Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etravirine has been approved in several ...countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo, etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur. When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Co-administration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St John's wort (Hypericum perforatum) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied.
Objectives
Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by ...tropisetron, a 5‐hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans.
Methods
Twenty‐six rapid metabolizers of tropisetron were included in this double‐blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self‐evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0–4 hours) (mean ± SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction.
Results
The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time % · min) (2145 ± 2901 % · min) was totally inhibited by both tropisetron (89 ± 1747 % · min, P = .007) and granisetron (45 ± 2020 % · min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309).
Conclusion
These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients.
Clinical Pharmacology & Therapeutics (2006) 79, 371–378; doi: 10.1016/j.clpt.2005.12.307
To study the main comedications associated with major bleeding during anticoagulant therapy with coumarins in a non-selected population under everyday circumstances.
The study population for this ...retrospective cohort study included all new users of phenprocoumon or acenocoumarol aged 40-80 years, during the period 1992-2000 in the PHARMO Record Linkage System. All patients were followed until the last dispensing of phenprocoumon or acenocoumarol, the first bleeding complication requiring hospitalization, death, or the end of the study period. The number of days on coumarins alone and the number of days on coumarins in combination with several potentially interactive drugs during follow-up were determined for each patient.
The inclusion criteria of this study were met by 19,935 new users of phenprocoumon or acenocoumarol. During follow-up, 552 patients were hospitalized for bleeding. Of all potentially interactive drugs started during anticoagulant therapy by at least 50 patients and with at least five bleedings, antibacterial drugs were associated with a four to seven times increased risk of bleeding. Among non-steroidal anti-inflammatory drugs, naproxen had the highest relative risk. Antithrombotic salicylates and tramadol were associated with a three times increased risk of bleeding.
Antibacterial drugs, non-steroidal anti-inflammatory drugs, antithrombotic salicylates and tramadol were the main potentially interactive drugs associated with major bleeding during anticoagulant therapy with coumarins under everyday circumstances.
Orlistat, an anti-obesity drug, is a potent and specific inhibitor of intestinal lipases. In light of the recent US FDA approval of the over-the-counter sale of orlistat (60 mg three times daily), ...clinicians need to be aware that its use may be associated with less well known, but sometimes clinically relevant, adverse effects. More specifically, the use of orlistat has been associated with several mild-to-moderate gastrointestinal adverse effects, such as oily stools, diarrhoea, abdominal pain and faecal spotting. A few cases of serious hepatic adverse effects (cholelithiasis, cholostatic hepatitis and subacute liver failure) have been reported. However, the effects of orlistat on non-alcoholic fatty liver disease are beneficial. Orlistat-induced weight loss seems to have beneficial effects on blood pressure. No effect has been observed on calcium, phosphorus, magnesium, iron, copper or zinc balance or on bone biomarkers. Interestingly, the use of orlistat has been associated with rare cases of acute kidney injury, possibly due to the increased fat malabsorption resulting from the inhibition of pancreatic and gastric lipase by orlistat, leading to the formation of soaps with calcium and resulting in increased free oxalate absorption and enteric hyperoxaluria. Orlistat has a beneficial effect on carbohydrate metabolism. No significant effect on cancer risk has been reported with orlistat.Orlistat interferes with the absorption of many drugs (such as warfarin, amiodarone, ciclosporin and thyroxine as well as fat-soluble vitamins), affecting their bioavailability and effectiveness. This review considers orlistat-related adverse effects and drug interactions. The clinical relevance and pathogenesis of these effects is also discussed.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Serotonin toxicity is greatly increased by the co‐prescribing of serotonergic agents.
• Serotonin toxicity varies greatly in severity from mild to ...potentially life‐threatening, however even mild cases can impair quality of life, especially for older people, by causing agitation and sleep disturbance. Combinations including MAOI are most likely to cause severe toxicity.
• Few studies have used pharmaceutical claims data to quantify the use of serotonergic medicines in combination.
