Assessment Of Drug Interactions Research Articles

Potential protective effect of sunitinib after administration of diclofenac: biochemical and histopathological drug–drug interaction assessment in a mouse model

Sunitinib is a tyrosine kinase inhibitor for GIST and advanced renal cell carcinoma. Diclofenac is used in cancer pain management. Coadministration may mediate P450 toxicity. We evaluate their interaction, assessing biomarkers ALT, AST, BUN, creatinine, and histopathological changes in the liver, kidney, heart, brain, and spleen. ICR mice (male, n = 6 per group/dose) were administered saline (group A) or 30 mg/kg diclofenac ip (group B), or sunitinib po at 25, 50, 80, 100, 140 mg/kg (group C) or combination of diclofenac (30 mg/kg, ip) and sunitinib (25, 50, 80, 100, 140 mg/kg po). Diclofenac was administered 15 min before sunitinib, mice were euthanized 4 h post-sunitinib dose, and biomarkers and tissue histopathology were assessed. AST was 92.2 ± 8.0 U/L in group A and 159.7 ± 14.6 U/L in group B (p < 0.05); in group C, it the range was 105.1-152.6 U/L, and in group D, it was 156.0-209.5 U/L (p < 0.05). ALT was 48.9 ± 1.6 U/L (group A), 95.1 ± 4.5 U/L (p < 0.05) in group B, and 50.5-77.5 U/L in group C and 82.3-115.6 U/L after coadministration (p < 0.05). Renal function biomarker BUN was 16.3 ± 0.6 mg/dl (group A) and increased to 29.9 ± 2.6 mg/dl in group B (p < 0.05) and it the range was 19.1-33.3 mg/dl (p < 0.05) and 26.9-40.8 mg/dl in groups C and D, respectively. Creatinine was 5.9 pmol/ml in group A; 6.2 pmol/ml in group B (p < 0.01), and the range was 6.0-6.2 and 6.2-6.4 pmol/ml in groups C and D, respectively (p < 0.05 for D). Histopathological assessment (vascular and inflammation damages) showed toxicity in group B (p < 0.05) and mild toxicity in group C. Damage was significantly lesser in group D than group B (p < 0.05). Spleen only showed toxicity after coadministration. These results suggest vascular and inflammation protective effects of sunitinib, not shown after biomarker analysis.

Ethanol is a Significant Cofactor in HAART Induced Hepatotoxicity

Highly Active Antiretroviral Therapy (HAART) has significantly increased life expectancy of HIV patients; however, there are major side effects which include lipodystrophy and hepatotoxicity. Alcohol abuse is highly prevalent in HIV patients and can be a significant negative cofactor in HAART‐hepatotoxicity. Hence, the mechanisms underlying HAART and alcohol induced hepatotoxicity were investigated. Specifically, effects of HAART drugs (azidothymidine, and Indinavir sulphate) in combination with alcohol were examined both in vitro and in vivo. Individually, alcohol and AZT caused cytotoxicity in H4IIEC3 (a rat hepatoma) cells which was significantly increased in combination. These data indicate that alcohol can induce and further enhance HAART‐cytotoxicity.Assessment of Alcohol and HAART drug interaction and hepatotoxicity using an animal model of chronic alcohol feeding showed increased visceral adiposity compared to pair‐fed animals, suggesting disturbances in lipid metabolism. Lipodystrophy was seen as hepatic macro and microvesicular steatosis, elevated triglycerides and free fatty acids. These animals also exhibited increased inflammation and hepatic neutrophil infiltration. Overall, our data demonstrate that alcohol exacerbates HAART hepatotoxicity, and act as a significant cofactor in the development of hepatic steatosis and liver injury.

