Evaluation Of Drug Interactions Research Articles

Evaluating drug interaction potential from cytokine release syndrome using a physiologically based pharmacokinetic model: A case study of teclistamab.

Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL-6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL-6 kinetics profiles were assessed, the mean IL-6 profile with a maximum concentration (Cmax) of IL-6 (21 pg/mL) and the IL-6 profile of the patient presenting the highest IL-6 Cmax (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC-1. For the mean IL-6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87-1.20). For the maximum IL-6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90-2.23), and minimal for caffeine and s-warfarin (mean AUC ratios 0.82-1.25). Maximum change in exposure for these substrates occurred 3-4 days after step-up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL-6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step-up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.

Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation.

Several commonly used opioid analgesics, such as fentanyl, sufentanil, alfentanil, and hydrocodone, are by report primarily metabolized by the CYP3A4 enzyme. The concurrent use of ritonavir, a potent CYP3A4 inhibitor, can lead to significant drug interactions. Using physiologically based pharmacokinetic (PBPK) modeling and simulation, this study examines the effects of different dosing regimens of ritonavir on the pharmacokinetics of these opioids. The findings reveal that co-administration of ritonavir significantly increases the exposure of fentanyl analogs, with over a 10-fold increase in the exposure of alfentanil and sufentanil when given with ritonavir. Conversely, the effect of ritonavir on fentanyl exposure is modest, likely due to additional metabolism pathways. Additionally, the study demonstrates that the steady-state exposure of hydrocodone and its active metabolite hydromorphone can be increased by up to 87% and 95%, respectively, with concurrent use of ritonavir. The extended-release formulation of hydrocodone is particularly affected. These insights from PBPK modeling provide valuable guidance for optimizing opioid dosing and minimizing the risk of toxicity when used in combination with ritonavir-containing prescriptions.

Evaluation of drug interactions of Saposhnikoviae Radix and its major components with astragaloside IV and paeoniflorin using in vitro and in vivo experiments

Saposhnikoviae Radix (SR) may enhance the pharmacodynamics of Huangqi Chifeng Tang (HQCFT) in the treatment of cerebral infarction according to our previous research, but the underlying mechanism is unknown. Herein, an in vivo pharmacokinetic assay in rats and in vitro MDCK-MDR1 cell assays were used to investigate the possible mechanism of SR, its main components, and its interactions with Astragali Radix (AR) and Paeoniae Radix (PR). An ultrahigh-performance liquid chromatography–tandem mass spectrometry (UPLC‒MS/MS)-based analytical method for quantifying astragaloside IV (ASIV) and paeoniflorin (PAE) in microdialysis and transport samples was developed. The pharmacokinetic parameters of SR were determined using noncompartmental analyses CCK-8 assays were used to detect the cytotoxicity of ASIV, PAE, cimifugin (CIM), prim-o-glucosylcimifugin (POG) and their combinations. Moreover, drug transport was studied using MDCK-MDR1 cells. Western blotting was performed to measure the protein expression levels of P-GP and MRP1. Claudin-5, ZO-1, and F-actin expression was determined via immunohistochemical staining of MDCK-MDR1 cells. harmacokinetic studies revealed that, compared with those of Huangqi Chifeng Tang-Saposhnikoviae Radix (HQCFT-SR), the Tmax of ASIV increased by 11.11 %, and the MRT0-t and Tmax of PAE increased by 11.19 % and 20 %, respectively, in the HQCFT group. Transport studies revealed that when ASIV was coincubated with 28 μM CIM or POG, the apparent permeability coefficient (Papp) increased by 71.52 % and 50.33 %, respectively. Coincubation of PAE with 120 μM CIM or POG increased the Papp by 87.62 % and 60.95 %, respectively. Moreover, CIM and POG significantly downregulated P-gp and MRP1 (P < 0.05), inhibited the expression of Claudin-5, ZO-1, and F-actin (P < 0.05), and affected intercellular tight junctions (TJs). In conclusion, our study successfully established a selective, sensitive and reproducible UPLC‒MS/MS analytical method to detect drug‒drug interactions between SR, AR and PR in vivo and in vitro, which is beneficial for enhancing the therapeutic efficacies of AR and PR. Moreover, this study provides a theoretical basis for further research on the use of SR as a drug carrier.