WHAT THIS STUDY ADDS
• In a cohort of elderly Australian veterans and dependants, we found widespread use of serotonergic medicines: 115 969 (42%) of the study population (n = 273 228) were dispensed at least one of these medicines between July 2000 and June 2004.
• Approximately 8% (20 658 individuals) experienced at least one episode of potential concomitant use of serotonergic medicine combinations.
• Potentially life‐threatening combinations involving MAOIs were of concern: 1811 (0.7%) individuals had at least one episode with such combinations.
• This study demonstrates the utility and benefits of pharmaceutical claims data to provide insights into real‐world prescribing.
AIMS
We examined potential risk of serotonin toxicity in Australian veterans by quantifying the concomitant use of serotonergic medicine combinations from claims data collected by the Department of Veterans’ Affairs (DVA).
METHODS
This was a retrospective cohort study of 273 228 Australian veterans, war widows, widowers and dependants aged ≥55 years and holding full treatment entitlement for the period July 2000 to June 2004 or until death. The main outcome measure was potential concomitant use, estimated as the number of cohort members with an overlap in days of supply for serotonergic medicine combinations over the 4 year period for all medicine combinations and potentially life threatening combinations.
RESULTS
From July 2000 to June 2004, 115 969 (42%) cohort members were dispensed at least one serotonergic medicine. 20 658 (8%) had at least one episode of potential concomitant use. We identified 1811 (0.7%) cohort members with at least one overlapping period of potentially life‐threatening serotonergic medicine combinations, 937 of whom had the combinations dispensed within the recommended washout period. Three hundred and seventeen of these individuals were dispensed potentially life‐threatening medicine combinations on the same day. The most common combinations were moclobemide with a selective serotonin reuptake inhibitor or tramadol.
CONCLUSIONS
The individuals potentially at risk of mild to moderate serotonin toxicity were considerable and potentially life threatening combinations were not infrequent. While we were unable to determine how many individuals experienced serotonin toxicity this study indicates, for the first time, the potential size of the problem in a subgroup of elderly Australians. Clinicians and patients need to be vigilant regarding inadvertent concomitant use, especially that of moclobemide with a selective serotonin reuptake inhibitor or tramadol.
Vicriviroc is a next-generation antiretroviral compound that blocks HIV from entering uninfected cells by binding to the virus's cellular co-receptor chemokine receptor 5 (CCR5). A potent inhibitor ...of HIV infection of human cells both in vitro and in vivo, vicriviroc is in development for use in treatment-naïve HIV-1-infected individuals. These patients often receive antiretroviral therapy regimens that include a ritonavir-enhanced protease inhibitor. Such regimens have a high potential for drug-drug interactions because many of the antiretroviral agents inhibit or induce elements of drug elimination pathways, such as the hepatic cytochromes, which may alter drug concentrations and affect both safety and efficacy. The aim of this set of studies was to determine what, if any, dose adjustments or monitoring would be required to use vicriviroc in regimens containing the most common antiretroviral agents.
Drug-drug interactions between vicriviroc and 11 other antiretroviral compounds were investigated in fixed-sequence or parallel-group clinical trials lasting 12-35 days. Fixed-sequence studies were conducted with the protease inhibitors atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, saquinavir and tipranavir. In these studies vicriviroc was administered with ritonavir for a fixed duration, followed by administration of vicriviroc with ritonavir plus the protease inhibitor. Parallel-group studies conducted with lopinavir, zidovudine/lamivudine and tenofovir disoproxil fumarate randomized subjects to receive vicriviroc with or without the study drug. All subjects enrolled in the studies were healthy male and female adults.
The log-transformed data for vicriviroc primary pharmacokinetic parameters on appropriate days were statistically analysed using a one-way analysis of variance (ANOVA) model extracting the effects due to treatment. Steady state was evaluated by an ANOVA model on trough concentrations using day and subject as class variables.
Vicriviroc exposure was not affected by the concurrently administered antiretroviral drugs in any clinically relevant manner, nor did vicriviroc have a clinically relevant effect on the exposure of other drugs. The drug combinations studied were safe and well tolerated, with most adverse events reported as mild to moderate. Aside from the known toxicities of the other antiretroviral drugs, no clinically relevant changes in blood chemistry, haematological parameters, ECGs or vital signs were associated with either vicriviroc or combination treatment.