Assessment of potential drug interactions by characterization of human drug metabolism pathways using non‐invasive bile sampling

Characterization of the biliary disposition of GSK1325756, using a non-invasive bile sampling technique and spectrometric analyses, to inform the major routes of metabolic elimination and to enable an assessment of victim drug interaction risk. Sixteen healthy, elderly subjects underwent non-invasive bile capture using a peroral string device (Entero-Test(®)) prior to and following a single oral dose of GSK1325756 (100 mg). The device was swallowed by each subject and once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth and bile samples were analyzed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. Nuclear magnetic resonance spectroscopy (NMR) indicated that the O-glucuronide metabolite was the major metabolite of GSK1325756, representing approximately 80% of drug-related material in bile. As bile is the major clearance route for GSK1325756 (only 4% of the administered dose was excreted in human urine), this result indicates that uridine 5'-diphospho-glucuronosyltransferases (UGTs) are the major drug metabolizing enzymes responsible for drug clearance. The relatively minor contribution made by oxidative routes reduces the concern of CYP-mediated victim drug interactions. The results from this study demonstrate the utility of deploying the Entero-Test® in early human studies to provide information on the biliary disposition of drugs and their metabolites. This technique can be readily applied in early clinical development studies to provide information on the risk of interactions for drugs that are metabolized and eliminated in bile.

A dedicated clinic for HIV-positive individuals over 50 years of age: a multidisciplinary experience

The HIV-infected population is ageing. Issues including polypharmacy and co-morbidities led us to develop a dedicated clinic for HIV-infected individuals over 50. We describe our service evaluation after two years. The over 50 clinic commenced in January 2009. The team comprises a registrar, consultant, nurse practitioner and is supported by a pharmacist and mental health services. Patients undergo a full medication and drug interactions review, neurocognitive assessment, adherence self-assessment and investigations including therapeutic drug monitoring (TDM), coronary artery calcium scores (CACS) and bone mineral density. Over two years of activity, 150 patients attended the service. Median (range) age was 58 (50-88), all were on combined antiretroviral therapy and 38% (57/150) were on ≥3 non-HIV drugs. CACS was high (>90th centile) in 14%. Thirty-eight percent had osteopaenia and 18% had osteoporosis requiring treatment. Thirteen out of 125 men had an increased prostate specific antigen, four were diagnosed with prostate cancer. Drug interaction, TDM and neurocognitive assessments were useful for several patients. Asymptomatic patients over 50 in long-term follow-up had new pathologies detected through targeted screening. The clinic has improved general practitioner (GP) liaison and facilitated closer working relationships with other specialties. Patients have reacted positively to the clinic, particularly as many do not routinely access their GP.

Abstract 3710: Preclinical dose scheduling studies of LOR-253, a novel anticancer drug, in combination with chemotherapeutics in lung and colon cancers

Abstract LOR-253 is an anticancer small molecule that is currently in a Phase I clinical study in patients with advanced or metastatic solid tumors. LOR-253 has a novel anticancer mechanism based on chelation of intracellular labile zinc, leading to inhibition of angiogenesis as well as G1/S cell cycle arrest due to induction of the tumor suppressor Kruppel-like factor 4 (KLF4). In preclinical studies, LOR-253 has shown potent antitumor activity against several cancers, including non-small cell lung cancer (NSCLC) and colon cancer, without significant toxicity. To support the clinical development of LOR-253 in combination with chemotherapeutics, we investigated the effect of dose scheduling of LOR-253 plus chemotherapy agents on anticancer activity in NSCLC (H226) and colon cancer (SW620) cell lines. Treatment of H226 cells in vitro with docetaxel, paclitaxel, or cisplatin for two days followed by increasing doses of LOR-253 resulted in significantly higher anti-proliferative activity than either agent alone. Assessment of drug interactions by determination of the combination index (D) (Berenbaum MC, Adv Cancer Res., 1981; 35:269-335) showed that the anticancer activities of the combination of LOR-253 with these chemotherapy agents were synergistic (D &amp;lt; 1). In studies with LOR-253 and docetaxel, synergistic anticancer activity against H226 was maintained with either concurrent or sequential treatments of each agent. Anticancer synergy was also seen in SW620 cells treated with LOR-253 in combination with oxaliplatin, CPT-11, or Fluorouracil. The effects of dose scheduling on activity of LOR-253 and docetaxel in vivo was also examined. Nude mice with H226 tumor xenografts were treated with repeat cycles of docetaxel once per week, followed two days later by treatment with LOR-253 for three consecutive days. Docetaxel was administered at an experimentally-determined ED50 dose level (defined as the effective dose at which 50% of mice showed tumor growth inhibition), while LOR-253 was given at its maximum efficacious dose in this model (10 mg/kg) or sub-optimal dose (5 mg/kg). Sequential administration of docetaxel followed by LOR-253 showed significant antitumor activity when docetaxel was given at either ED50 or sub-ED50 doses plus 10 mg/kg of LOR-253, compared to either agent alone given at the same dose, or with concurrent administration of LOR-253 and docetaxel at these dose levels. Preliminary results also show significant antitumor activity of LOR-253 plus docetaxel against H226 tumors in mice treated with repeat cycles of the reverse order of these treatments (LOR-253 for three days, followed by docetaxel 1X/week). In summary, dose scheduling studies with LOR-253 plus chemotherapy drugs demonstrate strong anticancer activities in NSCLC and colon cancer, providing support for the design of LOR-253 combination strategies for treatment of these cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3710. doi:1538-7445.AM2012-3710

