Zhang
Mirikizumab is a humanized anti-interleukin-23p19 monoclonal antibody being developed for ulcerative colitis (UC) and Crohn's disease. We characterized the relationship of mirikizumab systemic exposure with efficacy and safety end points in patients with UC using phase II (NCT02589665) and III (NCT03518086, NCT03524092) trial data. Exposure-response models were developed for clinical remission, clinical response, endoscopic remission, and change in modified Mayo score following induction (50-1,000 mg i...
May 26, 2024: Clinical Pharmacology and Therapeutics
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