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Background Several studies have suggested that proton pump inhibitors (PPIs) may reduce the antiplatelet effects of clopidogrel and/or aspirin, possibly leading to cardiovascular events. Aims We aimed to investigate the association between PPI and clinical outcomes in patients treated with ticagrelor monotherapy or conventional antiplatelet therapy after percutaneous coronary intervention (PCI). Methods This is a subanalysis of the randomized GLOBAL LEADERS trial, comparing the experimental antiplatelet arm (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with the reference arm (12-month aspirin monotherapy following 12-month DAPT) after PCI. Patient-oriented composite endpoints (POCEs: all-cause mortality, myocardial infarction, stroke, or repeat revascularization) and its components were assessed stratified by PPI use as a time-dependent covariate in patients with the experiment or reference antiplatelet arm. Results Among 15,839 patients, 2115 patients (13.5%) experienced POCE at 2 years. In the reference arm, the use of PPIs was independently associated with POCE (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.12-1.44) and its individual components, whereas it was not in the experimental arm (HR: 1.04; 95% CI: 0.92-1.19; p(interaction) = 0.035). During the second-year follow-up, patients taking aspirin with PPIs had a significantly higher risk of POCE compared to those on aspirin without PPIs (HR: 1.57; 95% CI: 1.27-1.94), whereas the risk did not differ significantly irrespective of PPI in ticagrelor monotherapy group (HR: 1.03; 95% CI: 0.83-1.28; p(interaction) = 0.008). Conclusions In contrast to conventional antiplatelet strategy, there were no evidence suggesting the interaction between ticagrelor monotherapy and PPIs on increased cardiovascular events, which should be confirmed in further studies. Clinical Trial Registration URL: The GLOBAL LEADERS trial was supported by unrestricted grants from AstraZeneca, Biosensors, and The Medicines Company. ECRI (European Cardiovascular Research Institute) was formally the sponsor of the study. GLOBAL LEADERS was sponsored by the European Clinical Research Institute, which received funding from Biosensors International, AstraZeneca, and the Medicines Company. P. J. is a Tier 1 Canada Research Chair in Clinical Epidemiology of Chronic Diseases. This study was completed, in part, with funding from the Canada Research Chairs Program. Open access funding provided by IReL.

AIMS: P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. METHODS: A meta-analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients. RESULTS: Fifteen studies were included, investigating 21 711 and 306 421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only 1 study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01-1.19]) and all-cause mortality risks (RR 1.14, 95%CI [1.05-1.23]) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77-1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68-1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91-1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61-0.92]), similar major bleeding (RR 0.92, 95%CI [0.80-1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05-1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31-2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75-1.61]) and mortality risks (RR 1.01, 95%CI [0.77-1.33]). CONCLUSION: Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors, close monitoring is warranted.

Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) −10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI −16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.

Objective Several studies have demonstrated that anti-angiogenic agents (AAs) have the ability to regulate immune-related cells in the tumor microenvironment and may affect the clinical effect of immune checkpoint inhibitors (ICIs). Therefore, we investigated the drug interaction between ICI and AA for advanced non-small cell lung cancer (NSCLC). Materials and methods We systematically searched PubMed-MEDLINE, Embase-Scopus, and ISI Web of Science before August 23, 2021. ICI and AA therapy included the concomitant and sequential use of ICIs and AAs. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of patients who received ICI and AA therapy were evaluated and compared to those of patients who received either monotherapy. Subgroup analyses were performed to clarify the cause of heterogeneity; the timing and sequence of ICI and AA administration were predefined as the subgroups. Results Thirteen studies involving 2414 patients were included in the meta-analysis. ICI and AA therapy had significantly higher ORR than either monotherapy (OR [95% CI]: 0.61 [0.50–0.74]; p Conclusion ICI and AA therapy can provide favorable clinical effects compared to either monotherapy; however, ICI administered immediately after AA may not show survival benefits.

Background: Having various limitations in conventional drug delivery system, it is important to focus on the target-specific drug delivery system where we can deliver the drug without any degradation. Among various challenges that are thrown to a formulation scientist, delivering the drug to its right site, in its right dose, is also an important aim. A focused drug transport aims to extend, localize, target and have a safe drug interaction with the diseased tissue. Objective: The aim of targeted drug delivery is to make the required amount of the drug available at its desired site of action. Drug targeting can be accomplished in a number of ways that include enzyme mediation, pH-dependent release, use of special vehicles, receptor targeting, among other mechanisms. Intelligently designed targeted drug delivery systems also offer the advantages of a low dose of the drug along with reduced side effects which ultimately improves patient compliance. Incidences of dose dumping and dosage form failure are negligible. A focused drug transport aims to have a safe drug interaction with the diseased tissue. Conclusion: This review focuses on the available targeting techniques from experiment to perfection for delivery to the colon, brain, and other sites of interest. Overall, the article should make an excellent read for the researchers in this area. Newer drug targets may be identified and exploited for successful drug targeting.