Comparative assessment of drug interactions in pediatrics at private and public sector hospitals of Sargodha and Faisalabad

The present study was performed in the cities of Faisalabad and Sargodha, and pediatric in-patient prescriptions were collected from four private and D.H.Q hospitals of these two cities. The collected data of 1420 prescriptions was analyzed for drug interactions by using the software developed by the Medical Letter. The drug interactions found were divided into severe, moderate and mild depending on the type of effect produced. The results showed that the public sector showed 820 drug interactions, that is 74.55%; on the other hand, the private sector showed 130 drug interactions, that is 40.63%. The private sector hospital of Faisalabad showed only 40 drug interactions, that is 20%; while 90 drug interactions, that is 75% were found in private sector hospital of Sargodha. The public sector hospital of Sargodha showed 390 drug interactions, 92.86% and 430 drug interactions, that is 63.24% were found in public sector hospital of Faisalabad. The results showed that the frequency of drug interactions was much less in private hospitals as compared to the public sector hospitals. The possible reason was the presence of clinical pharmacists in more numbers in the private hospitals as compared to the public sector hospitals. It is therefore required that the role of pharmacist should be increased in the hospitals.

Assessment of the appropriateness of serum digoxin concentration measurement in a medical group setting.

Recent quality initiatives require that the routine annual therapeutic drug-monitoring (TDM) parameters for the high-risk medication digoxin include a measure of renal function and a serum potassium level but not a serum digoxin concentration (SDC) measurement. Several studies have shown that the majority of the SDCs obtained in hospital settings provide little clinically actionable information. To evaluate the appropriateness and utility of SDCs ordered in a medical group practice setting by categorizing the reason the SDC was ordered and identifying action taken in response to the result. The descriptive study was conducted as a retrospective, electronic medical record (EMR) review of 90 primary care patients with continuous prescriptions for digoxin current on their medication profile with no gaps in therapy for at least 2 years prior to an SDC result entered into the EMR between January 1, 2009, and September 30, 2009. The reason the SDC was ordered was abstracted independently by 2 reviewers, who then assigned it to 1 of 8 predefined indication categories based on previously published criteria and practice guidelines. A third reviewer resolved inter-reviewer discrepancy (n = 1). A total of 90 patients with at least 1 SDC met inclusion criteria. Routine monitoring was the most frequent SDC order indication category with 35 patients (38.9%), 17 (48.6%) of whom did not have the recommended monitoring measures of potassium or renal function drawn concurrently. Patients were included in other categories as follows: confirmation of signs/symptoms of toxicity 30 (33.3%); assessment of factors altering pharmacokinetics 5 (5.6%); assessment of dosage change 5 (5.6%); assessment of drug interaction 3 (3.3%); assessment of clinical response 3 (3.3%); assessment of adherence 1 (1.1%); and other 2 (2.2%). Across all categories, a total of 19 (21.1%) of SDC results were outside the therapeutic range of 0.5 nanograms (ng) per mL and 2.0 ng per mL, 18 of which were below 0.5 ng per mL, with none of the subtherapeutic levels leading to a change in digoxin therapy. Only 1 patient (1.1%) had therapy changed in response to an elevated abnormal SDC result of 2.1 ng per mL and was in the routine monitoring category. The majority of SDC results obtained in our medical group setting did not lead to clinical action, such as dose adjustment or drug discontinuation. SDCs were commonly measured as part of routine monitoring, which is considered an inappropriate indication, and often without being accompanied by better markers for digoxin toxicity such as serum potassium levels and measures of renal function as recommended by drug-monitoring quality initiatives. Provider education is needed regarding the most indicative digoxin TDM parameters to obtain in order to satisfy quality initiatives.

