Nature Of Drug-drug Interactions Research Articles

In vitro to clinical translation of combinatorial effects of doxorubicin and dexrazoxane in breast cancer: a mechanism-based pharmacokinetic/pharmacodynamic modeling approach.

Dexrazoxane (DEX) is the only drug clinically approved to treat Doxorubicin-induced cardiotoxicity (DIC), however its impact on the anticancer efficacy of DOX is not extensively studied. In this manuscript, a proof-of-concept in vitro study is carried out to quantitatively characterize the anticancer effects of DOX and DEX and determine their nature of drug-drug interactions in cancer cells by combining experimental data with modeling approaches. First, we determined the static concentration-response of DOX and DEX in breast cancer cell lines, JIMT-1 and MDA-MB-468. With a three-dimensional (3D) response surface analysis using a competitive interaction model, we characterized their interaction to be modestly synergistic in MDA-MB-468 or modestly antagonistic in JIMT-1 cells. Second, a cellular-level, pharmacodynamic (PD) model was developed to capture the time-course effects of the two drugs which determined additive and antagonistic interactions for DOX and DEX in MDA-MB-468 and JIMT-1, respectively. Finally, we performed in vitro to in vivo translation by utilizing DOX and DEX clinical dosing regimen that was previously identified to be maximally cardioprotective, to drive tumor cell PD models. The resulting simulations showed that a 10:1 DEX:DOX dose ratio over three cycles of Q3W regimen of DOX results in comparable efficacy based on MDA-MB-468 (additive effect) estimates and lower efficacy based on JIMT-1 (antagonistic effect) estimates for DOX + DEX combination as compared to DOX alone. Thus, our developed cell-based PD models can be used to simulate different scenarios and better design preclinical in vivo studies to further optimize DOX and DEX combinations.

The intersection of drug interactions and adverse reactions in contemporary antiretroviral therapy.

Advances in antiretroviral therapy (ART) have transformed HIV infection into a chronic and manageable condition. The introduction of potent and more tolerable antiretrovirals (ARVs) with favorable pharmacokinetic profiles has changed the prevalence and nature of drug-drug interactions (DDIs). Here, we review the relevance of DDIs in the era of contemporary ART. Management of DDIs remains an important challenge with modern ART, primarily due to increased polypharmacy in older persons living with HIV. Significant DDIs exist between boosted ARVs or older nonnucleoside reverse transcriptase inhibitors and comedications for chronic comorbidities (e.g., anticoagulants, antiplatelets, statins) or complex conditions (e.g., anticancer agents, immunosuppressants). Newer ARVs such as unboosted integrase inhibitors, doravirine, and fostemsavir have reduced DDI potential, but there are clinically relevant DDIs that warrant consideration. Potential consequences of DDIs include increased toxicity and/or reduced efficacy of ARVs and/or comedications. Management approaches include switching to an ARV with less DDI potential, changing comedications, or altering medication dosage or dosing frequency. Deprescribing strategies can reduce DDIs and polypharmacy, improve adherence, minimize unnecessary adverse effects, and prevent medication-related errors. Management of DDIs requires close interdisciplinary collaboration from multiple healthcare disciplines (medicine, nursing, pharmacy) across a spectrum of care (community, outpatient, inpatient).

Clinically Relevant Drug-Drug Interactions and Management Strategies: A Hospital based Study

Background: Drug-drug interactions (DDIs) are one of the significant drug related problems encountered in clinical settings. Better understanding of the mechanisms, severity, and likely consequences of clinically significant DDIs are essential for proper medication therapy management (MTM). This study is conducted with the aim to aware clinical practitioners about clinically significant DDIs that occur in clinical settings and to help them manage such events with the accurate knowledge and technique.
 Methods: A descriptive cross-sectional study was conducted in Shree Birendra Hospital, Kathmandu on the prescription of medical out-patient department from June to November 2020. Total 483 prescriptions were selected randomly. A panel of physicians, pharmacologists and clinical pharmacists under the supervision of a consultant physician using MICROMEDEX DRUG-REAX, Evaluation of Drug Interactions, Drug Interaction Facts, Drug Interactions: Analysis and Management was conducted. Main outcome measure was obtained by the supervisor’s endorsement on panelists' opinion about clinical importance of DDIs.
 Results: A total of 2006 medicines were prescribed in 483 prescription samples. The number of drugs per prescription was in a range from 2 to 11 with 4.15 on average. DDIs were found in 21.53% prescriptions (n=104). 168 DDIs were identified with major, moderate, and minor types in 32 (19%), 85 (51%), and 51 (30%) respectively. As per occurrence, the panel determined that 13 interactions were clinically important.
 Conclusion: The drug interactions identified by a panel of expert using standard evaluation tool are considered to be clinically important and likely to occur in the clinical settings. Clinically significant DDIs can be preventable and can also be used for the beneficial effects in MTM. Adequate knowledge regarding nature of DDIs, inclusion of automated system in prescribing and dispensing area, and inter-professional collaboration of a clinical team is liable to prevent and manage such events and help in rational drug therapy.