Background The Interaction between anti-tuberculous and immunosuppressive drugs which may increase the risk of graft rejections is a major challenge in managing transplant recipients with tuberculosis (TB). Instead of rifampicin (RFM), most guidelines recommended the use of rifabutin (RFB) because of its reduced capacity to induce immunosuppressant metabolism while maintaining the same efficacy as RFM against TB. However, there has been no available data directly comparing the outcome of RFB from RFM-based anti-TB regimens in liver transplant patients with TB. This study aimed to compare the effects of RFB from RFM-based treatment in terms of the drug interaction with immunosuppressants, as well as the safety, efficacy and clinical outcomes of living donor liver transplant (LDLT) recipients with active TB. Patients and methods A retrospective study was conducted on all adult LDLT recipients diagnosed with active TB from June 1994 to May 2016 that had concurrently and continuously received either RFB or RFM-based treatment and immunosuppressants. Results Twenty-two patients were included. Twelve (55%) patients were in the RFM group. Ten (45%) patients were in the RFB group. RFB group showed a lesser rate of immunosuppressant trough level reduction (20% vs 50%, p = 0.009) during TB treatment. There was no TB recurrence and no significant change in platelet or leukocyte count in either group. Acute cellular rejection (ACR), rate of TB-treatment completion and overall survival, rates were excellent and statistically similar in both groups. Conclusion The use of RFB in LDLT recipients with active TB, had a lesser drug interaction than when RFM was used. However, RFB did not significantly reduced the rate of ACR. RFB and RFM are both effective and safe to use in LDLT recipients with active TB.

Triple whammy (TW) is a potentially dangerous drug combination that can lead to acute kidney injury (AKI). This drug interaction (DI) occurs when angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are used together with diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). One of the most serious consequences of TW DI is an increased risk of developing pre-renal acute kidney injury (pr-AKI). The term TW, in the context of a DI affecting kidney function, is not very widespread. The aim of this article was to gather information on this interaction. Previous knowledge on the mechanism of TW and how to increase patient awareness of this interaction is described. In addition, the specific nature of the acute kidney injury (AKI) caused by triple whammy (AKITW) is presented. On the basis of the current state of knowledge, recommendations on how to manage the TW DI are also demonstrated.

Introduction Chronic hand eczema (CHE) is a frequent skin disorder affecting up to 10% of the population and strongly reduces Quality of Life (QoL). The first-line therapeutic strategies for the management of CHE include a change of lifestyle, an education program for the skin and the application of specific emollients. Topical corticosteroids or calcineurin inhibitors are the most used anti-inflammatory drugs. However, up to 65% of patients require systemic options. Alitretinoin, a retinoid structurally related to vitamin A, is the first systemic treatment approved in the European Union (EU) for severe CHE refractory to potent topical corticosteroids. Areas covered This review summarizes the available data on the pharmacokinetics, pharmacodynamics, efficacy, and safety profile of oral alitretinoin for the treatment of CHE. Expert opinion Alitretinoin can be considered as a valid therapeutic option for the treatment of CHE in patients not responding to ordinary treatments. Clinical trials and real-life experiences showed that it acts effectively on both objective and subjective clinical signs, resulting in a significant improvement in QoL of patients. As for other retinoids, caution should be taken in patients with certain chronic diseases (hepatopathies, kidney failure, hyperlipidemia, thyroid dysfunction) or childbearing potential women.

OBJECTIVE: In this study, we aimed to overview the drug interactions between colchicine and cardiovascular drugs and performed a meta-analysis to evaluate the safety profile of colchicine in cardiovascular treatment. METHODS: The drug interactions between colchicine and cardiovascular drugs were evaluated using Medscape-Drug-Interaction-checker. For safety meta-analysis, a systematic literature search was carried out to retrieve eligible studies. Randomized controlled clinical trials that reported a safety analysis and with at least one-year follow-up period were included into the analysis. Meta-analysis was performed using RevMan 5.4 software provided by the Cochrane Collaboration. RESULTS: Serious drug interactions were found between colchicine and lipid-lowering treatments, including all statins and fibrates; carvedilol among the beta-blockers; non-dihydropyridine calcium channel blockers (verapamil and diltiazem); and amiodarone, digoxin, and quinidine. The safety meta-analysis involved 11,594 patients with coronary disease from four trials. The incidences of gastrointestinal adverse events; hematological adverse events; infection; pneumonia; cancer; myalgia; and abnormal nerve sensations were similar between colchicine and control arm. The incidence of cardiovascular death was lower in the colchicine arm; however, the difference did not reach a significant level [relative risk (RR): 0.71, 95% confidence interval (CI) 0.48–1.05; p=0.09]. The incidence of non-cardiovascular death was significantly higher in the colchicine arm (RR: 1.53, 95% CI 1.10–2.14; p=0.01). The rate of all-cause mortality was similar between the two arms (RR: 1.04, 95% CI 0.61–1.78; p=0.88). CONCLUSION: Cardiac patients on colchicine therapy should be carefully monitored to avoid the complications of serious drugs interactions. The reported data in the literature were not sufficient to evaluate the common side effects such as gastrointestinal events and myalgia. The higher incidence of non-cardiovascular death cannot be ignored and should be thoroughly investigated in future studies.

Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP‐drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies’ guidance documents about drug‐drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions.

Introduction: Multi-pathological patients are at high risk of drug interactions and side effects. We aimed to assess the usefulness of 3 online drug interaction checkers. Methods: In a cross-sectional study, carried out in the Medicine Department of Hospital General of Castellon, Spain, in February 2020, we assessed drug interaction detection with 3 online electronic checkers, Drugs.com, Lexicomp®, and Medscape, and compared results obtained with the 3 tools. From every hospitalized patient, we obtained the list of drugs he or she had been taking until admission. Bivariable tests were used for analysis. p values Results: We included data from 134 patients; 68 (51%) were male; median (and interquartile range) of their age was 82 (76–88) years. A total of 1,082 substance drugs were entered in the checkers. The number of highest grade interactions found with every program was Drugs.com 85, Lexicomp® 33, and Medscape 67. Positive correlations were found between age and number of drug substances prescribed (p = 0.009) and between number of drug substances prescribed and interactions found with any of the 3 checkers (p < 0.001 in all 3 cases). Regarding highest grade interactions, agreement among all 3 checkers was poor. Conclusions: The 3 online checkers we assessed found a large number of interactions. The 3 programs gave very discrepant results. Impact on Practice Statements: The analyzed programs, Drugs.com, Lexicomp®, and Medscape Interactions, found a large number of drug interactions in the studied patients. The 3 programs gave very discrepant results among them.

Islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, is in clinical development for the treatment and prevention of HIV-1 infection. Because islatravir may be coadministered with other antiretroviral agents, assessment of potential drug-drug interactions are warranted. This phase 1, open-label, fixed-sequence, 2-period trial in adults without HIV (N = 12) assessed the safety and pharmacokinetic interactions of islatravir administered with dolutegravir and tenofovir disoproxil fumarate (TDF). In period 1, participants received a single oral dose of islatravir (20 mg). In period 2, participants received oral doses of dolutegravir (50 mg) and TDF (300 mg) once daily on days 1 through 11, with a single oral dose of islatravir (20 mg) coadministered on day 8. There were no clinically significant changes in islatravir, dolutegravir, or TDF pharmacokinetics following coadministration. Islatravir was generally well tolerated when administered alone or in combination with dolutegravir and TDF. Coadministration of islatravir, dolutegravir, and TDF is supported, with no clinically meaningful effect on pharmacokinetics, safety, or tolerability in participants without HIV.

Background Older patients are at increased risk of drug-drug interactions (DDIs) due to polypharmacy. Cardiovascular and central nervous system (CNS) drugs are commonly implicated in serious DDIs. Objectives This study aimed to determine the prevalence and factors associated with potential ‘severe’ cardiovascular and CNS DDIs among older (≥ 70 years) community-dwellers. Methods This was a prospective cohort study using linked data from a national pharmacy claims database and waves 1 and 2 of The Irish LongituDinal study on Ageing (TILDA). ‘Severe’ cardiovascular and CNS DDIs were identified using the British National Formulary 77 and Stockley’s Drug Interactions. The prevalence of ‘severe’ DDIs (any DDI vs. none) was calculated. Logistic regression was used to examine the association between sociodemographic, functional ability, and medication-related factors and the risk of DDI exposure between waves 1 and 2. Results A total of 1466 patients were included [mean age (standard deviation) = 78 (5.5) years; female n = 795, 54.2%]. In total, 332 community-dwellers aged ≥ 70 years [22.65%, 95% confidence interval (CI) 20.58–24.86] were potentially exposed to at least one ‘severe’ cardiovascular or CNS DDI, with more than half (54.82%) of this cohort dispensed the same DDI for a prolonged time (≥ 3 consecutive claims). Aspirin-warfarin was the most frequently dispensed (co-prescribed) DDI (n = 34, 10.24%, 95% CI 7.39–14.00), followed by atorvastatin-clarithromycin (n = 19, 5.72%, 95% CI 3.64–8.81). Polypharmacy [≥ 10 vs. < 5 drugs, odds ratio (OR) 13.40, 95% CI 8.22–21.85] and depression (depressed vs. not, OR 2.12, 95% CI 1.34–3.34) were significantly associated with these DDIs, after multivariable adjustment. Conclusion ‘Severe’ cardiovascular and CNS DDIs are prevalent in older community-dwellers in Ireland, and those with polypharmacy and depression are at a significantly increased risk. Supplementary Information The online version contains supplementary material available at 10.1007/s40266-021-00898-8.

