Interactions between SSRI's and statins: Clinical relevance versus statistical significance

2017 ◽  
Vol 41 (S1) ◽  
pp. S757-S758 ◽  
Author(s):  
S. Petrykiv ◽  
L. De Jonge ◽  
M. Arts
Keyword(s):  
Drug Interactions ◽  
Clinical Relevance ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Absolute Risk ◽  
Statistical Significance ◽  
Developed Countries ◽  
Lipid Lowering ◽  
Supporting Evidence ◽  
Cytochrome P450 Enzyme

IntroductionDepression and hypercholesterolemia are two of the most commonly treated conditions in the developed countries, while the lipid–lowering agents and antidepressants are among the most widely prescribed drugs in the world. There is a common concern that selective serotonin reuptake inhibitors (SSRIs) can trigger statin adverse effects, especially myopathy. However, the supporting evidence originates from studies in-vitro and big epidemiological studies. Recent pharmacokinetic insights indicate that the magnitude of pharmacokinetic interaction between SSRIs and statins is likely to be below the threshold for clinical significance.Objectives and aimsExplorative study on pharmacokinetic effects of SSRIs on statin drugs.MethodsWe performed a detailed literature review through PubMed, EMBASE and Cochran's Library to assess the clinical relevance of combined SSRIs and statin use. To address pharmacokinetic interactions between two drug groups, we focused on:– cytochrome P450 enzyme metabolism of statins;– CYP enzyme inhibition by SSRIs;– SSRIs–statin drug interactions;– non-CYP pharmacokinetic pathways.ResultsWith regard to pharmacokinetic drug interactions and the risk of statin related myopathy, escitalopram, citalopram, and paroxetine are to be safe in co-therapy with all statins. Rosuvastatin and pravastatin are almost certain to be safe in co-therapy with all SSRIs. Fluoxetine and sertraline are also likely to be safe, even when combined with atorvastatin, simvastatin, and lovastatin.ConclusionThough the absolute risk of concomitant use of SSRIs with statins seems to be negligible, even this risk can be minimized by using lower statin doses and monitoring the patient.Disclosure of interestThe authors have not supplied their declaration of competing interest.

2020 FDA Drug-drug Interaction Guidance: A Comparison Analysis and Action Plan by Pharmaceutical Industrial Scientists

2020 ◽  
Vol 21 (6) ◽  
pp. 403-426 ◽  
Author(s):  
Sirimas Sudsakorn ◽  
Praveen Bahadduri ◽  
Jennifer Fretland ◽  
Chuang Lu
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Drug Interactions ◽  
Action Plan ◽  
European Medicines Agency ◽  
Cytochrome P450 Enzyme ◽  
Interaction Studies ◽  
P450 Enzyme ◽  
Us Fda

Background: In January 2020, the US FDA published two final guidelines, one entitled “In vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry” and the other entitled “Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry”. These were updated from the 2017 draft in vitro and clinical DDI guidance. Methods: This study is aimed to provide an analysis of the updates along with a comparison of the DDI guidelines published by the European Medicines Agency (EMA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) along with the current literature. Results: The updates were provided in the final FDA DDI guidelines and explained the rationale of those changes based on the understanding from research and literature. Furthermore, a comparison among the FDA, EMA, and PMDA DDI guidelines are presented in Tables 1, 2 and 3. Conclusion: The new 2020 clinical DDI guidance from the FDA now has even higher harmonization with the guidance (or guidelines) from the EMA and PMDA. A comparison of DDI guidance from the FDA 2017, 2020, EMA, and PMDA on CYP and transporter based DDI, mathematical models, PBPK, and clinical evaluation of DDI is presented in this review.

Update on Drug Interactions with Azole Antifungal Agents

1998 ◽  
Vol 32 (9) ◽  
pp. 915-928 ◽  
Author(s):  
Ben M Lomaestro ◽  
Michelle Ann Piatek
Keyword(s):  
Drug Interactions ◽  
Clinical Relevance ◽  
Antimicrobial Agents ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Case Reports ◽  
Improve Patient Care ◽  
Double Blind ◽  
Medline Search