QT Interval Screening in Methadone Maintenance Treatment: Report of a SAMHSA Expert Panel

ABSTRACT In an effort to enhance patient safety in opioid treatment programs, the Substance Abuse and Mental Health Saervices Administration convened a multi-disciplinary Expert Panel on the Cardiac Effects of Methadone. Panel members (Appendix A) reviewed the literature, regulatory actions, professional guidances, and opioid treatment program experiences regarding adverse cardiac events associated with methadone. The Panel concluded that, to the extent possible, every opioid treatment program should have a universal Cardiac Risk Management Plan (incorporating clinical assessment, electrocardiogram assessment, risk stratification, and prevention of drug interactions) for all patients and should strongly consider patient-specific risk minimization strategies (such as careful patient monitoring, obtaining electrocardiograms as indicated by a particular patient's risk profile, and adjusting the methadone dose as needed) for patients with identified risk factors for adverse cardiac events. The Panel also suggested specific modifications to informed consent documents, patient education, staff education, and methadone protocols.

Rebuttal to the Response of Chou

We appreciate the opportunity to clarify and refute the serious issues raised by Dr. Chou in the rebuttal to our response to his letter. The main question he posed is how a probabilistic/statistical approach can lead to a quantitative/deterministic equation based on the mass-action law. He also

Datenbankgestützte Prüfung von möglichen Psychopharmakainteraktionen nach Entlassung aus stationärem Aufenthalt

Psychiatry is confronted with increasing requirements in quality management, guidelines and an increasing proportion of elderly, chronic multimorbid patients with psychiatric disorders. The latter give rise to polypharmacy which may lead to drug-drug interactions. Assessment of drug interactions is more and more difficult as the total number of drugs taken increases. In the present study hospital discharge medication was analysed semiautomatically for possible drug-drug interactions. In-hospital cases were randomly selected. Discharge medication was analysed using PsiacOnline, a large web-based database for drug interactions. The selection yielded 342 cases from 213 patients (mean age 46.3 years, 53 % females). 86 patients had one psychiatric diagnosis; the other patients had at least two or more diagnoses. The discharge prescription was analysed for 55 different psychotropic drugs from 4 large drug groups (18 antidepressants; 17 antipsychotic drugs; 5 mood stabilisers/epileptic drugs and 13 different hypnotic/anxiolytic drugs). Antipsychotic drugs were the most frequent drugs (n = 334); followed by antidepressants (n = 312) and mood stabilizers (n = 112). 47 patients (13.7 %) were discharged with monotherapy. Mean drug number was 2.7. PsiacOnline revealed 535 hits: 126 (23.6 %) combinations were non-critical, 86 (16.1 %) combinations were critical based on pharmacological properties of the drugs; 232 (43.4 %) combinations were critical according to in vitro studies or animal experiments; critical drug combinations in high-risk patients: 67 × (12.5 %); combinations with reported risks for side effects due to interaction: 17 × (3.2 %) and combinations with documented risks for severe drug interactions: 7 × (1.3 %). Although the majority of drug combinations was considered not critical, approximately 3 % of cases had an increased risk for adverse drug actions and a further 1.3 % cases with a severe risk gave evidence that integration of an IT-based pharmacological expert system in a computerised physician order entry (CPOE) should be considered. Suggested beneficial effects need to be shown by an appropriately-designed clinical study.