Approximately 30% to 70% of patients with cirrhosis have QT interval prolongation. In patients without cirrhosis, QT prolongation is associated with an increased risk of ventricular arrhythmias, such as torsade de pointes (TdP). In cirrhotic patients, there is likely a significant association between the corrected QT (QTc) interval and the severity of liver disease, and possibly with increased mortality. We present a stepwise overview of the pathophysiology and management of acquired long QT syndrome in cirrhosis. The QT interval is mainly determined by ventricular repolarization. To compare the QT interval in time it should be corrected for heart rate (QTc), preferably by the Fridericia method. A QTc interval >450 ms in males and >470 ms in females is considered prolonged. The pathophysiological mechanism remains incompletely understood, but may include metabolic, autonomic or hormonal imbalances, cirrhotic heart failure and/or genetic predisposition. Additional external risk factors for QTc prolongation include medication (IKr blockade and altered cytochrome P450 activity), bradycardia, electrolyte abnormalities, underlying cardiomyopathy and acute illness. In patients with cirrhosis, multiple hits and cardiac-hepatic interactions are often required to sufficiently erode the repolarization reserve before long QT syndrome and TdP can occur. While some risk factors are unavoidable, overall risk can be mitigated by electrocardiogram monitoring and avoiding drug interactions and electrolyte and acidbase disturbances. In cirrhotic patients with prolonged QTc interval, a joint effort by cardiologists and hepatologists may be useful and significantly improve the clinical course and outcome. ispartof: GUT AND LIVER vol:16 issue:6 pages:849-860 ispartof: location:Korea (South) status: published

Aims Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose–response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. Methods and results Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1–3 clinical studies. Dose–response models were developed for bempedoic acid monotherapy and bempedoic acid–statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose–response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. Conclusion These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID‐19) treatment in a large‐scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients’ drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub‐payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug‐induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two‐to‐seven points, p

Introduction Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy. Areas covered The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism. Expert opinion Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.

While the use of excipients is widespread, a thorough understanding of the drug interaction potential of these compounds remains a frequent topic of current research. Not only can excipients alter the disposition of co-formulated drugs, but it is likely that these effects on co-administered drugs can reach to clinical significance leading to potential adverse effects or loss of efficacy. These risks can be evaluated through use of in silico methods of mechanistic modeling, including approaches such as population pharmacokinetic and physiologically-based pharmacokinetic modeling, which require a comprehensive understanding of the compounds to ensure accurate predictions. We established a knowledgebase of the available compound (or substance) and interaction-specific parameters with the goal of providing a single source of physiochemical, in vitro, and clinical pharmacokinetic and interaction data of commonly used excipients. To illustrate the utility of this knowledgebase, a model for cremophor EL was developed and used to hypothesize the potential for CYP3A- and P-gp-based interactions as a proof of concept.

Purpose Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. Methods We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). Results Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. Conclusion Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose.

Almonertinib is a novel third-generation EGFR tyrosine kinase inhibitor. It is mainly metabolized by CYP3A in vitro, and N-desmethylated almonertinib (HAS-719) is the major active metabolite in human plasma. In this study, we investigated the effects of CYP3A inhibitor itraconazole and CYP3A inducer rifampicin on the pharmacokinetics of almonertinib and HAS-719 in 64 healthy volunteers. We found that when co-administered with itraconazole, the maximal plasma concentration (C(max)) and the plasma exposure (AUC(0–t)) of almonertinib were increased by 56.3% and 2.38-fold, respectively, whereas the C(max) and AUC(0–t) of HAS-719 were reduced by 86.8% and 71.8%, respectively. Co-administration with rifampicin reduced the C(max) and AUC(0–t) of almonertinib by 79.3% and 92.6%, but the AUC(0–t) of HAS-719 was unexpectedly decreased by 72.5%. In vitro assays showed that both almonertinib and HAS-719 were substrates of CYP3A and P-gp. Co-administration of rifampicin in Beagle dogs reduced the fecal recovery of almonertinib and HAS-719, and markedly increased the levels of metabolites derived from further metabolism of HAS-719, which was consistent with human plasma data, suggesting that although rifampicin was also a potent inducer of P-gp, the pharmacokinetic alternation of HAS-719 was mainly due to its further metabolism but not excretion changes. Moreover, we revealed that almonertinib was a moderately sensitive substrate of CYP3A in vivo. Special attention should be paid to the interaction between almonertinib and drugs or food affecting CYP3A activity in the clinical application of almonertinib.

Cytochrome P450 2C8 (CYP2C8) is a major drug-metabolizing enzyme in humans and is responsible for the metabolism of ∼5% drugs in clinical use. Thus, inhibition of CYP2C8, which causes potential adverse drug events, cannot be neglected. The in vitro drug interaction studies guidelines for industry issued by the FDA also point out that it needs to be determined whether investigated drugs are CYP2C8 inhibitors before clinical trials. However, current studies mainly focus on predicting the inhibitors of other major P450 enzymes, and the importance of CYP2C8 inhibition has been overlooked. Therefore, there is a need to develop models for identifying potential CYP2C8 inhibition. In this study, in silico classification models for predicting CYP2C8 inhibition were built by five machine-learning methods combined with nine molecular fingerprints. The performance of the models built was evaluated by test and external validation sets. The best model had AUC values of 0.85 and 0.90 for the test and external validation sets, respectively. The applicability domain was analyzed based on the molecular similarity and exhibited an impact on the improvement of prediction accuracy. Furthermore, several representative privileged substructures such as 1H-benzo[d]imidazole, 1-phenyl-1H-pyrazole, and quinoline were identified by information gain and substructure frequency analysis. Overall, our results would be helpful for the prediction of CYP2C8 inhibition.

Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients with suspected acute myocardial infarction. After single‐dose emergency treatment with selatogrel, patients are switched to long‐term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long‐term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three‐compartment model. The PD model included a receptor‐pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel‐receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times. WHAT QUESTION DID THIS STUDY ADDRESS? The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Model‐based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.

Introduction Calcineurin inhibitors are commonly used in hematopoietic stem cell transplant (HSCT) patients to prevent graft versus host disease, but as CYP3A4 substrates they are frequently involved in drug-drug interactions. The purpose of this study is to characterize the effects of isavuconazole, fluconazole, and posaconazole on tacrolimus and cyclosporine serum concentrations and dose adjustments in allogeneic HSCT patients. Methods This retrospective study included patients admitted to Oregon Health and Science University between April 2008 and December 2018 who underwent hematopoietic stem cell transplantation and received concomitant tacrolimus or cyclosporine and fluconazole, isavuconazole or posaconazole therapy. Data on patient characteristics, drug dosing, and serum drug concentrations were collected through chart review, and descriptive statistics were used to summarize the results. Results A total of 139 patients were included in this study. We found fluconazole initiation leads to a 25% reduction in both tacrolimus and cyclosporine doses in order to maintain goal serum concentrations. Posaconazole and isavuconazole initiation requires tacrolimus dose reductions by 53% and 21%, respectively. Conclusions Based on our experience, FLC, POS, and ISA initiation may require CNI dose reductions and close monitoring of CNI levels to ensure levels remain within goal serum concentrations. Larger studies are needed to fully quantify the percentage in CNI dose reductions and characterize differences among these antifungals.

Hee Ji Shin,1,&ast; Min Jeong Jo,1,&ast; Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul, 04310, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Dae Hwan ShinCollege of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, 28160, Republic of KoreaTel +82 43 261 2820Fax +82 43 268 2732Email dshin@chungbuk.ac.krPurpose: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles.Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles.Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration–time curve from 0 to 2 h (AUC0– 2 h) and 0 to 8 h (AUC0– 8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution.Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.Keywords: combination therapy, drug interaction, cytotoxicity, biodistribution, bioavailability

Background and Objectives Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. Methods Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. Results Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0–24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0–24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. Conclusion These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01046-1.

Objective To evaluate the literature on a potential dexamethasone–direct oral anticoagulant (DOAC) drug interaction and provide management considerations with COVID hypercoagulability. Data Sources A search of EMBASE, PubMed, and Google Scholar (January 1990 to May 2021), limited to the English language, using applicable search terms resulted in 137 articles, with 21 relevant articles included. Regulatory agency and clinical guidance documents were also reviewed. Study Selection and Data Extraction Included articles describe in vitro or in vivo animal or human data for dexamethasone induction of cytochrome P450 (CYP) 3A4 or P-glycoprotein (P-gp). Data Synthesis Dexamethasone has the potential to interact with the DOACs via CYP3A4 and/or P-gp induction. Only apixaban and rivaroxaban have CYP3A4 metabolism. Dexamethasone can increase CYP3A4 activity by up to 70% and reduce the area under the concentration-time curve (AUC) of CYP3A4 substrates by >40%, which is consistent with criteria for a weak CYP inducer. In rodents, dexamethasone P-gp induction is associated with AUC reductions of 20% to 50%. Human data are lacking. Relevance to Patient Care and Clinical Practice Severe COVID-19 infection is associated with hypercoagulability. Although heparins are the preferred anticoagulants for hospitalized COVID-19 patients, DOACs are being utilized. Dexamethasone is recommended for hospitalized COVID-19 patients requiring supplemental oxygen. The concurrent use of dexamethasone and apixaban or rivaroxaban in such patients carries the potential for reduced anticoagulant effect during a state of heightened thrombotic risk. Conclusions Concurrent use of dexamethasone and apixaban or rivaroxaban in hospitalized COVID-19 patients with laboratory evidence of COVID coagulopathy should be avoided until higher-quality data are available.

Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

Over the past 15 years, there has been an increase in the development and utilization of newer antifungal agents. The ideal antifungal, however, in regard to spectrum of activity, pharmacokinetic/pharmacodynamic properties, development of resistance, safety, and drug interaction profile remains elusive. This article reviews pharmacologic aspects of Food and Drug Administration-approved polyenes, flucytosine, azoles, and echinocandins as well as promising pipeline antifungal agents. Unique properties of these newer agents are highlighted. The clinical role of established and investigational antifungal agents as treatment and/or prevention of invasive fungal infections is discussed.

