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1.
CPT Pharmacometrics Syst Pharmacol ; 13(5): 853-869, 2024 May.
Article in English | MEDLINE | ID: mdl-38487942

ABSTRACT

Warfarin is a widely used anticoagulant, and its S-enantiomer has higher potency compared to the R-enantiomer. S-warfarin is mainly metabolized by cytochrome P450 (CYP) 2C9, and its pharmacological target is vitamin K epoxide reductase complex subunit 1 (VKORC1). Both CYP2C9 and VKORC1 have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug-drug interactions (DDIs). This study provides a whole-body physiologically-based pharmacokinetic/PD (PBPK/PD) model of S-warfarin for predicting the effects of drug-drug-gene interactions on S-warfarin PKs and PDs. The PBPK/PD model of S-warfarin was developed in PK-Sim and MoBi. Drug-dependent parameters were obtained from the literature or optimized. Of the 34 S-warfarin plasma concentration-time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S-warfarin plasma concentration-time profiles with CYP2C9 genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration-time curve to the last measurable timepoint (AUClast) ratio within twofold of the observed values. The anticoagulant effect of S-warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose-adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators.


Subject(s)
Anticoagulants , Cytochrome P-450 CYP2C9 , Drug Interactions , Fluconazole , Models, Biological , Vitamin K Epoxide Reductases , Warfarin , Warfarin/pharmacokinetics , Warfarin/pharmacology , Warfarin/administration & dosage , Humans , Fluconazole/pharmacology , Fluconazole/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Cytochrome P-450 CYP2C9/metabolism , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Anticoagulants/administration & dosage , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Polymorphism, Genetic , International Normalized Ratio
2.
Xenobiotica ; 54(2): 75-82, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38445636

ABSTRACT

This study investigated whether Safflower Yellow for injection (SYI) would affect the anticoagulation of warfarin in rats.Wistar male rats were divided into six groups randomly and administered with SYI (9 mg/kg, intraperitoneal injection) in single-dose and steady-dose warfarin (0.2 mg/kg, oral gavage), respectively. The pharmacodynamic parameters of PT and APTT were measured by a coagulation analyser. R/S-warfarin concentration was measured by UHPLC-MS/MS, and pharmacokinetic parameters calculated using DAS 2.0 software.The single-dose study demonstrated that SYI, alone or co-administered with warfarin, could significantly increase PT, INR, and APTT values (p < 0.01). R-warfarin Cmax, AUC, and t1/2 values increased by 9.25% (p > 0.05), 25.96% (p < 0.01), and 26.17% (p < 0.01), respectively, whereas the CL/F value reduced by 22.22% (p < 0.01) in the presence of SYI. Meanwhile, S-warfarin Cmax, AUC, and t1/2 values increased by 37.41%, 32.11%, and 31.73% (all p < 0.01), respectively, whereas the CL/F value reduced by 33.33% (p < 0.01). The steady-dose study showed that PT, INR, APTT, and the concentrations of R/S-warfarin increased significantly when SYI was co-administered with warfarin (p < 0.01).SYI can enhance warfarin's anticoagulation intensity and decelerate its metabolism in rats.


Subject(s)
Anticoagulants , Chalcone/analogs & derivatives , Warfarin , Rats , Male , Animals , Warfarin/pharmacokinetics , Anticoagulants/pharmacokinetics , Tandem Mass Spectrometry , Rats, Wistar
3.
Drugs R D ; 24(1): 97-108, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38472696

ABSTRACT

BACKGROUND AND OBJECTIVES: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin. METHODS: In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. RESULTS: Midazolam maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. CONCLUSIONS: Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. CLINICAL TRIAL REGISTRATION: This trial (NCT05480488) was registered on 29 July, 2022.


Subject(s)
Drug Interactions , Imidazoles , Midazolam , Pyrrolidines , Warfarin , Humans , Male , Midazolam/pharmacokinetics , Midazolam/administration & dosage , Adult , Warfarin/pharmacokinetics , Warfarin/administration & dosage , Warfarin/pharmacology , Young Adult , Healthy Volunteers , Triazoles/pharmacokinetics , Triazoles/administration & dosage , Triazoles/pharmacology , Prospective Studies , Orexin Receptor Antagonists/pharmacokinetics , Orexin Receptor Antagonists/pharmacology , Orexin Receptor Antagonists/administration & dosage , Area Under Curve
4.
Phytomedicine ; 128: 155479, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38493714

