Browsing by Subject "Drug interactions"

Now showing 1 - 10 of 12
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    Comparative risk of severe hypoglycemia among concomitant users of thiazolidinedione antidiabetic agents and antihyperlipidemics
    (Elsevier, 2016-05) Leonard, Charles E.; Han, Xu; Bilker, Warren B.; Flory, James H.; Brensinger, Colleen M.; Flockhart, David A.; Gagne, Joshua J.; Cardillo, Serena; Hennessy, Sean; Department of Medicine, IU School of Medicine
    We conducted high-dimensional propensity score-adjusted cohort studies to examine whether thiazolidinedione use with a statin or fibrate was associated with an increased risk of severe hypoglycemia. We found that concomitant therapy with a thiazolidinedione+fibrate was associated with a generally delayed increased risk of severe hypoglycemia.
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    Drug Interactions Affecting Oral Anticoagulant Use
    (American Heart Association, 2022) Mar, Philip L.; Gopinathannair, Rakesh; Gengler, Brooke E.; Chung, Mina K.; Perez, Arturo; Dukes, Jonathan; Ezekowitz, Michael D.; Lakkireddy, Dhanunjaya; Lip, Gregory Y. H.; Miletello, Mike; Noseworthy, Peter A.; Reiffel, James; Tisdale, James E.; Olshansky, Brian; American Heart Association Electrocardiography & Arrhythmias Committee of the Council of Clinical Cardiology; Medicine, School of Medicine
    Oral anticoagulants (OAC) are medications commonly used in patients with atrial fibrillation and other cardiovascular conditions. Both warfarin and direct oral anticoagulants (DOAC) are susceptible to drug-drug interactions (DDI). DDI are an important cause of adverse drug reactions and exact a large toll on the healthcare system. DDI for warfarin mainly involve moderate to strong inhibitors / inducers of cytochrome P450 (CYP) 2C9, which is responsible for the elimination of the more potent S-isomer of warfarin. However, inhibitor / inducers of CYP3A4 and CYP1A2 may also cause DDI with warfarin. Recognition of these precipitating agents along with increased frequency of monitoring when these agents are initiated or discontinued will minimize the impact of warfarin DDI. DOAC DDI are mainly affected by medications strongly affecting the permeability glycoprotein (P-gp), and to a lesser extent, strong CYP3A4 inhibitors / inducers. Dabigatran and edoxaban are affected by P-gp modulation. Strong inducers of CYP3A4 or P-gp should be avoided in all patients taking DOAC unless previously proven to be otherwise safe. Simultaneous strong CYP3A4 and P-gp inhibitors should be avoided in patients taking apixaban and rivaroxaban. Concomitant antiplatelet / anticoagulant use confers additive risk for bleeding, but their combination is unavoidable in many cases. Minimizing duration of concomitant anticoagulant/antiplatelet therapy as indicated by evidence-based clinical guidelines is the best way to reduce the risk of bleeding.
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    Evaluation of US Food and Drug Administration Drug Label Recommendations for Coadministration of Antivirals and Acid-Reducing Agents
    (Wiley, 2022) Shugg, Tyler; Powell, Nicholas R.; Marroum, Patrick J.; Skaar, Todd C.; Younis, Islam R.; Medicine, School of Medicine
    Coadministration with acid-reducing agents (ARAs), including proton pump inhibitors (PPIs), histamine H2 -receptor antagonists (H2 blockers), and antacids has been demonstrated to reduce antiviral exposure and efficacy. Therefore, it is essential that US Food and Drug Administration (FDA) drug labels include recommendations to manage these drug-drug interactions (DDIs). This investigation analyzed information in FDA drug labels to manage DDIs between ARAs and antivirals approved from 1998 to 2019. To ascertain clinical adoption, we assessed whether FDA label recommendations were incorporated into current antiviral clinical practice guidelines. We identified 82 label recommendations for 43 antiviral approvals. Overall, 56.1% of recommendations were deemed clinically actionable, with the most common actionable management strategies being dose adjustment during coadministration (40.2%) and coadministration not recommended (9.8%). The sources informing DDI recommendations were clinical DDI studies (59.8%) and predictions of altered exposure (40.2%). Antivirals with low aqueous solubility were more likely to have label recommendations and were more commonly investigated using clinical DDI studies (P < 0.01). For recommendations informed by clinical DDI studies, changes in drug exposure were associated with actionable label recommendations (P < 0.01). The frequency of exposure changes in clinical DDI studies was similar across antiviral indications, but exposure changes were numerically higher for antacids (71.4%) relative to PPIs (42.9%) and H2 blockers (28.6%). Of DDI pairs identified within drug labels, 76.8% were included in guidelines, and recommended management strategies were concordant in 90.5% of cases. Our findings demonstrate that current regulatory oversight mostly (but not completely) results in actionable label recommendations to manage DDIs for high-risk antivirals.