Role of the Pharmacist in the Management of Polypharmacy and Drug Interactions in the Elderly Patient with Chemotherapy

Introduction: This study aimed to review the role of the pharmacist in cases of polypharmacy in the care of elderly patients with cancer. Methods: An narrative literature review was carried out using the descriptors "Polypharmacy", "Pharmacological interactions", "Geriatrics" and "Antineoplastic agents", in the ScienceDirect, MEDLINE, and CAPLUS databases. Results: One hundred and ten articles were identified, of which 82 were included in this review. The articles showed the importance of evaluating drug interactions in the treatment of cancer in oncogeriatric patients due to the high amount of drugs that these patients use, which can exceed 6 drugs per day, and that these interactions can compromise the treatment of the patient, as well as induce serious toxic effects, causing the patient to be hospitalized or even die. Conclusion: The inclusion of the pharmacist in the care of oncogeriatric patients reduces the risk of interaction through pharmacotherapeutic monitoring.

Gambaran Interaksi Obat Pada Pasien Diabetes Mellitus Tipe 2 di Rumah Sakit X

Diabetes mellitus is a chronic condition characterized by higher than normal blood glucose levels and problems with protein, carbohydrate, and lipid metabolism caused by a relative or total lack of the hormone insulin. In addition, as a result of more prescriptions being written, the danger of drug interactions increases due to potential interactions among diabetic inpatients. The purpose of this study was to describe drug interactions in patients with Type 2 Diabetes Mellitus at X Hospital in the period January-March 2023. Data taken retrospectively from medical records were used in this kind of study, and Lexicomp Interact Online was used to evaluate drug interaction data. The results of this study showed that females 46-55 experienced. Most drug interactions in the hospital. Based on lexicomp interact online, drug interactions were categorized into 3 categories, B minor (23.6%), C moderate (62.5%) and D major (13.9%). This study may encourage healthcare workers to increase their awareness to counteract drug interactions in diabetic patients with complications to improve their clinical outcomes.

Sitagliptin with Piperine Pharmacodynamic and Pharmacokinetic Studies in Normal and Diabetic Rabbits

Background: Food-drug interactions caused by dietary alkaloids like piperine may significantly impact medication metabolism and excretion. In this study, we studied piperine's effect on sitagliptin's PD and PK. Method: The research assessed the food-drug interaction in normal and diabetic rabbits to demonstrate how piperine affects the PD and PK of sitagliptin. Piperine, sitagliptin, and sitagliptin plus piperine treatment were administered to normal and diabetic rabbits. Blood samples were taken from the treated rabbits at predetermined intervals on days 1, 3, 7, and 21. Plasma was extracted from the obtained blood samples, and glucose levels were measured by the GOD-POD technique and insulin levels by ELISA. The extracted plasma samples collected on days 1 &amp; 21 at predetermined intervals were exposed to HPLC analysis for estimation of PK parameters of sitagliptin. In both normal and diabetic rabbits, statistically comparisons were done between PK/PD of sitagliptin alone and in combination with piperine. Results: Piperine plus sitagliptin has no significant difference in glucose levels, percent blood glucose reductions, and insulin levels on 0, 1, 3, 7, 14 &amp; 21st days in normal rabbits as compared with sitagliptin alone, and this may be because sitagliptin has no hypoglycemic effect. In diabetic rabbits, sitagliptin plus piperine significantly reduced blood glucose levels, raised the percent blood glucose reductions, and increased insulin levels on days 1, 3, 7, 14, and 21, compared with sitagliptin alone, demonstrating antihyperglycemic efficacy. Antihyperglycemic efficacy results indicate that sitagliptin with piperine has an additive effect on releasing more insulin, which is considered a PD interaction. In the PK study, sitagliptin plus piperine significantly raised the AUC0-∞, AUC0-t, AUMC0-∞, and AUMC0-t and lowered the CL of sitagliptin compared to sitagliptin alone on days 1 and 21 in normal and diabetic rabbits. Furthermore, the Tmax of sitagliptin did not change significantly, and the Ke, t1/2, and MRT varied non-significantly when piperine was administered concurrently. Additionally, Vd was also non-significantly altered in normal rabbits. This study's results suggest that piperine inhibits the CYP3A4 metabolic enzyme and P-gp (P-glycoprotein) substrate of sitagliptin in normal and diabetic rabbits, indicating a food-drug interaction. Conclusion: In normal rabbits, this study found no PD interaction. A PD interaction between piperine and sitagliptin showed the additive effect in diabetic rabbits by showing an antihyperglycemic activity. As per study findings, in normal and diabetic rabbits, piperine significantly increased the bioavailability of sitagliptin. However, the anticipated clinical response in humans cannot always be predicted from animal studies, so further research is required to evaluate drug interaction in humans.

