scholarly journals Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions

2021 ◽  
Vol 24 ◽  
pp. 277-291
Author(s):  
Subrata Deb ◽  
Anthony Allen Reeves
Keyword(s):  
Renal Function ◽  
Drug Interaction ◽  
Liver Function ◽  
Drug Interactions ◽  
Spatial Data ◽  
Water Solubility ◽  
Pbpk Modeling ◽  
Strong Interactions ◽  
Hydrophilic Lipophilic Balance ◽  
Drug Regimens

Purpose: Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug Administration’s recent assent of remdesivir as the only approved agent for COVID-19, there is limited information available about the physicochemical, metabolism, transport, pharmacokinetic (PK), and drug-drug interaction (DDI) properties of this drug. The objective of this in silico simulation work was to simulate the biopharmaceutical and DDI behavior of remdesivir and characterize remdesivir PK properties in special populations which are highly affected by COVID-19. Methods: The Spatial Data File format structures of remdesivir prodrug (GS-5734) and nucleoside core (GS-441524) were obtained from the PubChem database to upload into the GastroPlus software 9.8 version (Simulations Plus Inc., USA). The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules of GastroPlus were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug Interaction module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for comorbidities. Results: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas agents used for COVID-19 treatment such as chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir. Conclusions: GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potentially be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities. Methods: The Spatial Data File format structures of remdesivir prodrug and nucleoside core were obtained from the PubChem database to upload into the GastroPlus software 9.8 version. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) PredictorTM and PKPlusTM modules were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug InteractionTM module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for commodities. Results: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir. Conclusions: GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potential be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities.

P0048THE EFFECT OF GENOTYPING ON THE NUMBER OF PHARMACOTHERAPEUTIC GENE-DRUG INTERVENTIONS IN CKD3-5 PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Marieke Kerskes ◽  
Carien Van den Eijnde ◽  
Birgit Deiman ◽  
Albert-Jan Aarnoudse ◽  
Rene Grouls ◽  
...  
Keyword(s):  
Renal Function ◽  
Drug Interaction ◽  
Drug Interactions ◽  
Hospital Pharmacist ◽  
Added Value ◽  
Pharmacogenetic Testing ◽  
Cyp Enzymes ◽  
Single Centre Study ◽  
The Individual ◽  
Relevant Gene

Abstract Background and Aims Most patients with CKD (Chronic Kidney Disease) 3-5 are polypharmacy patients (i.e. use of ≥5 drugs). As renal function is important for the clearance of many drugs, dose adjustment is often necessary and some drugs are even contra-indicated in patients with CKD. Many of these drugs are metabolized by cytochrome P450 (CYP-enzymes) in the liver. Several genetic mutations in these CYP enzymes are known to result in an altered metabolism capacity of drugs. Knowledge of the patients CYP450 genotype may thereby be of added value in reducing the incidence of supratherapeutic concentrations of drugs and reducing side effects, especially in this patient population with already reduced renal function. The aim of this study was to determine the added value of pharmacogenetic testing to the routine medication evaluation in polypharmacy patients with CKD3-5 disease, defined as the total number of pharmacotherapeutic interventions based on a relevant gene-drug interaction as assessed by the nephrologist and hospital pharmacist. Method This was a prospective single-centre study in adult polypharmacy patients with CKD3-5 disease not on dialysis who visited the outpatient clinic of the Catharina Hospital Eindhoven, the Netherlands. In each patient enrolled in the study we determined a pharmacogenetic profile consisting of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and VKORC1. A gene-drug interaction was considered as relevant based on the DPWG (Dutch Pharmacogenetics Working Group) guideline. Of all these according to the DPWG guideline relevant gene-drug interactions the treating nephrologist and hospital pharmacist assessed the clinical relevance and necessity of a pharmacotherapeutic intervention in the individual patient. Primary endpoint of the study was the total number of applied pharmacotherapeutic interventions based on a relevant gene-drug interaction. Results A total of 61 patients were enrolled. Median eGFR in the study population was 18 ml/min. Patients used a median (range) number of 12 (5-20) drugs. Genotyping resulted in a total of 172 altered phenotypes based on a pharmogenetic mutation. We observed a total of 66 gene-drug interactions, of which 56 were considered relevant and resulted in 26 applied pharmacotherapeutic interventions in 20 (32.8%) patients. These interventions consisted of 10 dose adjustments (38.5%), 7 drug stops (26.9%) and 9 drug changes (34.6%). Conclusion Pharmacogenetic testing leads to additional pharmacotherapeutic interventions based on relevant gene-drug interactions. This study shows that pharmacogenetic testing in CKD3-5 patients can be of added value to the routine medication evaluation, and may further optimize pharmacotherapy in this population.