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    Hydralazine-associated antineutrophil cytoplasmic antibody vasculitis with pulmonary-renal syndrome
    (BMJ, 2018-11-08) Aeddula, Narothama Reddy; Pathireddy, Samata; Ansari, Asif; Juran, Peter J.; Medicine, School of Medicine
    Hydralazine, a vasodilator, is commonly used as an adjunctive treatment for moderate to severe hypertension, heart failure and hypertensive emergencies in pregnancy. Hydralazine-induced lupus was first described in 1953. Clinical presentation ranges from arthralgia, myalgia, petechiae, or rash to single or multiorgan involvement. An occurrence of systemic vasculitis is a rare complication. When presented as the pulmonary-renal syndrome, it could have a rapidly progressive course which can be fatal. Here, we describe a case of hydralazine-associated rapidly progressive glomerulonephritis and pulmonary haemorrhage. We use this case to review the current literature and discuss and highlight the importance of a high degree of clinical acumen, early diagnosis and prompt treatment for better clinical outcomes.
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    Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers
    (American Society for Pharmacology and Experimental Therapeutics, 2022-07-07) Gufford, Brandon T.; Metzger, Ingrid F.; Bamfo, Nadia O.; Benson, Eric A.; Masters, Andrea R.; Lu, Jessica Bo Li; Desta, Zeruesenay; Medicine, School of Medicine
    We investigated the acute and chronic effects of efavirenz, a widely used antiretroviral drug, and CYP2B6 genotypes on the disposition of racemic and stereoisomers of bupropion (BUP) and its active metabolites, 4-hydroxyBUP, threohydroBUP and erythrohydroBUP. The primary objective of this study was to test how multiple processes unique to the efavirenz-CYP2B6 genotype interaction influence the extent of efavirenz-mediated drug-drug interaction (DDI) with the CYP2B6 probe substrate BUP. In a three-phase, sequential, open-label study, healthy volunteers (N=53) were administered a single 100 mg oral dose of BUP alone (control phase), with a single 600 mg oral efavirenz dose (inhibition phase), and after 17-days pretreatment with efavirenz (600 mg/day) (induction phase). Compared to the control phase, we show for the first time that efavirenz significantly decreases and chronically increases the exposure of hydroxyBUP and its diastereomers, respectively, and these interactions were CYP2B6 genotype dependent. Chronic efavirenz enhances the elimination of racemic BUP and its enantiomers as well as of threo- and erythro-hydroBUP and their diastereomers, suggesting additional novel mechanisms underlying efavirenz interaction with BUP. The effects of efavirenz and genotypes were nonstereospecific. In conclusion, acute and chronic administration of efavirenz inhibits and induces CYP2B6 activity. Efavirenz-BUP interaction is complex involving time- and CYP2B6 genotype-dependent inhibition and induction of primary and secondary metabolic pathways. Our findings highlight important implications to the safety and efficacy of BUP, study design considerations for future efavirenz interactions, and individualized drug therapy based on CYP2B6 genotypes. Significance Statement: The effects of acute and chronic doses of efavirenz on the disposition of racemic and stereoisomers of BUP and its active metabolites were investigated in healthy volunteers. Efavirenz causes an acute inhibition, but chronic induction of CYP2B6 in a genotype dependent manner. Chronic efavirenz induces BUP reduction and the elimination of BUP active metabolites. Efavirenz's effects were non-stereospecific. These data reveal novel mechanisms underlying efavirenz DDI with BUP and provide important insights into time- and CYP2B6 genotype dependent DDIs.
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    Mechanisms and quantitative prediction of Efavirenz metabolism, pharmacogenetics and drug interactions
    (2013-08) Xu, Cong; Desta, Zeruesenay; Queener, Sherry F.; Li, Lang; Jones, David R.; Zhang, Jian-Ting
    The antiretroviral drug efavirenz remains a cornerstone for treatment-naïve HIV patients. Subsequent to the demonstration that efavirenz is a substrate of cytochrome P450 (CYP) 2B6, a number of clinical studies found that the CYP2B6*6 allele is significantly associated with higher efavirenz exposure and/or adverse reactions. However, the mechanism of reduced efavirenz metabolism by this genetic variant is not fully understood and whether this variant exhibits differential susceptibility to metabolic inhibition is also unknown. Ths use of efavirenz is further complicated by the drug interactions associated with it. Therefore, I hypothezised that 1) the CYP2B6*6 allele reduces efavirenz metabolism by altering catalytic properties of CYP2B6; 2) efavirenz alters the pharmacokinetics of co-administered drugs by inhibiting drug metabolizing enzymes. A series of studies was carried out in hepatic microsomal preparations to determine the functional consequences of the CYP2B6*6 allele and to assess inhibition potency of efavirenz on 8 CYPs. The major findings for these studies include: 1) the CYP2B6*6 allele reduces efavirenz metabolism by decreasing substrate binding and catalytic efficiency; 2) functional consequences of the CYP2B6*6 allele appear to be substrate- and cytochrome b5-dependent; 3) the CYP2B6*6 allele confers increased susceptibility to metabolic inhibition; and 4) efavirenz inhibits the activities of CYP2B6, 2C8, 2C9 and 2C19 at therapeutically relevant concentrations. In addition, I explored the hypothesis that the incorporation of in vitro mechanism by which the CYP2B6*6 allele reduced efavirenz metabolism predicts the genetic effect of this allele on efavirenz clearance after a single oral dose by modeling approach. A pharmacogenetics-based in vitro-in vivo extrapolation (IVIVE) model was developed to predict human efavirenz clearance. Taken together, results from this dissertation provide new mechanistic information on how the CYP2B6*6 allale alters substrate metabolism and drug interactions; demonstrate new mechanisms of efavirenz-mediated inhibition interactions; and demonstrate the utility of a pharmacogenetics-based predictive model that can serve as a basis for future studies with efavirenz and other CYP2B6 substrates. Overall these data provide improved understanding of genetic and non-genetic determinant of efavirenz disposition and drug interactions associated with it.