ABSTRACT

BACKGROUND: Warfarin is a widely prescribed anticoagulant in the clinic. It has a more considerable individual variability, and many factors affect its variability. Mathematical models can quantify the quantitative impact of these factors on individual variability. PURPOSE: The aim is to comprehensively analyze the advanced warfarin dosing algorithm based on pharmacometrics and machine learning models of personalized warfarin dosage. METHODS: A bibliometric analysis of the literature retrieved from PubMed and Scopus was performed using VOSviewer. The relevant literature that reported the precise dosage of warfarin calculation was retrieved from the database. The multiple linear regression (MLR) algorithm was excluded because a recent systematic review that mainly reviewed this algorithm has been reported. The following terms of quantitative systems pharmacology, mechanistic model, physiologically based pharmacokinetic model, artificial intelligence, machine learning, pharmacokinetic, pharmacodynamic, pharmacokinetics, pharmacodynamics, and warfarin were added as MeSH Terms or appearing in Title/Abstract into query box of PubMed, then humans and English as filter were added to retrieve the literature. RESULTS: Bibliometric analysis revealed important co-occuring MeShH and index keywords. Further, the United States, China, and the United Kingdom were among the top countries contributing in this domain. Some studies have established personalized warfarin dosage models using pharmacometrics and machine learning-based algorithms. There were 54 related studies, including 14 pharmacometric models, 31 artificial intelligence models, and 9 model evaluations. Each model has its advantages and disadvantages. The pharmacometric model contains biological or pharmacological mechanisms in structure. The process of pharmacometric model development is very time- and labor-intensive. Machine learning is a purely data-driven approach; its parameters are more mathematical and have less biological interpretation. However, it is faster, more efficient, and less time-consuming. Most published models of machine learning algorithms were established based on cross-sectional data sourced from the database. CONCLUSION: Future research on personalized warfarin medication should focus on combining the advantages of machine learning and pharmacometrics algorithms to establish a more robust warfarin dosage algorithm. Randomized controlled trials should be performed to evaluate the established algorithm of warfarin dosage. Moreover, a more user-friendly and accessible warfarin precision medicine platform should be developed.


Subject(s)
Anticoagulants , Machine Learning , Precision Medicine , Warfarin , Warfarin/pharmacokinetics , Warfarin/pharmacology , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Anticoagulants/administration & dosage , Humans , Precision Medicine/methods , Bibliometrics , Algorithms
5.
BMC Complement Med Ther ; 24(1): 87, 2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38355450

ABSTRACT

BACKGROUND: Herb-drug interactions may result in increased adverse drug reactions or diminished drug efficacy, especially for drugs with a narrow therapeutic index such as warfarin. The current study investigates the effects of sodium ferulate for injection (SFI) on anticoagulation of warfarin from aspects of pharmacodynamics and pharmacokinetics in rats and predicts the risk of the combination use. METHODS: Rats were randomly divided into different groups and administered single- or multiple-dose of warfarin (0.2 mg/kg) with or without SFI of low dose (8.93 mg/kg) or high dose (26.79 mg/kg). Prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected by a blood coagulation analyzer, and international normalized ratio (INR) values were calculated. UPLC-MS/MS was conducted to measure concentrations of warfarin enantiomers and pharmacokinetic parameters were calculated by DAS2.0 software. RESULTS: The single-dose study demonstrated that SFI alone had no effect on coagulation indices, but significantly decreased PT and INR values of warfarin when the two drugs were co-administered (P < 0.05 or P < 0.01), while APTT values unaffected (P > 0.05). Cmax and AUC of R/S-warfarin decreased but CL increased significantly in presence of SFI (P < 0.01). The multiple-dose study showed that PT, APTT, INR, and concentrations of R/S-warfarin decreased significantly when SFI was co-administered with warfarin (P < 0.01). Warfarin plasma protein binding rate was not significantly changed by SFI (P > 0.05). CONCLUSIONS: The present study implied that SFI could accelerate warfarin metabolism and weaken its anticoagulation intensity in rats.