Serotonin Syndrome: Analysis of Cases Registered in the French Pharmacovigilance Database.

More information would be required for a better understanding of the actual circumstances of serotonin syndrome (SS) occurrence in routine clinical practice. The objective of the study was to analyze characteristics of SS French pharmacovigilance reports, especially involved drugs and nature of drug-drug interactions (DDIs). We performed a retrospective analysis of SS registered in the French pharmacovigilance database between January 1, 1985 and May 27, 2013. Only cases whose clinical symptoms fulfilled Sternbach, Radomski, or Hunter SS diagnostic criteria were retained for the analysis. Most of the 125 (84.0%) analyzed cases were associated with a recent change in a serotonergic drug (introduction, increasing the dose or overdose). Antidepressants were the most often involved serotonergic drugs, mostly serotonin reuptake inhibitors (SRIs, 42.1%) and to a lesser extent serotonin-noradrenalin reuptake inhibitors (9.1%, mainly venlafaxine), tricyclic antidepressants (8.6%, mainly clomipramine), and some monoamine oxidase inhibitors (6.2%, mainly moclobemide). Nonpsychotropic medications were also involved, generally opioids (14.8%, mainly tramadol). Most of the cases (59.2%) resulted from pharmacodynamic DDIs, most often involving SRIs + opioids (mostly paroxetine + tramadol). However, SS also occurred with a single serotonergic drug in a significant number of cases (40.8%), most often SRIs (mainly fluoxetine) or venlafaxine at usual doses. Lastly, a major pharmacokinetic DDI could have played a role in 1/5 (20.8%) of cases. This is the first study about SS based on a large pharmacovigilance database and published in English. Our results reveal not only the frequent involvement of antidepressants and tramadol, the importance of DDIs (both pharmacodynamic and pharmacokinetic), but also the significant risk of SS even with a single serotonergic drug used at normal dose.

Drug-Drug Interactions in the Hematology and Oncology Department: A Real-Life Assessment of Frequency and Severity

Abstract 4250 Introduction:Drug-drug interactions (DDI) may lead to adverse drug events and constitute a risk for patients and a major challenge for treating physicians. Especially cancer patients receive a considerable number of concomitant drugs for the treatment of the underlying disease, the side effects of cancer therapy and due to preexisting comorbidities. As more and more older and severely compromised patients are treated today, polypharmacy and its related problems are of growing importance. However, data on the frequency and nature of DDI in cancer patients during hospitalization are rare. Methods:To determine the prevalence and nature of potential DDI, we performed a detailed chart review of all hospitalized patients in our hematology and oncology department during two randomly appointed days. All medications administered on these very days were extracted from the electronically archived patients' medical charts. DDI were identified and rated for severity and level of evidence using two different electronic interaction databases, Micromedex 2.0 and Lexi-Interact. Only DDI of at least moderate severity (i.e. rated as moderate, major or contraindicated) were included in the analysis, and documented irrespective of their actual clinical consequences. At the time of analysis, no routinely performed DDI screening or electronic DDI alert system was in place in our department. Results:Medication profiles from 157 inpatients were analyzed. Patients’ median age was 62 years (range: 25–94). Underlying diseases were leukemia (n=51), lymphoma (n=49), solid tumors (n=49) and non-malignant diseases (n=8). We evaluated a total of 1748 drug prescriptions with a median of 11 drugs per patient and day (range: 1–22). The median number of drugs was 9 in patients with solid tumors, 11 in patients with leukemia, and 12 in patients with lymphoma or non-malignant diseases. We found a total of 1153 drug interactions rated as of at least moderate severity by either Micromedex or Lexi-Interact, which corresponds to 734 DDI/100 patient days. The drug classes most frequently involved comprised antibiotics (23%), antifungals (21%), diuretics (20%), corticosteroids (17%), calcium channel blockers (11%), immunosuppressants (10%), benzodiazepines (9%) and opioid analgesics (8%). Antineoplastic drugs constituted 2.7% of all prescribed drugs, and were involved in 47 DDI (4%). The severity rating for all DDI was contraindicated, major and moderate in 2%, 24% and 74% of cases, respectively, according to the respective higher rating of both databases. The median number of DDI per patient was 5 (range: 0–31), and was highest for patients with leukemia with a median number of 7. 85% of patients experienced at least one DDI, and 26% of patients were exposed to ≥10 DDI on the evaluated day. The level of evidence of the 1153 DDI identified was excellent, good, fair and poor in 10%, 45%, 44% and 1% of cases, respectively.To identify the most clinically relevant DDI, we also determined the frequency and nature of those DDI which were rated as major severity or contraindicated by both databases. 61 DDI fulfilled these criteria and occurred in 33/157 patients (21%). The level of evidence of those 61 DDI was excellent, good and fair in 18%, 28% and 54% of cases, respectively. The most frequently detected potential clinical consequences of the 61 DDI rated as major or contraindicated by both databases were QT-prolongation with a variety of drug combinations (n=36), extrapyramidal reactions of different combinations including metoclopramide (n=5), and cyclosporine toxicity in combination with voriconazole (n=4). Conclusions:This retrospective DDI analysis revealed a high percentage of patients encountering DDI, including contraindicated drug combinations. Although some of these DDI are difficult to avoid or well manageable through close monitoring of the patients' clinical condition or laboratory results, there is a strong need for rising awareness of DDI to avoid patient harm. This is of particular relevance in the hematology and oncology setting, where numerous drugs are being applied, including cytotoxic agents. By identifying the most relevant DDI in this setting, these results allow targeted physician education and highlight the need to implement an electronic prescription system with DDI alerts in close cooperation with clinical pharmacists. Disclosures:No relevant conflicts of interest to declare.

