Do All Histamine2-Antagonists Cause a Warfarin Drug Interaction?

DICP ◽  
1989 ◽  
Vol 23 (9) ◽  
pp. 675-679 ◽  
Author(s):  
Dennis F. Thompson ◽  
Marsha A. Raebel ◽  
Elizabeth K. Hussey ◽  
George E. Dukes
Keyword(s):  
Drug Interaction ◽  
Receptor Antagonist ◽  
Clinical Significance ◽  
Therapeutic Range ◽  
Warfarin Therapy ◽  
Package Insert ◽  
Careful Examination ◽  
Once Daily ◽  
Drug Drug Interaction ◽  
Cytochrome P 450

Cimetidine, the first marketed histamine2-receptor antagonist, has been shown to decrease the clearance of warfarin consistently through inhibition of cytochrome P-450 metabolism. The clinical significance of this drug–drug interaction has been questioned due to: (1) the lowering of the warfarin therapeutic range, (2) the lowering of the total daily therapeutic cimetidine dosage, (3) the advent of once-daily cimetidine dosing, and (4) the demonstration that the clearance of the less active warfarin R-enantiomer is decreased to a greater extent than the more active S-enantiomer. Ranitidine has been implicated in both increasing and decreasing warfarin's hypoprothrombinemic effect (noted in the warfarin package insert), despite the majority of investigations demonstrating no warfarin clearance changes. Careful examination of the implicating data indicates that the majority of the warfarin pharmacodynamic and pharmacokinetic variance that occurs with combined ranitidine-warfarin therapy cannot be attributed to a drug–drug interaction. No data are available to implicate the newer histamine2-antagonists, famotidine and nizatidine, in causing a decrease in warfarin metabolism.

scholarly journals Analysis of Potential Drug Drug Interaction with Warfarin Therapy in Hospitalized Patients

2015 ◽  
Vol 32 (2) ◽  
pp. 93-103
Author(s):  
문정연 ◽  
한현주 ◽  
이용화 ◽  
이혜숙 ◽  
박현희 ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Warfarin Therapy ◽  
Hospitalized Patients ◽  
Potential Drug ◽  
Drug Drug Interaction

Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with nab-paclitaxel in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2553-2553
Author(s):  
Raghad Muhsin Abdul-Karim ◽  
Anthony W. Tolcher ◽  
Shivaani Kummar ◽  
Manish R. Patel ◽  
Alexander I. Spira ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Antitumor Activity ◽  
Glucocorticoid Receptor ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Nuclear Hormone Receptor ◽  
Tolerability Profile ◽  
Once Daily ◽  
Multiple Tumor ◽  
Drug Drug Interaction

2553 Background: ORIC-101 is a potent and selective, orally bioavailable, small molecule antagonist of the glucocorticoid receptor (GR). Preclinical studies have demonstrated that activation of GR signaling leads to decreased responsiveness to chemotherapeutics (eg, taxanes) and antiandrogens across multiple tumor types. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the prosurvival signals mediated by the activated nuclear hormone receptor. Methods: A 3+3 dose escalation design was used to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and select the Recommended Phase 2 Dose (RP2D) of ORIC-101 in combination with nab-paclitaxel (nab-pac; NCT03928314). ORIC-101 doses ranging from 80 to 240 mg once daily, given either intermittently or in a continuous dosing regimen, were evaluated in combination with weekly nab-pac at 75 or 100 mg/m2. Plasma PK and PD biomarkers were assessed on day 1 and after repeat dosing. PD modulation in blood-derived peripheral blood mononuclear cells (PBMCs) was assessed by RT-qPCR for GR target genes. Antitumor activity was assessed by RECIST v1.1. Results: 21 patients with 10 different solid tumors, with and without a prior taxane, were treated in 5 cohorts. ORIC-101 exposure increased with dose, with no evidence for drug-drug interaction with nab-pac. In the initial cohort at 240 mg ORIC-101 and 100 mg/m2 nab-pac, 2 patients experienced dose limiting toxicities (DLTs) of Grade 3 fatigue and Grade 4 neutropenia/thrombocytopenia, respectively. No further DLTs were observed in subsequent cohorts and the RP2D was established as 160 mg ORIC-101 dosed once daily continuously for 21 days with nab-pac 75 mg/m2 given on days 1, 8, and 15 of each 28-day cycle, without requirement for prophylactic granulocyte colony-stimulating factor (G-CSF). The most common (> 15%), all grade treatment-related adverse events (AEs) were nausea (38%), diarrhea (33%), fatigue (29%), leukopenia (29%), neutropenia (29%), anemia (24%), and 19% of patients had increased liver function tests and alopecia. Biomarker data demonstrated ORIC-101-induced reduction in GR target gene expression in PBMCs, indicating PD modulation at all dose levels of ORIC-101. Preliminary antitumor activity was observed in 3 taxane-refractory patients with breast, endometrial, and pancreatic cancers. Conclusions: The combination of ORIC-101 and nab-paclitaxel demonstrated an acceptable tolerability profile and does not require prophylactic G-CSF. PK and PD showed no evidence of drug-drug-interaction and demonstrated GR target inhibition. Preliminary antitumor activity was observed in patients with solid tumors that previously progressed on a taxane-containing regimen. Dose expansion is ongoing at the RP2D in dedicated pancreatic, ovarian, triple negative breast cancers, and tissue-agnostic cohorts. Clinical trial information: NCT03928314.