Subject(s)
Coumaric Acids , Tandem Mass Spectrometry , Warfarin , Rats , Animals , Warfarin/pharmacokinetics , Warfarin/therapeutic use , Chromatography, Liquid , Blood Coagulation , Anticoagulants/pharmacology
6.
Pharmacogenet Genomics ; 34(3): 61-72, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38372412

ABSTRACT

Antiplatelets and anticoagulants are extensively used in cardiovascular medicine for the prevention and treatment of thrombosis in the venous and arterial circulations. Wide inter-individual variability has been observed in response to antiplatelets and anticoagulants, which triggered researchers to investigate the genetic basis of this variability. Data from extensive pharmacogenetic studies pointed to strong evidence of association between polymorphisms in candidate genes and the pharmacokinetics and pharmacodynamic action and clinical response of the antiplatelets clopidogrel and the anticoagulant warfarin. In this review, we conducted an extensive search on Medline for the time period of 2009-2023. We also searched the PharmGKB website for levels of evidence of variant-drug combinations and for drug labels and clinical guidelines. We focus on the pharmacogenetics of novel antiplatelets and anticoagulants while excluding acetylsalicylic acid, warfarin and heparins, and discuss the current knowledge with emphasis on the level of evidence.


Subject(s)
Anticoagulants , Warfarin , Humans , Anticoagulants/therapeutic use , Anticoagulants/pharmacokinetics , Warfarin/therapeutic use , Warfarin/pharmacokinetics , Pharmacogenetics , Clopidogrel , Polymorphism, Genetic , Platelet Aggregation Inhibitors/therapeutic use
7.
Br J Clin Pharmacol ; 90(3): 828-836, 2024 03.
Article in English | MEDLINE | ID: mdl-37953511

ABSTRACT

AIMS: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function. METHODS: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates. RESULTS: A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m2 ). The final kinetic-pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased. CONCLUSIONS: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.


Subject(s)
Anticoagulants , Warfarin , Adult , Humans , Anticoagulants/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Genotype , International Normalized Ratio , Japan , Prothrombin , Prothrombin Time , Retrospective Studies , Vitamin K Epoxide Reductases/genetics , Warfarin/pharmacokinetics
8.
Clin Ther ; 45(7): 655-661, 2023 07.
Article in English | MEDLINE | ID: mdl-37451912

ABSTRACT

PURPOSE: While controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects. METHODS: This single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (Cmax,ss and AUCτ,ss), the effects of henagliflozin on the PK properties of warfarin (Cmax, AUC0-t, and AUC0-∞), and the influences of henagliflozin on the PD properties of warfarin (PTmax, PTAUC, INRmax, and INRAUC) were evaluated. FINDINGS: The geometric mean ratios (GMRs; 90% CIs) of henagliflozin Cmax,ss and AUCτ,ss were 101.75% (96.11%-107.72%) and 102.21% (100.04%-104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin Cmax, AUC0-t, and AUC0-∞ were as follows: Cmax, 114.31% (106.30%-122.91%) and 115.09% (109.46%-121.01%), respectively; AUC0-t, 120.15% (116.71%-123.69%) and 119.01% (116.32%-121.76%); and AUC0-∞, 120.81% (117.17%-124.58%) and 121.94% (118.90%-125.05%). The GMRs (90% CIs) of warfarin PTmax and PTAUC were 92.73% (91.25%-94.22%) and 97.42% (96.61%-98.24%). The GMRs (90% CIs) of warfarin INRmax and INRAUC were 92.66% (91.17%-94.17%) and 97.36% (96.52%-98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported. IMPLICATIONS: No significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Drug Interactions , Sodium-Glucose Transporter 2 Inhibitors , Warfarin , Humans , Male , Area Under Curve , Cross-Over Studies , East Asian People , Healthy Volunteers , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics , Warfarin/adverse effects , Warfarin/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics
9.
Drug Metab Dispos ; 51(2): 257-267, 2023 02.
Article in English | MEDLINE | ID: mdl-36379708

ABSTRACT

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high interindividual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiology-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin that integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of a single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. SIGNIFICANCE STATEMENT: The present study found that a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.