Fluorescence-based assays for the assessment of drug interaction with the human transporters OATP1B1 and OATP1B3

Hepatic disposition plays a significant role in the pharmacokinetics and pharmacodynamics of a variety of drugs. Sinusoidal membrane transporters have been shown to participate in the hepatic disposition of many pharmaceuticals. Two sinusoidal membrane transporters with an established role in hepatic disposition are OATP1B1 and OATP1B3 (organic anion-transporting polypeptides 1B1 and 1B3, respectively). OATP1B1 and OATP1B3 have been implicated in the hepatic uptake of statin drugs, and polymorphisms linked to OATP1B1 have been associated with deleterious patient endpoints. As a result, OATP1B1 and OATP1B3 represent sites for potential drug–drug interactions. Numerous methods exist for identifying potential drug–drug interactions with transporters. However, relatively few offer the convenience and speed of fluorescence-based assays. Here a fluorescence-based assay was developed for measuring the OATP1B1- and OATP1B3-mediated transport of 8-fluorescein-cAMP (8-FcA). The OATP1B1- and OATP1B3-mediated transport of 8-FcA was time dependent and saturable ( K m = 2.9 and 1.8 μM, V max = 0.20 and 0.33 pmol/min/cm 2, respectively). Molecules known to interact with OATPs, including cyclosporin A, rifampicin, and glibenclamide, each demonstrated concentration-dependent inhibition of 8-FcA transport by OATP1B1 and OATP1B3. The in vitro fluorescence-based assays described here using 8-FcA as the substrate are convenient and rapid and have utility in screening drug candidates for potential drug–drug interactions with OATP1B1 and OATP1B3.

OncoRx-IQ: a tool for quality assessment of online anticancer drug interactions

The quality of online anticancer drug interaction information varies among online drug databases. We describe the creation of OncoRx-IQ, a tool which assesses the information quality of online drug databases for anticancer drug interactions, and a pilot study done with the tool. OncoRx-IQ was designed in the form of a questionnaire containing 25 questions in three quality domains, separated into two sections (Section A: content accuracy and Section B: ease-of-use and reliability). Each question was scored based on the number of options assigned. A pilot study utilizing this tool was done on four drug databases (Drugs.com, Drug Digest, Medscape and Micromedex). Statistical analyses of the composite and domain scores were done using descriptive statistics, Spearman's correlation coefficient and Friedman and Wilcoxon signed-rank tests. Six pre-registration pharmacists participated in the pilot study. The drug databases were evaluated based on the accuracy of their drug interaction content, usability and reliability, as well as their overall quality. Micromedex (66.9%) and Drug Digest (35.8%) were the highest and lowest scoring databases, respectively. Micromedex scored the highest in all quality domains (content accuracy 56.3%, ease-of-use 75.0% and reliability 73.6%), whereas Drug Digest scored the lowest in content accuracy (8.0%) and reliability (48.2%). We have created and pilot-tested OncoRx-IQ, a quality assessment tool, which helps clinicians systematically evaluate the quality and information accuracy of drug databases for anticancer drug interaction information. We hope this tool can lay the groundwork for future long-term evaluation of online drug interaction information.

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Recombinant cytochrome P450 (P450) phenotyping, different approaches for estimating fraction metabolized (f(m)), and multiple measures of in vivo inhibitor exposure were tested for their ability to predict drug interaction magnitude in dogs. In previous reports, midazolam-ketoconazole interaction studies in dogs have been attributed to inhibition of CYP3A pathways. However, in vitro phenotyping studies demonstrated higher apparent intrinsic clearances (CL(int,app)) of midazolam with canine CYP2B11 and CYP2C21. Application of activity correction factors and isoform hepatic abundance to liver microsome CL(int,app) values further implicated CYP2B11 (f(m) >or= 0.89) as the dog enzyme responsible for midazolam- and temazepam-ketoconazole interactions in vivo. Mean area under the curve (AUC) in the presence of the inhibitor/AUC ratios from intravenous and oral midazolam interaction studies were predicted well with unbound K(i) and estimates of unbound hepatic inlet inhibitor concentrations and intestinal metabolism using the AUC-competitive inhibitor relationship. No interactions were observed in vivo with bufuralol, although significant interactions with bufuralol were predicted with fluoxetine via CYP2D and CYP2C pathways (>2.45-fold) but not with clomipramine (<2-fold). The minor caffeine-fluvoxamine interaction (1.78-fold) was slightly higher than predicted values based on determination of a moderate f(m) value for CYP1A1, although CYP1A2 may also be involved in caffeine metabolism. The findings suggest promise for in vitro approaches to drug interaction assessment in dogs, but they also highlight the need to identify improved substrate and inhibitor probes for canine P450s.