BackgroundDrug-drug interaction (DDI) is a serious public health issue. The L1000 database of the LINCS project has collected millions of genome-wide expressions induced by 20,000 small molecular compounds on 72 cell lines. Whether this unified and comprehensive transcriptome data resource can be used to build a better DDI prediction model is still unclear. Therefore, we developed and validated a novel deep learning model for predicting DDI using 89,970 known DDIs extracted from the DrugBank database (version 5.1.4).ResultsThe proposed model consists of a graph convolutional autoencoder network (GCAN) for embedding drug-induced transcriptome data from the L1000 database of the LINCS project; and a long short-term memory (LSTM) for DDI prediction. Comparative evaluation of various machine learning methods demonstrated the superior performance of our proposed model for DDI prediction. Many of our predicted DDIs were revealed in the latest DrugBank database (version 5.1.7). In the case study, we predicted drugs interacting withsulfonylureasto cause hypoglycemia and drugs interacting withmetforminto cause lactic acidosis, and showed both to induce effects on the proteins involved in the metabolic mechanism in vivo.ConclusionsThe proposed deep learning model can accelerate the discovery of new DDIs. It can support future clinical research for safer and more effective drug co-prescription.

The incidence of melanoma is steadily increasing worldwide. Melanoma is the most lethal skin cancer, and new therapeutic methods are being sought. Our research aimed to investigate the cytotoxic and antiproliferative effects of betulinic acid in vitro, used alone and in combination with taxanes (paclitaxel, docetaxel) in four melanoma cell lines. Isobolographic analysis allowed us to assess the interactions between these compounds. Betulinic acid had no cytotoxic effect on normal human keratinocyte HaCaT cells; the amount of LDH released by them was significantly lower compared to melanoma cell lines. The present study shows that betulinic acid significantly inhibits the growth of melanoma cell lines in vitro. The IC50 values of betulinic acid ranged from 2.21 µM to 15.94 µM against the four melanoma lines. Co-treatment of betulinic acid with paclitaxel or docetaxel generated desirable drug–drug interactions, such as an additive and additive with a tendency to synergy interactions.

Drug-drug interactions (DDIs) between warfarin (WF) and fluoropyrimidines are well known. Co-administration of WF and 5-fluorouracil (5-FU) leads to elevations in prothrombin time international normalised ratio (PT-INR). The inhibition of drug metabolism through suppression of CYP activity is a possible cause of prolonged PT-INR elevations. 5-FU and its metabolites are suspected to inhibit CYPs, but the precise mechanisms of action remain unknown. This study aimed to investigate the possible DDI effects of the co-administration of 5-FU with WF using PT-INR and PT-INR/dose ratio as pharmacodynamic parameters. Retrospective case series data were collected from patients who received parenteral 5-FU chemotherapy from April 2009 to December 2019 at the University of the Ryukyus Hospital. Seven patients who received 5-FU in combination with WF were analysed. There was a significant increase in PT-INR and PT-INR/dose during the co-administration of WF and 5-FU (p = 0.0018 and p = 0.0187, respectively; paired t-test). The findings demonstrated significant DDI between 5-FU and WF evident as elevated PT-INR and PT-INR/dose ratio.

Aims: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium–glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial. Methods and results: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dl) versus tertile 1 (2), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06–1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI −0.93 to −0.74) over 12 months (p < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration. Conclusion: Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.

Ipatasertib is a pan-AKT inhibitor in development for the treatment of cancer. Ipatasertib was metabolized by CYP3A4 to its major metabolite, M1 (G-037720), and was a P-gp substrate and OATP1B1/1B3 inhibitor in vitro. A phase I drug-drug interaction (DDI) study (n = 15) was conducted in healthy subjects to evaluate the effect of itraconazole (200-mg solution QD, 4 days), a strong CYP3A4 and P-gp inhibitor, on pharmacokinetics of ipatasertib (100-mg single dose). Itraconazole increased the Cmax and AUC0-∞ of ipatasertib by 2.3- and 5.5-fold, respectively, increased the half-life by 53%, and delayed the tmax by 1 hour. The Cmax and AUC0-72h of its metabolite M1 (G-037720) reduced by 91% and 68%, respectively. This study confirmed that CYP3A4 plays a major role in ipatasertib clearance. Furthermore, the interaction of ipatasertib with coproporphyrin (CP) I and CPIII, the two endogenous substrates of OATP1B1/1B3, was evaluated in this study. CPI and CPIII plasma levels were unchanged in the presence of ipatasertib, both at exposures of 100 mg and at higher exposures in combination with itraconazole. This indicated no in vivo inhibition of OATP1B1/1B3 by ipatasertib. Additionally, it was shown that CPI and CPIII were not P-gp substrates in vitro, and itraconazole had no effect on CPI and CPIII concentrations in vivo. The latter is an important finding because it will simplify interpretation of future DDI studies using CPI/CPIII as OATP1B1/1B3 biomarkers. SIGNIFICANCE STATEMENT This drug-drug interaction study in healthy volunteers demonstrated that CYP3A4 plays a major role in ipatasertib clearance, and that ipatasertib is not an organic anion transporting polypeptide 1B1/1B3 inhibitor. Furthermore, it was demonstrated that itraconazole, an inhibitor of CYP3A4 and several transporters, did not affect CPI/CPIII levels in vivo. This increases the understanding and application of these endogenous substrates as well as itraconazole in complex drug interaction studies.