No dose modification or monitoring of vicriviroc concentrations is necessary when vicriviroc is co-administered with any of the antiretroviral agents reviewed here. The lack of drug-drug interactions suggests that it will be possible to add vicriviroc at the single clinically prescribed dose level to various background regimens that include a boosted protease inhibitor, with all other drugs also prescribed at their standard doses.
Purpose
Due to polypharmacy and the rising popularity of complementary and alternative medicines (CAM), oncology patients are particularly at risk of drug–drug interactions (DDI) or herb–drug ...interactions (HDI). The aims of this study were to assess DDI and HDI in outpatients taking oral anticancer drug.
Method
All prescribed and non-prescribed medications, including CAM, were prospectively collected by hospital pharmacists during a structured interview with the patient. DDI and HDI were analyzed using four interaction software programs:
Thériaque
®
, Drugs.com
®
,
Hédrine
, and
Memorial Sloan Kettering Cancer Center (MSKCC)
database
.
All detected interactions were characterized by severity, risk and action mechanism. The need for pharmaceutical intervention to modify drug use was determined on a case-by-case basis.
Results
294 patients were included, with a mean age of 67 years 55–79. The median number of chronic drugs per patient was 8 1–29 and 55% of patients used at least one CAM. At least 1 interaction was found for 267 patients (90.8%): 263 (89.4%) with DDI, 68 (23.1%) with HDI, and 64 (21.7%) with both DDI and HDI. Only 13% of the DDI were found in
Thériaque
®
and Drugs.com
®
databases, and 125 (2.5%) were reported with similar level of risk on both databases. 104 HDI were identified with only 9.5% of the interactions found in both databases. 103 pharmaceutical interventions were performed, involving 61 patients (20.7%).
Conclusion
Potentially clinically relevant drug interaction were frequently identified in this study, showing that several databases and structured screening are required to detect more interactions and optimize medication safety.
Abstract
DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in ...2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education.
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.
Background
The concomitant use of tyrosine kinase inhibitors (TKIs) and proton pump inhibitors (PPIs) is a significant concern because of potential drug‐drug interaction that reduces TKI absorption, ...thus potentially reducing the effectiveness of TKIs. The objective of this study was to evaluate the prevalence and predictors of concomitant TKI‐PPI receipt and its impact on survival and therapy discontinuation in older adults with cancer.
Methods
This retrospective study used linked Surveillance, Epidemiology, and End Results‐Medicare data for the years 2007 through 2012. In total, 12,538 patients with lung cancer, renal cell cancer, chronic myelogenous leukemia, liver cancer, or pancreatic cancer were included. The primary exposure variable was concomitant receipt of TKI‐PPI, defined as at least 30 days of PPI use in the first 90 days from the start of the TKI (exposure period). The outcomes measured were overall survival and discontinuation of therapy in 90 days and 1 year after the end of the exposure period. Cox proportional‐hazards regression with inverse probability of treatment weighting was used to evaluate the association between exposure and outcome.
Results
The overall prevalence of TKI‐PPI receipt was 22.7%. Predictors that were associated with increased use included polypharmacy and prior PPI receipt. TKI‐PPI use decreased survival in 90 days (hazard ratio, 1.16; 95% confidence interval, 1.05‐1.28) and in 1 year (hazard ratio, 1.10; 95% confidence interval, 1.04‐1.18) but was not associated with discontinuation.
Conclusions
Nearly 1 in 4 older adults with cancer who receive TKIs also receive PPIs concomitantly, and concomitant use is associated with an increased risk of death. Concerted efforts to manage medications are needed to identify and reduce the receipt of PPIs when TKIs are initiated.
Nearly 1 in 4 older adults with cancer concomitantly receive interacting tyrosine kinase inhibitors and proton pump inhibitors. The concomitant use of these drugs is associated with an increased risk of death.
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