A Review of Warfarin Dosing With Concurrent Acetaminophen Therapy

2013 ◽  
Vol 26 (5) ◽  
pp. 518-521 ◽  
Author(s):  
G. Michelle Pinson ◽  
Jennifer W. Beall ◽  
Jeffrey A. Kyle
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Warfarin Therapy ◽  
International Normalized Ratio ◽  
Over The Counter ◽  
Pain Medications ◽  
Concurrent Use ◽  
Prevention And Treatment ◽  
Drug Drug Interaction ◽  
Warfarin Dosing

Warfarin is frequently used for the prevention and treatment of thromboembolism, yet it is associated with numerous drug interactions. Regarding over-the-counter pain medications, the preferred analgesic for those patients who are taking warfarin is acetaminophen. There are, however, reports of elevation in the international normalized ratio (INR) in those patients taking concurrent warfarin and acetaminophen. For those practitioners who manage warfarin therapy, there is little guidance regarding management of the drug–drug interaction between warfarin and acetaminophen. This review seeks to evaluate the drug interaction between warfarin and acetaminophen and provides recommendations for concurrent use of these drugs.

Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype

2004 ◽  
Vol 91 (01) ◽  
pp. 95-101 ◽  
Author(s):  
Arian Plat ◽  
Alieke van Dijk ◽  
Margriet Piersma-Wichers ◽  
Anne de Vries-Bots ◽  
Jennita Slomp ◽  
...  
Keyword(s):  
Cohort Study ◽  
Drug Interaction ◽  
Therapeutic Range ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Case Reports ◽  
Cyp2c9 Genotype ◽  
Range Type ◽  
Drug Drug Interaction

SummaryNSAIDs are reported to increase the risk of bleeding in coumarin users. The mechanism underlying this risk is inhibition of platelet aggregation, however a pharmacokinetic mechanism resulting in an increased International Normalised Ratio (INR) was proposed in some case reports in warfarin treated patients. In this retrospective cohort study the influence of diclofenac, naproxen and ibuprofen on the INR of outpatients stabilised on acenocoumarol therapy was investigated. We also determined the role of cytochrome P450 2C9 (CYP2C9) polymorphism on coumarin dosage and INR in NSAID users. The study was carried out at the Groningen Outpatient Thrombosis Service. A retrospective cohort study among patients who received both acenocoumarol and one of the NSAIDs under study was performed. Patients whose INR rose above the upper level of the therapeutic range (INR above 3.5 or 4.0) after an NSAID under study was added to the acenocoumarol therapy, were compared with patients who did not show such an elevation. A two-sample t-test (average acenocoumarol dosage, age), and chi-square tests (sex, therapeutic range, type of NSAID) were used to test for differences. Genotyping was carried out by analysing blood samples for the relevant CYP2C9 alleles. The study population consisted of 112 patients on stable acenocoumarol therapy, of which 52 (46%) showed an elevation of the INR above the desired therapeutic level (INR3.5 and 4.0 respectively) after the start of an NSAID under study. In 12 patients, the INR increased above 6. The INR of the other 60 patients (54%) remained constant after the start of one of the NSAIDs under study. There were no statistically significant differences between patients with increased INR and patients without increased INR with regard to age, sex, therapeutic range and average acenocoumarol dosage. Eighty patients, of whom 36 showed an increased INR as a result of a potential acenocoumarol-NSAID drug interaction, were included in the genotyping study. No association between CYP2C9 genotype and an increased INR as a result of the drug-drug interaction was found. In nearly half of a cohort of elderly patients, the INR increased beyond the therapeutic range (INR 3.5 or 4.0) as a result of a potential pharmacokinetic drug-drug interaction between acenocoumarol and diclofenac, naproxen and ibuprofen. The average increase in INR was between 1 and 4. Polymorphism of CYP2C9 does not seem to be a relevant risk factor for the NSAID-acenocoumarol interaction.

scholarly journals Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug–Drug Interaction in Healthy Volunteers

2021 ◽  
Vol 11 (6) ◽  
pp. 457
Author(s):  
Xue-Qing Li ◽  
Roslyn Stella Thelingwani ◽  
Leif Bertilsson ◽  
Ulf Diczfalusy ◽  
Tommy B. Andersson ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Healthy Volunteers ◽  
Deoxycholic Acid ◽  
Cyp3a Activity ◽  
Once Daily ◽  
Spot Urine ◽  
Non Invasive ◽  
Drug Drug Interaction ◽  
Cyp3a Inhibitor ◽  
Inhibitor Treatment

In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug–drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ; 100 mg once daily; n = 10), fluconazole (FKZ; 50 mg once daily; n = 9), or alprazolam (APZ; 1 mg once daily; n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1β-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1β-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (rs = 0.53, p < 0.01). The half-life of urinary endogenous 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug–drug interaction in clinical studies.

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