Evaluation of drug interaction between cyclosporine and lercanidipine: a descriptive study

ObjectivesCyclosporine is an immunosuppressive drug with a high potential for drug interactions that is frequently used in renal transplant patients. The purpose of this study was to assess the change...

IMSEA: A Novel Metabolite Set Enrichment Analysis Strategy to Decipher Drug Interactions.

Drug combinations are commonly used to treat various diseases to achieve synergistic therapeutic effects or to alleviate drug resistance. Nevertheless, some drug combinations might lead to adverse effects, and thus, it is crucial to explore the mechanisms of drug interactions before clinical treatment. Generally, drug interactions have been studied using nonclinical pharmacokinetics, toxicology, and pharmacology. Here, we propose a complementary strategy based on metabolomics, which we call interaction metabolite set enrichment analysis, or iMSEA, to decipher drug interactions. First, a digraph-based heterogeneous network model was constructed to model the biological metabolic network based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Second, treatment-specific influences on all detected metabolites were calculated and propagated across the whole network model. Third, pathway activity was defined and enriched to quantify the influence of each treatment on the predefined functional metabolite sets, i.e., metabolic pathways. Finally, drug interactions were identified by comparing the pathway activity enriched by the drug combination treatments and the single drug treatments. A data set consisting of hepatocellular carcinoma (HCC) cells that were treated with oxaliplatin (OXA) and/or vitamin C (VC) was used to illustrate the effectiveness of the iMSEA strategy for evaluation of drug interactions. Performance evaluation using synthetic noise data was also performed to evaluate sensitivities and parameter settings for the iMSEA strategy. The iMSEA strategy highlighted synergistic effects of combined OXA and VC treatments including the alterations in the glycerophospholipid metabolism pathway and glycine, serine, and threonine metabolism pathway. This work provides an alternative method to reveal the mechanisms of drug combinations from the viewpoint of metabolomics.

US FDA Postmarketing Requirements and Commitments: A Systematic Assessment of Clinical Pharmacology Studies and Their Impact on US FDA Prescribing Information.

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology-related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology-related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one-third were clinical pharmacology-related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology-related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval.

Evaluation of Drug Interactions in Hospitalized Patients with Respiratory Disorders in Greece

Background: Patients with respiratory disorders often have additional diseases and are usually treated with more than one medication to manage their respiratory conditions as well as additional comorbidities. Thus, they are frequently exposed to polypharmacy (≥5 drugs), which raises the risk for drug-drug interactions (DDIs) and adverse drug reactions (ADRs). In this work, we present the results regarding the prevalence of DDIs in hospitalized patients with respiratory disorders in Greece. Methods: A 6-month descriptive single-center retrospective observational study enrolled 102 patients with acute or chronic respiratory disorders. Clinical characteristics and medication regimens were recorded upon admission, hospitalization, and discharge. The prevalence of DDIs and their clinical significance was recorded and analyzed. Results: Unspecified acute lower respiratory tract infection (25%), exacerbations of chronic obstructive pulmonary disease (12%) and pneumonia (8%) were the most frequent reasons for admission. Cardiovascular disorders (46%), co-existing respiratory disorders (32%), and diabetes (25%) were the most prevalent comorbidities. Polypharmacy was noted in 61% of patients upon admission, 98% during hospitalization, and 63% upon discharge. Associated DDIs were estimated to be 55% upon admission, 96% throughout hospitalization, and 63% on discharge. Pharmacodynamic (PD) DDIs were the most prevalent cases (81%) and referred mostly to potential risk for QT-prolongation (31.4% of PD-DDIs) or modulation of coagulation process as expressed through the international normalized ratio (INR) (29.0% of DDIs). Pharmacokinetic (PK) DDIs (19% of DDIs) were due to inhibition of Cytochrome P450 mediated metabolism that could lead to elevated systemic drug concentrations. Clinically significant DDIs characterized as "serious-use alternative" related to 7% of cases while 59% of DDIs referred to combinations that could be characterized as "use with caution-monitor". Clinically significant DDIs mostly referred to medication regimens upon admission and discharge and were associated with outpatient prescriptions. Conclusions: Hospitalized patients with respiratory disorders often experience multimorbidity and polypharmacy that raise the risk of DDIs. Clinicians should be conscious especially if any occurring arrhythmias, INR modulations, and prolonged or increased drug action is associated with DDIs.