Kajian Interaksi Obat Metformin pada Pasien Diabetes Mellitus

2019 ◽  
Vol 8 (2) ◽  
pp. 55-58
Author(s):  
Havizur Rahman ◽  
Teresia Anggi Octavia
Keyword(s):  
Diabetes Mellitus ◽  
Drug Interaction ◽  
Data Collection ◽  
Drug Interactions ◽  
Degenerative Disease ◽  
Moderate Severity ◽  
Purposive Sampling ◽  
Chronic Degenerative Disease ◽  
Over Time ◽  
Diabetes Melitus

Diabetes melitus merupakan penyakit degeneratif kronis yang apabila tidak ditangani dengan tepat, lama kelamaan bisa timbul berbagai komplikasi, ini cenderung menyebabkan pasien mendapatkan banyak obat dalam satu resep yang dapat menimbulkan interaksi antar obat. Tujuan dari penelitian ini adalah mengetahui persentase terjadinya interaksi obat metformin secara teori serta mengkaji efek yang mungkin timbul dan solusinya. Teknik pengambilan data dengan purpossive sampling, yaitu resep pasien rujuk balik yang menderita diabetes mellitus yang menggunakan metformin. Data yang diperoleh ditemukan bahwa obat yang berinteraksi dengan metformin dengan tingkat keparahan minor ialah sebesar 60%. Kemudian untuk tingkat keparahan moderat ialah sebesar 20%. Sedangkan untuk tingkat keparahan mayor tidak ditemukan. Dari tabel diatas juga dapat diketahui bahwa terdapat 4 obat yang saling berinteraksi dengan metformin, sedangkan untuk obat yang tidak saling berinteraksi dengan metformin terdapat 9 obat. Jumlah obat yang berinteraksi secara teori sebesar 6,85% dan yang tidak berinteraksi 93,15%. Terdapat interaksi obat metformin dengan beberapa obat yaitu furosemid, lisinopril, acarbose dan ramipril.   Kata kunci: interaksi obat, metformin, diabetes mellitus   STUDY OF METFORMIN INTERACTION IN MELLITUS DIABETES PATIENTS   ABSTRACT Mellitus is a chronic degenerative disease which if not handled properly, over time can arise various complications, this tends to cause patients to get many drugs in one recipe that can cause interactions between drugs. The purpose of this study is to determine percentage of metformin drug interactions in theory and examine the effects that may arise and solutions. Data collection techniques using purposive sampling, which is a recipe for reconciliation patients who suffer from diabetes mellitus using metformin. The data obtained it was found that drugs that interact with metformin with minor severity were 60%. Then for moderate severity is 20%. Whereas the major severity was not found. From the table above it can also be seen that there are 4 drugs that interact with metformin, while for drugs that do not interact with metformin there are 9 drugs. The number of drugs that interacted theoretically was 6.85% and 93.15% did not interact. An interaction of the drug metformin with several drugs namely furosemide, lisinopril, acarbose and ramipril.   Keywords: drug interaction, metformin, diabetes mellitus

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.

scholarly journals Herb–Drug Interactions: Worlds Intersect with the Patient at the Center