Synergistic inhibition of human colon cancer cell growth by the cannabinoid CB1 receptor antagonist rimonabant and oxaliplatin

Rimonabant (SR141716), a highly selective cannabinoid receptor antagonist, exerts along with its anti-obesity action, pleiotropic functions affecting a broad range of diseases, from obesity-related co-morbidities to drug dependence and cancer. Several studies suggested an anti-tumour activity of rimonabant in several in vitro and in vivo models. In this study, we compared the anti-proliferative effect of SR141716 in the human colon cancer cell line DLD-1 with oxaliplatin, one of the cytotoxic drugs currently used in the treatment of colorectal cancer. We show that SR141716 inhibits DLD-1 cell proliferation similarly to oxaliplatin and if administered in combination SR141716 potentiated the inhibitory effect caused by oxaliplatin. Assessment of drug interaction was performed calculating combination index that showed a strong synergistic effect between the two drugs added to cells in combination. Our findings suggest that the combined synergic effect of SR141716 and oxaliplatin improves the blocking of colon cancer cell proliferation. Therefore, this combination merits further explorations in preclinical and clinical settings.

Coadministration of Pioglitazone or Glyburide and Alogliptin: Pharmacokinetic Drug Interaction Assessment in Healthy Participants

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

Synergistic increases of metabolism and oxidation–reduction genes on their expression after combined treatment with a CYP1A inducer and andrographolide

We previously reported that andrographolide greatly enhanced the expression of CYP1A1. Since andrographolide is a major constituent of Andrographis paniculata, which has been employed for centuries in Asia and Europe as a folk remedy, we further analyzed genes whose expression was modified by andrographolide using primary-cultured mouse hepatocytes in a microarray assay. With the threshold for modification set at 2-fold, andrographolide up-regulated 18 genes among 28,853 genes, most of them related to metabolism/oxidation/reduction. Meanwhile, 5 genes, related to protein binding or calcium ion binding, were down-regulated. A combination of β-naphthoflavone (β-NF), a CYP1A inducer, and andrographolide modified the expression of 45 genes (27 up-regulated and 18 down-regulated), although β-NF single treatment up-regulated 4 genes. The affected genes were again mostly related to metabolism and oxidation–reduction. Among P450 isoforms, andrographolide by itself induced CYP1A1, CYP2A4, CYP2B9, and CYP2B10 expression. Synergistic expression of CYP1A1 and CYP1B1 mRNA was confirmed by quantitative RT-PCR. These observations suggest that drug interaction and risk assessment with the use of andrographolide or A. paniculata should be elucidated.

Predicting Drug–Drug Interactions: An FDA Perspective

Pharmacokinetic drug interactions can lead to serious adverse events, and the evaluation of a new molecular entity's drug-drug interaction potential is an integral part of drug development and regulatory review prior to its market approval. Alteration of enzyme and/or transporter activities involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by other concomitant drugs may lead to a change in exposure leading to altered response (safety or efficacy). Over the years, various in vitro methodologies have been developed to predict drug interaction potential in vivo. In vitro study has become a critical first step in the assessment of drug interactions. Well-executed in vitro studies can be used as a screening tool for the need for further in vivo assessment and can provide the basis for the design of subsequent in vivo drug interaction studies. Besides in vitro experiments, in silico modeling and simulation may also assist in the prediction of drug interactions. The recent FDA draft drug interaction guidance highlighted the in vitro models and criteria that may be used to guide further in vivo drug interaction studies and to construct informative labeling. This report summarizes critical elements in the in vitro evaluation of drug interaction potential during drug development and uses a case study to highlight the impact of in vitro information on drug labeling.