Study on the approach to HIV: health management and the healthcare process in Spain

IntroductionHIV continues to represent a problem of great relevance for public health in Spain. This study aims to carry out an analysis that will provide in-depth knowledge of the resources, clinical care, and management during the diagnosis, follow-up, and treatment phases of HIV infection in Spain. MethodsIn the first phase, a multidisciplinary Scientific Committee designed an information collection tool in the form of a survey. In the second phase, carried out in the autonomous communities of Andalusia, Catalonia, and La Rioja, a multidisciplinary group of 42 experts, representatives of the public administration, clinical profiles, and representatives of NGOs in the field of HIV answered the survey. ResultsThe assessment of HIV resources is generally positive. As regards diagnosis, the experts considered that there was good coordination between Primary and Hospital care. Regarding treatment, the evaluations reflected good opinions on therapeutic conciliation and adherence, with a negative opinion in the evaluation of drug interactions with antiretroviral treatment. Regarding follow-up, the perception expressed was disparate concerning the coordination between Hospital and Primary Care as well as the adaptation of care to chronicity, aging, fragility, mental health, and oncological processes. ConclusionThere are certain processes that can be improved in the management of HIV infection in people with HIV in Spain, including protocols for follow-up and coordination between primary and hospital care in the treatment and follow-up of the disease

Evaluation of Drug Interactions in Patients Treated with DAAs for Hepatitis C Therapy with Comorbidities and Cardiovascular Issues—A Delphi Consensus Project

Orally administered direct-acting antivirals (DAAs) have dramatically changed the possibility of curing HCV (hepatitis C virus) infection, with the two principal HCV regimens based on the combination of glecaprevir + pibrentasvir (GLE-PIB) and sofosbuvir + velpatasvir (SOF-VEL). A combination of drugs containing NS3/4A protease inhibitors, as well as the fact that almost all HCV patients can be treated at present, may expose patients to a higher rate of drug-drug interactions (DDIs). The hepatitis C treatment recommendations from the EASL (European Association for the Study of the Liver) state that, prior to starting treatment with a DAA, a detailed drug history should be taken; yet, the decision on managing the potential DDIs is not always clear. For this reason, a group of Italian cardiologists and hepatologists promoted a survey among colleagues to assess the controversial issues when treating patients with chronic hepatitis C taking concomitant cardiovascular drugs, aiming to reach a consensus on the best practice to apply when treating a patient with chronic hepatitis C who is taking concomitant drugs for cardiovascular diseases. Two consecutive questionnaires were proposed between June and July 2022 to a qualitative Expert Panel (EP) of 14 gastroenterologists, infectologists, hepatologists, and internists, with statistical analyses performed on 100% of the responses for both questionnaires. Agreement among experts was assessed following the Delphi method as developed by the RAND Corporation. The interviewed experts consider DDIs a critical clinical problem to be evaluated in HCV patients. Therefore, dose changes, drug substitution, and discontinuation of concomitant cardiovascular drugs should be discouraged, even if planned for a relatively short period. Since oral DAAs have different DDIs profiles, hepatologists should prefer the antiviral DAA combination presenting the lowest instance of potential interactions.

Evaluation of Drug Interactions in Hospitalized Patients with Malignancy.