OBJECTIVE: T o review and update the incidence, mechanism, and clinical relevance of drug interactions with itraconazole, ketoconazole, and fluconazole. DATA SOURCES: Literature was identified by MEDLINE search (from January 1990 to May 1997) using the name of each antifungal and the term “interaction” as MeSH headings. Abstracts were identified by literature citation and by review of Interscience Conference on Antimicrobial Agents and Chemotherapy from 1995 to 1996. STUDY SELECTION: Randomized, controlled, double-blind studies were emphasized; however, uncontrolled studies and case reports were also included. In vitro data were selected from literature review and citations. DATA EXTRACTION: Data were evaluated with respect to study design, clinical relevance, magnitude of interaction, and recommendations provided. DATA SYNTHESIS: The incidence of fungal infections and consequent azole antifungal usage continues to increase. By virtue of their antifungal mechanism (i.e., inhibition of cytochrome P450 fungal enzyme systems), azoles have been investigated and implicated in several drug interactions. The magnitude of interactions can vary from trivial to potentially fatal, and also vary with specific azole and interactant. CONCLUSIONS: The azole antifungal agents represent a commonly used class of agents with a broad range of potential interactions. Recent data have increased our understanding of drug-drug interactions with azoles. Pharmacists are in a unique position to identify these interactions and to intervene to decrease their morbidity and improve patient care.

scholarly journals Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1566
Author(s):  
Kelly Bleasby ◽  
Robert Houle ◽  
Michael Hafey ◽  
Meihong Lin ◽  
Jingjing Guo ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Organic Anion Transporter ◽  
Uridine Diphosphate ◽  
Cancer Resistance ◽  
Treatment And Prevention ◽  
Anion Transporter

Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase–mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.

scholarly journals Meta-analysis of cardiovascular superiority trials published in the NewEnglandJournalofMedicine to elucidate the concept of superiority margin

2020 ◽  
pp. postgradmedj-2019-136569
Author(s):  
Nanda Gamad ◽  
Nusrat Shafiq ◽  
Samir Malhotra
Keyword(s):  
Clinical Relevance ◽  
Fixed Effects ◽  
Absolute Risk ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Effect Estimate ◽  
Number Needed To Treat ◽  
Significant Difference ◽  
Clinically Significant ◽  
Superiority Trials

ObjectiveTo show that overpowered trials claim statistical significance detouring clinical relevance and warrant the need of superiority margin to avoid such misinterpretation.DesignSelective review of articles published in the New England Journal of Medicine between 1 January 2015 and 31 December 2018 and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.Eligibility criteria for selecting studies and methodsPublished superiority trials evaluating cardiovascular diseases and diabetes mellitus with positive efficacy outcome were eligible. Fixed effects meta-analysis was performed using RevMan V.5.3 to calculate overall effect estimate, pooled HR and it was compared with mean clinically significant difference.ResultsThirteen eligible trials with 164 721 participants provided the quantitative data for this review. Largely, the primary efficacy endpoint in these trials was the composite of cardiovascular death, non-fatal myocardial infarction, unstable angina requiring rehospitalisation, coronary revascularisation and fatal or non-fatal stroke. The pooled HR was 0.86 (95% CI 0.84 to 0.89, I2=45%) which was lower than the mean clinically significant difference of 0.196 (19.6%, range: 0.09375–0.35) of these studies. There was a wide 95% CI in these studies from 0.56 to 0.99. The upper margin of CI in most of the studies was close to the line of no difference. Absolute risk reduction was small (1.19% to 2.3%) translating to a high median number needed to treat of 63 (range: 43 to 84) over a follow-up duration of 2.95 years.ConclusionsThe results of this meta-analysis indicate that overpowered trials give statistically significant results undermining clinical relevance. To avoid such misuse of current statistical tools, there is a need to derive superiority margin. We hope to generate debate on considering clinically significant difference, used to calculate sample size, as superiority margin.

The Carpentier-Edwards Classic and Physio Mitral Annuloplasty Rings: A Randomized Trial

2006 ◽  
Vol 8 (5) ◽  
pp. 389 ◽  
Author(s):  
Ghada M. M. Shahin ◽  
Geert J. M. G. van der Heijden ◽  
Michiel L. Bots ◽  
Maarten-Jan Cramer ◽  
Wybren Jaarsma ◽  
...  
Keyword(s):  
Left Ventricular Function ◽  
Ventricular Function ◽  
Absolute Risk ◽  
Statistical Significance ◽  
Nyha Class ◽  
Left Ventricular ◽  
Mitral Annuloplasty ◽  
Risk Of Death ◽  
Late Failure