Assessment of potential drug interactions in patients with epilepsy

To understand and quantify the exposure to concomitant medications other than antiepileptic drugs (AEDs) within an age-diverse group of men and women with epilepsy and explore the likelihood of relevant drug interactions as a result. The PharMetrics medical and pharmaceutical claims database was used to extract data for commercially insured adult patients with a diagnosis of epilepsy and treated with any AED during the period from July 1, 2001, to December 31, 2004. Data were analyzed for concomitant non-AEDs used after initiating AEDs in six age groups, spanning the ages 18 to 85+ years, in both men and women. Use of concomitant medications occurred in every age group and increased with age for both men and women (mean number of non-AEDs ranging from 2.41 to 7.67 in males aged 18-34 and 85+ years and from 4.04 to 7.05 in females aged 18-34 and 85+ years; p < 0.001 for age trend). beta-Hydroxy-beta-methylglutaryl-coenzyme A reductase inhibitors (statins), calcium channel blockers (CCBs), and selective serotonin reuptake inhibitors (SSRIs) were the most commonly used non-AED medications with the potential for adverse drug interactions. SSRIs use was substantial in all age groups and greater than for statins or CCBs in patients aged 18-54 years. Use of antipsychotics, tricyclic antidepressants, and warfarin was also noted in more than 10% of patients across different age groups. Polypharmacy with non-antiepileptic drug (AED) medications is common in both men and women, and is not a situation unique to only elderly patients with epilepsy. In particular, use of potentially interacting, enzyme inducing AEDs was common. These findings suggest that clinicians must be mindful of potential AED-non-AED drug interactions, in patients of all age groups.

Dielectrophoresis-Activated Multiwell Plate for Label-Free High-Throughput Drug Assessment

Dielectrophoresis (DEP) offers many advantages over conventional cell assays such as flow cytometry and patch clamp techniques for assessing cell electrophysiology as a marker for cancer studies and drug interaction assessment. However, despite the advantages offered by DEP analysis, uptake has been low, remaining largely in the academic arena, due to the process of analysis being time-consuming, laborious, and ultimately allowing only serial analysis on small numbers of cells. In this paper we describe a new method of performing DEP analysis based on laminate manufacturing methods. These use a three-dimensional "well" structure, similar in size and pitch to conventional microtiter well plates, but offer electrodes along the inner surface to allow easy measurement of cell properties through the whole population. The result can then be determined rapidly using a conventional well-plate reader. The nature of the device means that many electrodes, each containing a separate sample, can be tested in parallel, while the mode of observation means that analysis can be combined with simultaneous measurement of conventional fluorimetric well-based assays. Here we benchmark the device against standard DEP assays, then show how such a device can be used to (a) rapidly determine the effects both of ion channel blockers on cancer cells and antibiotics on bacteria and (b) determine the properties of multiple subpopulations of cells within a well simultaneously.

Synergistic interaction between ouabain and 8-methoxy-3,9-dihydroxy coumestan, a non-steroidal synthetic inhibitor of Na +,K +-ATPase

The use of combination drugs is very common in therapeutics as in the treatment of infectious diseases, cancer and heart failure but controversies about analysis of these interactions are frequent. The aim of the present work was to characterize the interaction between ouabain and 8-methoxy-3,9-dihydroxy coumestan (LQB93), a non-steroidal synthetic inhibitor of Na +,K +-ATPase, as well as the interaction between ouabain and ouabagenin, two cardiac glycosides sharing the same binding site. Inhibition of rat kidney Na +,K +-ATPase with increasing concentrations of the drugs alone or of mixtures of ouabain:ouabagenin and LQB93:ouabain in a fixed 1:4 ratio was performed. In other experiments, increasing concentrations of LQB93 (or ouabain) in the presence of a fixed concentration of ouabain (or ouabagenin) were used for determining the concentration pairs eliciting 50% inhibition in order to construct isobolograms. The mixture (experimental) curve for the ouabain:ouabagenin combination was superimposed on the additive (theoretical) curve indicating additivity, in accordance with the isobolographic analysis. On the other hand, the empirical curve for LQB93:ouabain (IC 50 = 10.6 μM) was significantly shifted to the left in relation to the theoretical curve (IC 50 = 30.7 μM) indicating synergism, further confirmed by the isobolographic analysis. As a conclusion, we show that the combination of a newly synthesized non-steroidal inhibitor and ouabain have a synergistic effect on Na +,K +-ATPase, further supporting a mechanism of inhibition different from ouabain. Present data also support the use of both the isobolograms and combination curves for the assessment of drug interactions occurring at the same molecular target, a situation poorly investigated.