Drug-drug interaction (DDI) occurs when the pharmacological effect of a drug is altered due to concomitant administration with other drugs. DDIs still remain a serious issue; thus, we conducted this retrospective study to evaluate DDIs prevalence in our care center. Methods: All admitted patients with any kind of malignancies that received at least two medications from oncology and non-oncology classifications during six months were enrolled in this study. All relevant data including, patients' demographic information, diagnosis, hospitalization duration, and all administered medication during hospitalization were recorded. The DDI was assessed by using the latest version of Lexi-interact. Results: Each patient received a mean number of 11.6±4.7 medications. The number of non-oncology drugs demonstrated a remarkable correlation with the number of interactions (P<0.001). Whereas, the number of oncology drugs does not have any relation with the number of interactions (P=0.64). Among the 763 detected DDIs during this study, the incidence of major, moderate and minor interactions were 31.2%, 61.4%, and 7.3%, respectively. Conclusion: Our results highlighted the clinical significance of DDIs, considering that 104 (92%) patients had at least one DDI. The main reason that could have potentially contributed to this outcome is the complicated nature of cancer treatment and clinical management. We believe that using computer software to collect all prescribed and OTC collaboration of clinical pharmacists with oncologists can reduce the potential interactions prior to drug administration.

Evaluation of drug interactions of saxagliptin with sildenafil in healthy volunteers

PurposeThe purpose of this study is to investigate the effect of sildenafil a CYP3A4 substrate and inhibitor on the pharmacokinetics and safety of saxagliptin. MethodsEighteen healthy volunteers were recruited in sequential; single-center study to determine pharmacokinetic parameters of saxagliptin and sildenafil, and (AUC0-∞), (AUC0-t); Cmax; tmax; t½, ke; ka were measured using validated LC–MS/MS method. Therapeutic doses were given as follows: Sildenafil 50 mg single dose on day one, then washout period from day two till day eight. Saxagliptin 5 mg once/day was given from day 9 till day 12; then on day 13, the two drugs were co-administered. Blood samples for pharmacokinetic analysis were collected on days 1 and 13 for sildenafil and on days 12 and 13 for saxagliptin.ResultsSaxagliptin ratios of T/R and 90% CI were 132.1% (122.7–142.3) for AUC0–t, and 167.6% (154.6–181.8) for Cmax. On the other hand, sildenafil pharmacokinetics were not affected. Gmax changed from 93.7 mg/dl to 95.6 mg/dl (P > 0.001) and AUCg0-t from 512.8 ng.h/ml to 532.75 ng.h/ml (P > 0.001) after co-administration of both drugs.ConclusionSildenafil significantly affected the pharmacokinetic parameters of saxagliptin when co-administered.RegistrationThis trial was registered at clinicaltrials.gov under identifier number: [NCT04170790] in November 2019.

Estudio sobre la aproximación al VIH: gestión sanitaria y el proceso asistencial en España

IntroductionHIV continues to represent a problem of great relevance for public health in Spain. This study aims to carry out an analysis that will provide in-depth knowledge of the resources, clinical care, and management during the diagnosis, follow-up, and treatment phases of HIV infection in Spain. MethodsIn the first phase, a multidisciplinary Scientific Committee designed an information collection tool in the form of a survey. In the second phase, carried out in the autonomous communities of Andalusia, Catalonia, and La Rioja, a multidisciplinary group of 42 experts, representatives of the public administration, clinical profiles, and representatives of NGOs in the field of HIV answered the survey. ResultsThe assessment of HIV resources is generally positive. As regards diagnosis, the experts considered that there was good coordination between primary and hospital care. Regarding treatment, the evaluations reflected good opinions on therapeutic conciliation and adherence, with a negative opinion in the evaluation of drug interactions with antiretroviral treatment. Regarding follow-up, the perception expressed was disparate concerning the coordination between hospital and primary care as well as the adaptation of care to chronicity, aging, fragility, mental health, and oncological processes. ConclusionThere are certain processes that can be improved in the management of HIV infection in people with HIV in Spain, including protocols for follow-up and coordination between primary and hospital care in the treatment and follow-up of the disease.