Medicines ◽  
2021 ◽  
Vol 8 (8) ◽  
pp. 44
Author(s):  
Mary Beth Babos ◽  
Michelle Heinan ◽  
Linda Redmond ◽  
Fareeha Moiz ◽  
Joao Victor Souza-Peres ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Case Report ◽  
Drug Interactions ◽  
Clinical Studies ◽  
Drug Information ◽  
Case Reports ◽  
Full Information ◽  
Information Need ◽  
Herbal Products ◽  
Reduce Risk

This review examines three bodies of literature related to herb–drug interactions: case reports, clinical studies, evaluations found in six drug interaction checking resources. The aim of the study is to examine the congruity of resources and to assess the degree to which case reports signal for further study. A qualitative review of case reports seeks to determine needs and perspectives of case report authors. Methods: Systematic search of Medline identified clinical studies and case reports of interacting herb–drug combinations. Interacting herb–drug pairs were searched in six drug interaction resources. Case reports were analyzed qualitatively for completeness and to identify underlying themes. Results: Ninety-nine case-report documents detailed 107 cases. Sixty-five clinical studies evaluated 93 mechanisms of interaction relevant to herbs reported in case studies, involving 30 different herbal products; 52.7% of these investigations offered evidence supporting reported reactions. Cohen’s kappa found no agreement between any interaction checker and case report corpus. Case reports often lacked full information. Need for further information, attitudes about herbs and herb use, and strategies to reduce risk from interaction were three primary themes in the case report corpus. Conclusions: Reliable herb–drug information is needed, including open and respectful discussion with patients.

scholarly journals Estimation of the retention behaviour of s-triazine derivatives applying multiple regression analysis of selected molecular descriptors

2013 ◽  
pp. 229-237 ◽  
Author(s):  
Lidija Jevric ◽  
Sanja Podunavac-Kuzmanovic ◽  
Strahinja Kovacevic ◽  
Natasa Kalajdzija ◽  
Bratislav Jovanovic
Keyword(s):  
Dissociation Constant ◽  
Water Solubility ◽  
Molecular Descriptors ◽  
Chemical Properties ◽  
Log P ◽  
Retention Factors ◽  
Solute Retention ◽  
Physico Chemical ◽  
Hydrophilic Lipophilic Balance ◽  
Triazine Derivatives

The estimation of retention factors by correlation equations with physico-chemical properties can be of great helpl in chromatographic studies. The retention factors were experimentally measured by RP-HPTLC on impregnated silica gel with paraffin oil using two-component solvent systems. The relationships between solute retention and modifier concentration were described by Snyder?s linear equation. A quantitative structure-retention relationship was developed for a series of s-triazine compounds by the multiple linear regression (MLR) analysis. The MLR procedure was used to model the relationships between the molecular descriptors and retention of s-triazine derivatives. The physicochemical molecular descriptors were calculated from the optimized structures. The physico-chemical properties were the lipophilicity (log P), connectivity indices (?), total energy (Et), water solubility (log W), dissociation constant (pKa), molar refractivity (MR), and Gibbs energy (GibbsE) of s-triazines. A high agreement between the experimental and predicted retention parameters was obtained when the dissociation constant and the hydrophilic-lipophilic balance were used as the molecular descriptors. The empirical equations may be successfully used for the prediction of the various chromatographic characteristics of substances, with a similar chemical structure.

scholarly journals HCIP: An Online database for prediction CYP450 Enzyme Inhibition potential of bioactive compounds

2021 ◽  
Vol 11 (2) ◽  
pp. 253-255
Author(s):  
Sabarathinam Sarvesh ◽  
Preethi L ◽  
Haripritha Meganathan ◽  
M Arjun Gokulan ◽  
Dhivya Dhanasekaran ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Enzyme Inhibition ◽  
Bioactive Compounds ◽  
Bioactive Compound ◽  
Concomitant Administration ◽  
Cyp3a4 Inhibitor ◽  
Online Database ◽  
Computer Aided ◽  
Cyp450 Enzyme

