Clinical Pharmacology and Therapeutics This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Pharmacologic heterogeneity and risk of severe hypoglycemia with concomitant use of sulfonylureas and DPP-4 inhibitors: population-based cohort study
Clin Pharmacol Ther. 2023 Jun 16. doi: 10.1002/cpt.2975. Online ahead of print.ABSTRACTDipeptidyl peptidase-4 inhibitors (DPP-4i) interact with sulfonylureas to increase their risk of hypoglycemia. Our population-based study assessed whether intra-class pharmacologic heterogeneity among sulfonylureas (long- versus short-acting) and DPP-4i (peptidomimetic versus non-peptidomimetic) modifies this interaction. We conducted a cohort study using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data. We assembled a cohort of patients initiating sulfonylureas (2007-2020). Using a t...
Source: Clinical Pharmacology and Therapeutics - June 16, 2023 Category: Drugs & Pharmacology Authors: Jenny Dimakos Ying Cui Robert W Platt Christel Renoux Kristian B Filion Antonios Douros Source Type: research

T1dCteGui: A User-Friendly Clinical Trial Enrichment Tool to Optimize T1D Prevention Studies by Leveraging AI/ML based Synthetic Patient Population
Clin Pharmacol Ther. 2023 Jun 16. doi: 10.1002/cpt.2976. Online ahead of print.ABSTRACTWhile islet autoantibodies (AAs) are well established risk factors for developing type 1 diabetes (T1D), there is a lack of biomarkers endorsed by regulators to enrich clinical trial populations for those at risk of developing T1D. As such, the development of therapies that delay or prevent the onset of T1D remains challenging. To address this drug development need, the Critical Path Institute's T1D Consortium (T1DC) acquired patient-level data from multiple observational studies and used a model-based approach to evaluate the utility of...
Source: Clinical Pharmacology and Therapeutics - June 16, 2023 Category: Drugs & Pharmacology Authors: Mike Pauley Nick Henscheid Sarah E David Stephen R Karpen Klaus Romero Jagdeep T Podichetty Type 1 Diabetes Consortium (T1DC) Source Type: research

Model-Informed Approaches and Innovative Clinical Trial Design for Adeno-Associated Viral Vector-based Gene Therapy Product Development - A White Paper
Clin Pharmacol Ther. 2023 Jun 14. doi: 10.1002/cpt.2972. Online ahead of print.ABSTRACTThe promise of viral vector-based gene therapy as a transformative paradigm for treating severely debilitating and life-threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno-associated virus (AAV) vector-based gene therapies. Because of the irreversible mode of action and incomplete und...
Source: Clinical Pharmacology and Therapeutics - June 14, 2023 Category: Drugs & Pharmacology Authors: Amitava Mitra Mariam A Ahmed Rajesh Krishna Kefeng Sun Francis D Gibbons Olivia Campagne Noha Rayad Youssef M Roman Salwa Albusaysi Maria Burian Islam Younis Source Type: research

Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants
Clin Pharmacol Ther. 2023 Jun 14. doi: 10.1002/cpt.2973. Online ahead of print.ABSTRACTUnderstanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults. Participant received, in a randomized cross-over manner (separated by ≥1 wee...
Source: Clinical Pharmacology and Therapeutics - June 14, 2023 Category: Drugs & Pharmacology Authors: Sumit Bansal C Austin Zamarripa Tory R Spindle Elise M Weerts Kenneth E Thummel Ryan Vandrey Mary F Paine Jashvant D Unadkat Source Type: research

Methotrexate Polyglutamates Exposure - Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients starting Methotrexate
Clin Pharmacol Ther. 2023 Jun 14. doi: 10.1002/cpt.2974. Online ahead of print.ABSTRACTMethotrexate polyglutamates (MTX-PG) concentrations in red blood cells (RBC) have been suggested as a biomarker of response in rheumatoid arthritis (RA) patients receiving low-dose MTX therapy. We investigated the association and inter-patient variability between RBC-MTX-PG3-5 -exposure and response in RA patients starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score (DAS28) was analysed using a population pharmacokinetic-pharmacodynamic (PKPD) model. Relevant covaria...
Source: Clinical Pharmacology and Therapeutics - June 14, 2023 Category: Drugs & Pharmacology Authors: Renske C F Hebing Imke H Bartelink Helen Gosselt Sandra G Heil Mauritis C F J de Rotte Pascal H P de Jong Mike T Nurmohamed Robert de Jonge Ron A A Math ôt Source Type: research

Clinical Pharmacogenomic MT-RNR1 Screening for Aminoglycoside-Induced Ototoxicity and the Post-Test Counseling Conundrum
Clin Pharmacol Ther. 2023 May 4. doi: 10.1002/cpt.2910. Online ahead of print.ABSTRACTAminoglycoside antibiotic exposure can result in ototoxicity and irreversible hearing loss among individuals that harbor the m.1555A>G variant in the mitochondrial 12S rRNA gene, MT-RNR1. Importantly, pre-emptive m.1555A>G screening has been shown to reduce the prevalence of pediatric aminoglycoside-induced ototoxicity; however, professional guidelines to support and guide post-test pharmacogenomic counseling in this context are not currently available. This Perspective highlights key issues with delivering MT-RNR1 results, includin...
Source: Clinical Pharmacology and Therapeutics - June 14, 2023 Category: Drugs & Pharmacology Authors: Robert Rigobello Jay Shaw Daniel Ilg Rebekah Zimmerman Lisa Edelmann Ruth Kornreich Stuart A Scott Neal Cody Source Type: research

Model-informed Precision Dosing Guidance of Ethosuximide Developed From a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy
This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance. Dose titration occurred over a 16-20-week period until patients experienced seizure-freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population PK model was created using plasma concentration data (n=1320), collected at 4 week-intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis wa...
Source: Clinical Pharmacology and Therapeutics - June 14, 2023 Category: Drugs & Pharmacology Authors: Kana Mizuno Edmund V Capparelli Tsuyoshi Fukuda Min Dong Peter C Adamson Jeffery L Blumer Avital Cnaan Peggy O Clark Michael D Reed Shlomo Shinnar Alexander A Vinks Tracy A Glauser Childhood Absence Epilepsy Study Group Source Type: research