Sensitive and valid assay for reliable evaluation of drug interactions mediated by human organic anion transporter 1 and 3 using 5-carboxyfluorescein.

Drug interactions can induce significant clinical impacts, either by increasing adverse effects or by decreasing the therapeutic effect of drugs, and thus, need to be explored thoroughly. Clinically significant drug interactions can be induced by organic anion transporter 1 (OAT1) and OAT3 when concomitant medications competitively interact with the transporters. The purposes of this study were to develop and validate a sensitive and selective analytical method for 5-carboxyfluorescein (5-CF) and optimize the experimental conditions for interaction studies. An analytical method using high-performance liquid chromatography (HPLC) equipped with a fluorescence detector was validated for accuracy, precision, matrix effect, recovery, stability, dilutional integrity, and carry-over effect. In addition, the 5-CF concentration, incubation period, and washing conditions for interaction study were optimized. Using a valid analytical method and optimized conditions, we performed an interaction study for OAT1 and OAT3 using 26 test articles. Some of the test articles showed strong inhibitory potency for the transporters, with IC50 values close to or less than 10μM. The valid analysis method and optimized systems developed in this study can be utilized to improve the predictability of drug interactions in humans and consequently aid in successful disease treatment by maintaining appropriate systemic exposures.

Potential drug-drug interactions of immunosuppressants in kidney transplant recipients: comparison of drug interaction resources.

Background Drug-drug interactions are frequently observed in kidney transplant recipients due to polypharmacy and use of immunosuppressants. However, there is only one study evaluating clinically relevant potential drug-drug interactions of immunosuppressants specially in kidney transplant recipients by means of online databases and Stockleys Drug Interactions, as a gold standard. Aim This study aimed to compare four online databases used frequently to determined clinically relevant potential drug-drug interactions of immunosuppressants in kidney transplant recipients according to the Renal Drug Handbook. Method This was a descriptive cross-sectional study conducted between October 1, 2019, and March 18, 2020, in the nephrology ward of Ankara University School of the Medicine, Ibn-i Sina Hospital. In total, 52 adult patients' discharge prescriptions were retrieved from their medical records and analyzed retrospectively. Micromedex®, Lexicomp®, Medscape, and Drugs.com databases were used to evaluate drug interactions. The Renal Drug Handbook was used as a gold standard to do specificity and sensitivity analysis. Results A total of 127 potential drug-drug interactions between the immunosuppressants and co-medications were detected by at least one online database. 32 (25.2%) of these were approved as clinically relevant potential drug-drug interactions by the Renal Drug Handbook. Lexicomp® and Drugs.com have exhibited the highest sensitivity (0.72 and 0.75) while Micromedex® has shown the highest specifity (0.83). Furthermore, the highest positive predictive value has been observed in Micromedex® (0.53). Micromedex® and Medscape had the highest negative predictive value (0.83 and 0.82). However, the kappa value of all was low. The values of inter-rater agreement (Kappa index) between online databases and the Renal Drug Handbook were weak (range 0.05-0.36). In addition, only 11 (8.7%) of potential drug-drug interactions were identified by all online databases. Conclusion This study showed that there was a weak compatibility between each database examined and the Renal Drug Handbook to detect clinically relevant potential drug-drug interactions for immunosuppressants in kidney transplant recipients. Therefore, we suggest that although databases might be practical to take a quick glance in detection of potential drug-drug interactions between immunosuppressants and co-medications, the data should be evaluated in detail and interpreted with caution in combination with a reference book like Renal Drug Handbook.

P556 The effect of multiple doses of upadacitinib 45 mg on the pharmacokinetics of cytochrome P450 substrates in healthy adult subjects