<P>Objective: To evaluate clinical and echocardiographic outcomes for the semi-flexible Carpentier-Edwards Physio and the rigid Classic mitral annuloplasty ring. </P><P>Methods: Ninety-six patients were randomized for either a Classic (n = 53) or a Physio (n = 43) ring from October 1995 through July 1997. Mean follow-up was 5.1 years (range .1-6.6). We included standard patient characteristics at baseline and during follow-up. Analyses were adjusted for age and gender, and for factors that differed across groups at baseline. In 2002, echocardiography was performed in 74% of the survivors. </P><P>Results: We found a 16% difference in mortality: 14% in the Physio group (n = 6) and 30% in the Classic group (n = 16) (adjusted P = .41). Life table analysis shows that the absolute risk of death after 30 months is lower in the Physio group. Intra-operative repair failure occurred in 3 patients (6%) of the Classic group, and in 4 (9%) of the Physio group, resulting in mitral valve replacement. Late failure occurred in 1 patient (2%) in the Classic group, and in 4 (9%) in the Physio group. At follow-up, left ventricular function did not differ across groups (ejection fraction 45% and 48% (adjusted P = .65)). The combined NYHA class III-IV had improved for the Classic group in 42% and for the Physio group in 34%. </P><P>Conclusion: Although the 16% difference in mortality did not reach statistical significance, it is considered clinically important. No differences in morbidity, valve function, and left ventricular function were found. Further research to explain the difference in mortality is required.</P>

Pharmacokinetic Drug-drug Interaction of Antibiotics Used in Sepsis Care in China

2020 ◽  
Vol 21 ◽  
Author(s):  
Xuan Yu ◽  
Zixuan Chu ◽  
Jian Li ◽  
Rongrong He ◽  
Yaya Wang ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Penicillin G ◽  
Literature Mining ◽  
Human Pharmacokinetics ◽  
P450 Enzyme ◽  
Drug Drug Interaction ◽  
Pharmacokinetic Drug ◽  
Sepsis Care

Background: Many antibiotics have a high potential for having an interaction with drugs, as perpetrator and/or victim, in critically ill patients, and particularly in sepsis patients. Methods: The aim of this review is to summarize the pharmacokinetic drug-drug interaction (DDI) of 45 antibiotics commonly used in sepsis care in China. Literature mining was conducted to obtain human pharmacokinetics/dispositions of the antibiotics, their interactions with drug metabolizing enzymes or transporters, and their associated clinical drug interactions. Potential DDI is indicated by a DDI index > 0.1 for inhibition or a treated-cell/untreated-cell ratio of enzyme activity being > 2 for induction. Results: The literature-mined information on human pharmacokinetics of the identified antibiotics and their potential drug interactions is summarized. Conclusion: Antibiotic-perpetrated drug interactions, involving P450 enzyme inhibition, have been reported for four lipophilic antibacterials (ciprofloxacin, erythromycin, trimethoprim, and trimethoprim-sulfamethoxazole) and three lipophilic antifungals (fluconazole, itraconazole, and voriconazole). In addition, seven hydrophilic antibacterials (ceftriaxone, cefamandole, piperacillin, penicillin G, amikacin, metronidazole, and linezolid) inhibit drug transporters in vitro. Despite no reported clinical PK drug interactions with the transporters, caution is advised in the use of these antibacterials. Eight hydrophilic antibacterials (all β-lactams; meropenem, cefotaxime, cefazolin, piperacillin, ticarcillin, penicillin G, ampicillin, and flucloxacillin), are potential victims of drug interactions due to transporter inhibition. Rifampin is reported to perpetrate drug interactions by inducing CYP3A or inhibiting OATP1B; it is also reported to be a victim of drug interactions, due to the dual inhibition of CYP3A4 and OATP1B by indinavir. In addition, three antifungals (caspofungin, itraconazole, and voriconazole) are reported to be victims of drug interactions because of P450 enzyme induction. Reports for other antibiotics acting as victims in drug interactions are scarce.

Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19

2020 ◽  
Vol 21 (6) ◽  
pp. 427-435 ◽  
Author(s):  
Cheng Cui ◽  
Siqi Tu ◽  
Valerie Sia Jie En ◽  
Xiaobei Li ◽  
Xueting Yao ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Clinical Efficacy ◽  
Relevant Literature ◽  
The United States ◽  
Efficacy And Safety ◽  
Open Label ◽  
Infected People ◽  
Treatment Regimens ◽  
Therapeutic Drugs

Background: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. Methods: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. Results: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. Conclusion: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

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