Purpose of review A number of pharmacokinetic and pharmacodynamic factors in critically ill or severely immunosuppressed patients influence the effectiveness of antifungal therapy making dosing less certain. Recent position papers from infectious diseases societies and working groups have proposed methods for dosage individualization of antibiotics in critically ill patients using a combination of population pharmacokinetic models, Monte-Carlo simulation and therapeutic drug monitoring (TDM) to guide dosing. In this review, we examine the current limitations and practical issues of adapting a pharmacometrics-guided dosing approaches to dosing of antifungals in critically ill or severely immunosuppressed populations. Recent findings We review the current status of antifungal susceptibility testing and challenges in incorporating TDM into Bayesian dose prediction models. We also discuss issues facing pharmacometrics dosage adjustment of newer targeted chemotherapies that exhibit severe pharmacokinetic drug-drug interactions with triazole antifungals. Summary Although knowledge of antifungal pharmacokinetic/pharmacodynamic is maturing, the practical application of these concepts towards point-of-care dosage individualization is still limited. User-friendly pharmacometric models are needed to improve the utility of TDM and management of a growing number of severe pharmacokinetic antifungal drug-drug interactions with targeted chemotherapies.

Background: Treatment of chronic Hepatitis C with directly acting antivirals (DAAs) can bring to sustained virologic response (SVR) in approximately 95% of patients. Efficacy and safety of DAAs in ...

This pharmacokinetic (PK) drug‐interaction trial investigated the effects of repeated dosing of a plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in Europe; 100 mg/mL oral solution) on caffeine clearance via modulation of cytochrome P450 (CYP) 1A2 activity in healthy adults. In this phase 1 open‐label, fixed‐sequence trial, all subjects received a single 200 mg caffeine dose and placebo on day 1. Subjects then titrated CBD from 250 mg once daily to 750 mg twice daily between days 3 and 11 and took 750 mg CBD twice daily between days 12 and 27. On day 26, subjects received a single 200‐mg caffeine dose with their morning CBD dose. Plasma concentrations of caffeine and its CYP1A2‐mediated metabolite, paraxanthine, were determined on days 1 and 26 and PK parameters derived using noncompartmental analysis. Safety was monitored throughout. Sixteen subjects enrolled, and 9 completed treatment. When caffeine was administered with steady‐state CBD, caffeine exposure increased by 15% for Cmax and 95% for AUC0‐∞, tmax increased from 1.5 to 3.0 hours, and t1/2 increased from 5.4 to 10.9 hours compared with caffeine administered with placebo. Under the same conditions, paraxanthine exposure decreased by 22% for Cmax and increased by 18% for AUC0‐∞, tmax increased from 8.0 to 14.0 hours, and t1/2 increased from 7.2 to 13.7 hours. Overall, there were no unexpected adverse events; diarrhea was most common, and 6 subjects discontinued because of elevated liver transaminases. These data suggest that CBD is an inhibitor of CYP1A2.

SPN‐812 (viloxazine extended‐release) is a novel nonstimulant recently approved as a treatment for attention‐deficit/hyperactivity disorder in children and adolescents. Given that SPN‐812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN‐812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single‐sequence, 3‐treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN‐812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN‐812 and paroxetine (period 3). Blood samples were collected for 72 hours post‐SPN‐812 dosing and analyzed for viloxazine and its primary metabolite, 5‐HVLX‐gluc. Twenty‐two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN‐812 and paroxetine was assessed using analysis of variance on the log‐transformed pharmacokinetic parameters Cmax, AUC0‐t, and AUCinf. The least‐squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN‐812 alone) Cmax, 116.04%; 90%CI, 109.49%‐122.99%; AUC0‐t, 134.65%; 90%CI, 127.65‐142.03; and AUCinf, 134.80%; 90%CI, 127.94%‐142.03%. CYP2D6 inhibition resulted in a modest change (

Dabrafenib; Drug interaction; Pharmacokinetics Dabrafenib; Interacción de fármacos; Farmacocinética Dabrafenib; Interacció de fàrmacs; Farmacocinètica Dabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation–positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open-label, fixed-sequence study in patients with BRAF V600 mutation–positive tumors. Repeat dabrafenib dosing resulted in a 2.56-fold increase in rosuvastatin maximum observed concentration (Cmax), an earlier time to Cmax, but only a 7% increase in area under the concentration-time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax. No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase. This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015.

Background Patients with kidney disease may have concurrent hypertension and infection. Dihydropyridine calcium-channel blockers (CCB) are the most popular class of antihypertensive drugs used in clinical settings and can be metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4). Voriconazole is a commonly used antifungal treatment and a CYP3A4-inhibitor. Insufficient attention to drug interactions from the concomitant use of CCB and voriconazole may result in serious adverse reactions. Case presentation Here, we report a patient with acute kidney injury on stable anti-neutrophil cytoplasm antibody associated vasculitis who developed hyperkalemia resulting in sinus arrest with junctional escape rhythm attributed to drug interactions of CCB with voriconazole. This is a very rarely reported case and may be an under-recognized complication. After continuous renal replacement therapy and changing the anti-hypertensive drugs, symptoms, and laboratory abnormalities of the patient fully recovered. Conclusions This case warns us of severe consequences of drug interactions. Co-prescription of CYP3A4-inhibitors with calcium-channel blockers increases the risk of hypotension and acute kidney injury, which may further induce hyperkalemia and arrhythmia.