Abstract Background Upadacitinib is a selective Janus kinase 1 inhibitor, which is approved for treatment of several inflammatory diseases. Upadacitinib 45 mg QD dose was evaluated for induction treatment in ulcerative colitis Phase 3 studies and is currently being evaluated in Crohn’s disease Phase 3 studies. A prior clinical study demonstrated that upadacitinib 30 mg QD dose resulted in no clinically relevant effects on plasma exposures of sensitive probe substrates for cytochrome P450 (CYP) enzymes. The objective of this study was to evaluate the effect of repeated doses of upadacitinib 45 mg on the pharmacokinetics of sensitive probe substrates of CYP enzymes in healthy adult subjects. Methods This was an open-label, multiple-dose, two-period study using the modified Cooperstown 5 + 1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]). Twenty healthy adults received single oral doses of the cocktail drugs without upadacitinib in Period 1, followed by daily dosing of upadacitinib 45 mg for 16 days and administration of the cocktail drugs on Day 11 (for midazolam) and Day 12 (rest of substrates) in Period 2. A washout period of 6 days separated each Period. Serial blood samples and 12-hour urine samples (for dextromethorphan and dextrorphan) were collected. Pharmacokinetic parameters were estimated using noncompartmental analysis and repeated-measures analyses were performed for the natural logarithms of Cmax and AUC to assess the effect of upadacitinib on the probe substrates. Results The ratio (90% confidence interval) of area under the plasma concentration-time curve from time 0 to infinity (AUCinf) central values when the cocktail drugs were administered with upadacitinib 45 mg relative to when administered alone were 0.76 (0.69–0.83) for midazolam, 1.04 (0.95–1.13) for caffeine, 1.12 (1.05–1.20) for S-warfarin, 1.35 (1.18–1.54) for dextromethorphan, and 0.98 (0.85–1.13) for omeprazole. The 5-hydroxy-omeprazole to omeprazole plasma AUC ratio was unchanged (90% confidence interval within the no effect limits of 0.8 to 1.25). Conclusion Administration of daily upadacitinib 45 mg doses resulted in a limited effect on midazolam (CYP3A) and dextromethorphan (CYP2D6) exposures and had no relevant effects on the sensitive probe substrates for CYP1A2, CYP2C9 and CYP2C19. These limited effects are not expected to be clinically relevant or necessitate dose adjustment of CYP3A or CYP2D6 substrates. These results are consistent with a previous drug interaction evaluation for upadacitinib 30 mg and support lack of relevant effects of upadacitinib on drugs metabolized by CYP enzymes.

Prediction of metabolizing enzyme-mediated clinical drug interactions using in vitro information.

Evaluation of drug interactions is an essential step in the new drug development process. Regulatory agencies, including U.S. Food and Drug Administrations and European Medicines Agency, have been published documents containing guidelines to evaluate potential drug interactions. Here, we have streamlined in vitro experiments to assess metabolizing enzyme-mediated drug interactions and provided an overview of the overall process to evaluate potential clinical drug interactions using in vitro data. An experimental approach is presented when an investigational drug (ID) is either a victim or a perpetrator, respectively, and the general procedure to obtain in vitro drug interaction parameters is also described. With the in vitro inhibitory and/or inductive parameters of the ID, basic, static, and/or dynamic models were used to evaluate potential clinical drug interactions. In addition to basic and static models which assume the most conservative conditions, such as the concentration of perpetrators as Cmax, dynamic models including physiologically-based pharmacokinetic models take into account changes in in vivo concentrations and metabolizing enzyme levels over time.

Analysis of potential drug interactions in medical clinic sector in a Hospital of João Pessoa - PB

The objective of this study was to evaluate drug interactions based on medical records of patients hospitalized in University Hospital Lauro Wanderley (UHLW) in João Pessoa-PB, Brazil. This was a quantitative, descriptive study with a cross-sectional design. This research was conducted in the medical clinic of the above hospital by analyzing pharmaceutical intervention in medical records. The investigated samples consisted of all medical profiles with drug interaction information of patients hospitalized from June 2016 to June 2017. Most of these drug interactions were determined and classified by Micromedex® Solutions database. This research was approved by the Ethics Committee in Institutional Human Research, protocol number 2.460.206. In total, 331 drug interactions were found in 131 medical profiles. Dipyrone, enoxaparin, sertraline, ondansetron, quetiapine, tramadol, bromopride, amitriptyline, and simvastatin were medications that showed highest interactions. According to Anatomical Therapy Classification (ATC), drugs that act on the central nervous system result in more interactions. The most prevalent interaction was between dipyrone and enoxaparin. Some limitations of this study are the lack of notifications and data on drug interactions.