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    Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants
    (Wiley, 2021) Salerno, Sara N.; Edginton, Andrea; Gerhart, Jacqueline G.; Laughon, Matthew M.; Ambalavanan, Namasivayam; Sokol, Gregory M.; Hornik, Chi D.; Stewart, Dan; Mills, Mary; Martz, Karen; Gonzalez, Daniel; Pediatrics, School of Medicine
    Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (KI ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUCss,0-24 ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUCss,0-24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.
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    Real-world use and outcomes of dolutegravir-containing antiretroviral therapy in HIV and tuberculosis co-infection: a site survey and cohort study in sub-Saharan Africa
    (Wiley, 2022) Romo, Matthew L.; Brazier, Ellen; Mahambou-Nsondé, Dominique; De Waal, Reneé; Sekaggya-Wiltshire, Christine; Chimbetete, Cleophas; Muyindike, Winnie R.; Murenzi, Gad; Kunzekwenyika, Cordelia; Tiendrebeogo, Thierry; Muhairwe, Josephine A.; Lelo, Patricia; Dzudie, Anastase; Twizere, Christelle; Rafael, Idiovino; Ezechi, Oliver C.; Diero, Lameck; Yotebieng, Marcel; Fenner, Lukas; Wools-Kaloustian, Kara K.; Shah, N. Sarita; Nash, Denis; International epidemiology Databases to Evaluate AIDS (IeDEA); Medicine, School of Medicine
    Introduction: Dolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co-infection, its use is complicated by a drug-drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug-drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co-infection receiving dolutegravir or efavirenz. Methods: Within the four sub-Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015-2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months. Results: In the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice-daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice-daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3-63.3%), switching ART regimen was 4.1% (95% CI: 2.6-6.2%) and loss to program/death was 23.4% (95% CI: 19.7-27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28-1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08-1.51). Conclusions: At a programmatic level, dolutegravir was being widely prescribed in sub-Saharan Africa for people with HIV and tuberculosis co-infection with a dose adjustment for the drug-drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression.
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    Severe hypoglycemia in users of sulfonylurea antidiabetic agents and antihyperlipidemics
    (Wiley, 2016-05) Leonard, Charles E.; Bilker, Warren B.; Brensinger, Colleen M.; Han, Xu; Flory, James H.; Flockhart, David A.; Gagne, Joshua J.; Cardillo, Serena; Hennessy, Sean; Department of Medicine, IU School of Medicine
    Drug-drug interactions causing severe hypoglycemia due to antidiabetic drugs is a major clinical and public health problem. We assessed whether sulfonylurea use with a statin or fibrate was associated with severe hypoglycemia. We conducted cohort studies of users of glyburide, glipizide, and glimepiride plus a statin or fibrate within a Medicaid population. The outcome was a validated, diagnosis-based algorithm for severe hypoglycemia. Among 592,872 persons newly exposed to a sulfonylurea+antihyperlipidemic, the incidence of severe hypoglycemia was 5.8/100 person-years. Adjusted hazard ratios (HRs) for sulfonylurea+statins were consistent with no association. Most overall HRs for sulfonylurea+fibrate were elevated, with sulfonylurea-specific adjusted HRs as large as 1.50 (95% confidence interval (CI): 1.24-1.81) for glyburide+gemfibrozil, 1.37 (95% CI: 1.11-1.69) for glipizide+gemfibrozil, and 1.63 (95% CI: 1.29-2.06) for glimepiride+fenofibrate. Concomitant therapy with a sulfonylurea and fibrate is associated with an often delayed increased rate of severe hypoglycemia.