Background: Concomitant administration of herbal medicine and conventional may lead to severe metabolism-oriented herb-drug interactions. However, detecting herb-drug interaction is expensive and higher time-consuming. Several computer-aided techniques have been proposed in recent years to predict drug interactions. However, most of the methods cannot predict herb-drug interactions effectively. Methods: Canonical SMILES of bioactive compounds was gathered from the PubChem online database, and its inhibition details were gathered PKCSM from the webserver. Results: By searching the bioactive compound name in the search bar of “The Herb-CYP450 Enzyme Inhibition Predictor online database” (HCIP- http://hcip.in/), it will provide the liver enzyme inhibition profile of the selected bioactive compound. For example; Guggulsterone:  CYP3A4 inhibitor.  Conclusion: The Herb-CYP450 Enzyme Inhibition Predictor online database is very peculiar and easy to determine the inhibition profile of the targeted bioactive compound. Keywords: CYP450; Enzyme inhibition; Bioactive Compounds; Online database; Herb-Drug Interaction

scholarly journals Review of Impact and Handling of Potential Antihypertensive Drug Interactions in Chronic Kidney Disease Patients

2021 ◽  
Vol 7 (1) ◽  
pp. 39-53
Author(s):  
Ni Made Susilawati ◽  
Eli Halimah ◽  
Siti Saidah
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Heart Function ◽  
Mortality Rates ◽  
Morbidity And Mortality ◽  
Potential Drug ◽  
Analysis Program ◽  
Drug Related Problems ◽  
Related Effect ◽  
Complete Knowledge

Drug interaction is a type of Drug-Related Problems (DRPs) that caneventually increase morbidity and mortality rates. CKD patients have asignificant risk of developing polypharmacy due to comorbid diseases andpharmacokinetics' alteration. The literature review was conducted byexploring all of the articles related to the drug interaction using druginteraction analysis program in CKD patients, which obtained from threedatabases, namely Google Scholar, PubMed, and Science Direct, usingseveral keywords combination. Based on the comprehensive reviewsconducted, it is known that the most common effects of antihypertensivedrug interactions in CKD patients are decreasing effects of antihypertensivedrugs, hypotension, and hyperkalemia. Handling management used for theemergence of potential drug interactions is based on the severity of the druginteractions and complete knowledge of the patients' clinical condition. Themanagement of drug interaction by monitoring blood pressure, diuresis, andpotassium levels; Monitor the related effect symptoms; Monitor the fluidand body weight; Monitor the kidney and heart function. On the conditionwhere the handling management of potential drug interactions is not carriedout, elevated morbidity and mortality rates are the risks of complicationsarising from the drug interactions.

scholarly journals A norovirus outbreak triggered by copper intoxication on a coach trip from the Netherlands to Germany, April 2010

2012 ◽  
Vol 17 (9) ◽  
Author(s):  
J Hoefnagel ◽  
D H van de Weerdt ◽  
O Schaefer ◽  
R Koene
Keyword(s):  
Renal Function ◽  
Chemical Analysis ◽  
Liver Function ◽  
Gastrointestinal Symptoms ◽  
Copper Level ◽  
Epidemic Curve ◽  
Potential Source ◽  
Toxic Concentration ◽  
Stool Samples ◽  
Copper Intoxication

We report an unusual outbreak of norovirus infection on a coach trip. Overall, 30 of 40 people (including drivers and crew) developed nausea, vomiting and/or diarrhoea, 11 of them on the first day of the trip. The incidence epidemic curve showed a first peak on Day 1 and a second on Day 4. Nine passengers were hospitalised with gastrointestinal symptoms. Norovirus was found in stool samples from two patients, but the infection could not explain the first peak in the epidemic curve only a few hours after departure. Interviews with the passengers and an inspection of the coach and its water supply implicated the water used for coffee and tea as the potential source. Microbiological investigations of the water were negative, but chemical analysis showed a toxic concentration of copper. Blood copper levels as well as renal and liver function were determined in 28 of the 32 passengers who had been exposed to the water. One passenger who did not have gastrointestinal symptoms had an elevated copper level of 25.9 µmol/L, without loss of liver or renal function. It is likely that the spread of norovirus was enhanced because of vomiting of one of the passengers due to copper intoxication.

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