Background and Purpose The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently call for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here, we investigated the therapeutic potential of targeting the interface of SARS CoV-2 with the host via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs in vitro. Experimental Approach We tested the antiviral potential of the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with the direct acting antiviral remdesivir, an inhibitor of viral RNA polymerase. Key Results Drug treatments were well-tolerated and potently impaired viral replication. Importantly, both itraconazole?remdesivir and fluoxetine?remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles?>?90% and displayed synergistic effects, as determined in commonly used reference models for drug interaction. Conclusion and Implications Itraconazole?remdesivir and fluoxetine?remdesivir combinations are promising starting points for therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.

Purpose The aim of our study was to analyse the frequency and severity of different types of potential interactions in oncological outpatients’ therapy. Therefore, medications, food and substances in terms of complementary and alternative medicine (CAM) like dietary supplements, herbs and other processed ingredients were considered. Methods We obtained data from questionnaires and from analysing the patient records of 115 cancer outpatients treated at a German university hospital. Drug–drug interactions were identified using a drug interaction checking software. Potential CAM-drug interactions and food–drug interactions were identified based on literature research. Results 92.2% of all patients were at risk of one or more interaction of any kind and 61.7% of at least one major drug–drug interaction. On average, physicians prescribed 10.4 drugs to each patient and 6.9 interactions were found, 2.5 of which were classified as major. The most prevalent types of drug–drug interactions were a combination of QT prolonging drugs (32.3%) and drugs with a potential for myelotoxicity (13.4%) or hepatotoxicity (10.1%). In 37.2% of all patients using CAM supplements the likelihood of interactions with medications was rated as likely. Food-drug interactions were likely in 28.7% of all patients. Conclusion The high amount of interactions could not be found in literature so far. We recommend running interaction checks when prescribing any new drug and capturing CAM supplements in medication lists too. If not advised explicitly in another way drugs should be taken separately from meals and by using nonmineralized water to minimize the risk for food–drug interactions.

Antibody–drug conjugates (ADCs) are important molecular entities in the treatment of cancer. These conjugates combine the target specificity of monoclonal antibodies with the potent anti-cancer activity of small-molecule therapeutics. The complex structure of ADCs poses unique challenges to characterize the drug’s pharmacokinetics (PKs) and pharmacodynamics (PDs) since it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (e.g., ADC conjugate, total antibody and unconjugated cytotoxic drug). As a result, clinical pharmacology strategy of an ADC is rather unique and dependent on the linker/cytotoxic drug technology, heterogeneity of the ADC, PK and safety/efficacy profile of the specific ADC in clinical development. In this review, we summarize the clinical pharmacology strategies in supporting development and approval of ADCs using the approved ADCs as specific examples to illustrate the customized approach to clinical pharmacology assessments in their clinical development.

Background: The interaction between azole antifungal therapy and immunosuppressant tacrolimus (TAC) is a barrier to use. Objective: This study quantified the drug interaction between low-dose fluconazole (LDF) and TAC to determine the appropriate TAC dose adjustment when used concurrently in renal transplant recipients. Methods: We conducted a single-center retrospective chart review of renal transplant patients >18 years who received LDF or nystatin (NYS), and TAC. The primary outcome was the difference in tacrolimus total daily dose (TAC TDD) for LDF versus NYS groups. Secondary outcomes included days with supratherapeutic, therapeutic and subtherapeutic tacrolimus levels, time to therapeutic level, incidence of adverse drug reactions and graft rejection. Results: We evaluated 94 patients and included 81. Low-dose fluconazole received a greater TAC TDD prior to post-operative day (POD) 10 (10.5 ± 4.7 mg vs. 7.1 ± 4.5 mg, p < 0.001), but a decreased TAC TDD POD 10 - 30 (8.6 ± 2.2 mg vs. 9.8 ± 0.8 mg, p < 0.001) and following LDF discontinuation (6.9 ± 0.1 mg vs. 9.0 ± 0.4 mg, p < 0.001). Low-dose fluconazole had more patient-days with supratherapeutic (17.9 ± 7.0 vs. 13.9 ± 8.5; p = 0.02) but fewer with subtherapeutic (6.7 ± 5.7 vs. 12.9 ± 7.2; p < 0.01) TAC levels. There was no difference in patient-days with therapeutic TAC levels (15.9 ± 5.8 vs. 14.4 ± 6.6, p = 0.28), meanwhile LDF required less patient-days to therapeutic TAC level (7.1 ± 2.7 vs. 11.5 ± 7.7; p < 0.01). There was no difference in adverse drug reactions between groups and no incidence of graft rejection. Conclusion: A 20% reduction in TAC TDD is warranted in renal transplant patients when used concomitantly with LDF to achieve therapeutic levels.