Drug-drug interaction study to assess the effects of atorvastatin co-administration on pharmacokinetics and anti-thrombotic properties of cilostazol in male Wistar rats

Cilostazol (CLZ) and atorvastatin (ATV) are often co-prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug-drug interaction potential of multi-dose ATV co-administration with CLZ on both pharmacokinetics and the anti-thrombotic property of CLZ is demonstrated. The pharmacokinetic parameters of CLZ (6 mg/kg, twice daily) were determined in male Wistar rats after 7 days co-administration with ATV (5 mg/kg, once daily) in order to assess the interaction potential between CLZ and ATV on chronic treatment. In vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Pharmacodynamic drug-drug interaction was evaluated on anti-thrombotic models including time to occlusion, platelet aggregation and rat tail bleeding time. A validated LC-MS/MS method was employed simultaneously to quantify both ATV and CLZ in rat plasma matrix. A statistically significant increase in systemic exposure (Css(max) by ~1.75 fold; AUC by ~3.0 fold) to CLZ was observed in ATV pre-treated rats. In vitro metabolism studies using liver microsomes (RLM and HLM) demonstrated statistically significant inhibition of CLZ metabolism when co-incubated with ATV. No change in apparent permeability of CLZ was observed in the presence of ATV. Atorvastatin showed a significant delay in artery occlusion time without altering CLZ's bleeding time and platelet aggregation profile. Collectively the results of these studies provide metabolic insight into the nature of drug-drug interaction between the selected drugs. Co-administration with ATV influences the pharmacokinetics and anti-thrombotic property of CLZ. A thorough clinical investigation is required before extrapolation of data to humans.

Frequency and nature of drug-drug interactions in a Swiss primary and secondary acute care hospital

Drug-drug interactions (DDI) are considered a risk factor in medication safety and computerised alerting tools are increasingly promoted and implemented in order to detect and minimise DDI. As only little is known about the frequency and nature of DDI in hospitalised patients in Switzerland as well as about the usefulness of current alerting systems, this analysis based on a computerised medication record in a typical regional hospital setting was performed. All inpatients with at least one drug prescription between 2006 and 2010 were included. A total of 1,654,987 prescriptions were analysed with regard to the maximal seriousness level of DDI between each added prescription versus the existing prescription and with regard to all underlying DDI. On average, each inpatient received 16 different drugs including on-demand prescriptions and encountered 5 DDI. A total of 27% of all prescriptions caused DDI. Within the last 12 months, 5% of all DDI were classified in category 1 (contraindicated), 3% in category 2, 53% in category 3, 8% in category 4 and 31% in category 5. The vast majority of DDI were caused by a very limited number of drugs. Drug-drug interactions were very frequent and were very stable over the years studied, involving on average 27% of all prescriptions and 44% in internal medicine. Only a very limited amount of drugs were responsible for the vast majority of DDI, especially when the most severe categories of DDI were considered. Most of the severe DDI alerts could be automatically handled, if for example laboratory values could be taken into account. The DDI database should ideally be supplemented by information enabling more sophisticated computerised support in order to deliver more reasonable results from DDI checks.

Mechanistic studies on metabolic interactions between gemfibrozil and statins.

A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administration of a single dose of SV (4 mg/kg p.o.) to dogs pretreated with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (approximately 4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but not to SV, similar to the observation in humans. GFZ pretreatment did not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. After i.v. administration of [(14)C]SVA to dogs, GFZ treatment significantly reduced (2-3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA, consistent with the in vitro findings in dogs. Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA. Further studies conducted in human liver microsomes with atorvastatin (AVA) showed that, as with SVA, GFZ was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation. However, with cerivastatin (CVA), the glucuronidation as well as the CYP2C8- and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by GFZ than was observed with SVA or AVA. Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction between GFZ and statins, and a possible explanation for the enhanced susceptibility of CVA to interactions with GFZ.