Subject(s)
Anticoagulants , Warfarin , Humans , Warfarin/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Anticoagulants/pharmacokinetics , Polymorphism, Genetic/genetics , Genotype , Models, Biological
10.
Clin Lab ; 68(12)2022 Dec 01.
Article in English | MEDLINE | ID: mdl-36546741

ABSTRACT

BACKGROUND: Genetic polymorphisms of CYP2C9 and VKORC1 play a major role in pharmacokinetics and pharmacodynamics of coumarin anticoagulants. The purpose of our study was to assess the relative frequency of the above mutations in Bulgarian population in order to predict bleeding tendencies and precisely manage the anticoagulant therapy during the postoperative period after cardiac surgery with extracorporeal circulation. METHODS: Genomic DNA samples from 200 Bulgarian patients subjected to cardiac surgery with extracorporeal circulation were analyzed for VKORC1 1639G>A and CYP2C9*2&*3 polymorphisms by real-time polymerase chain reaction (PCR), then allele frequencies of various genotypes were calculated by Hardy-Weinberg Equilibrium. RESULTS: Median patients' age was 63.9 ± 10.8 years; 66.5% were male. Median BMI was 28.6 ± 5.4 kg/m2. Genotype distribution for CYP2C9 was *1/*1 - 51%, *1/*2 - 21%, *1/*3 - 13.5%, *2/*3 - 4%, *3/*3 - 2%, and *2/*2 - 1.5%. The calculated frequency of CYP2C9*1 allele was 74.25%, CYP2C9*2 allele was 13%, and CYP2C9*3 allele was 12.75%, and all allelic frequencies were in Hardy-Weinberg equilibrium (p-value = 0.358). The major VKORC1 genotype was G/A - 47%, followed by G/G - 35.5% and A/A - 17.5%). Based on Hardy-Weinberg Equilibrium, there was no significant difference between observed and expected frequencies (X - -3.779), presumably as a result of the homogeneity in the population. CONCLUSIONS: Analysis of the data obtained in the course of the study suggested that identification of homozygous carriers of VKORC1-1639 G>A (rs9923231) in Bulgarians may be useful in developing recommendations for personalized therapy. On the contrary, homozygous carriers of CYP2C9*2 or *3, included only 4.5% of the studied patients, thus indicating that this group would benefit less from dosing algorithms. Our results demonstrated good agreement with the results obtained in other studies conducted in the Caucasian population.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Warfarin , Humans , Male , Middle Aged , Aged , Female , Cytochrome P-450 CYP2C9/genetics , Warfarin/pharmacokinetics , Bulgaria , Aryl Hydrocarbon Hydroxylases/genetics , Vitamin K Epoxide Reductases/genetics , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Gene Frequency , Genotype , Mutation
11.
Int J Mol Sci ; 23(19)2022 Oct 04.
Article in English | MEDLINE | ID: mdl-36233052

ABSTRACT

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease, with an estimated prevalence of between 20 and 30% worldwide. Observational data supported by in vitro and pre-clinical animal models of MAFLD suggest meaningful differences in drug disposition in MAFLD patients. This study aimed to build a physiologically based pharmacokinetic (PBPK) model reflecting observed changes in physiological and molecular parameters relevant to drug disposition that are associated with MAFLD. A comprehensive literature review and meta-analysis was conducted to identify all studies describing in vivo physiological changes along with in vitro and pre-clinical model changes in CYP 1A2, 2C9, 2C19, 2D6 and 3A4 protein abundance associated with MAFLD. A MAFLD population profile was constructed in Simcyp (version 19.1) by adapting demographic and physiological covariates from the Sim-Healthy population profile based on a meta-analysis of observed data from the published literature. Simulations demonstrated that single dose and steady state area under the plasma concentration time curve (AUC) for caffeine, clozapine, omeprazole, metoprolol, dextromethorphan and midazolam, but not s-warfarin or rosiglitazone, were increased by >20% in the MAFLD population compared to the healthy control population. These findings indicate that MAFLD patients are likely to be experience meaningfully higher exposure to drugs that are primarily metabolized by CYP 1A2, 2C19, 2D6 and 3A4, but not CYP2C9. Closer monitoring of MAFLD patients using drugs primarily cleared by CYP 1A2, 2C19 and 3A4 is warranted as reduced metabolic activity and increased drug exposure are likely to result in an increased incidence of toxicity in this population.


Subject(s)
Clozapine , Non-alcoholic Fatty Liver Disease , Animals , Caffeine , Cytochrome P-450 CYP1A2/genetics , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Dextromethorphan , Metoprolol , Midazolam , Omeprazole , Rosiglitazone , Warfarin/pharmacokinetics
12.
Clin Pharmacokinet ; 61(8): 1187-1198, 2022 08.
Article in English | MEDLINE | ID: mdl-35699912

ABSTRACT

BACKGROUND: CYP2C9 is a member of the cytochrome P450 (CYP) superfamily responsible for the metabolism of 16% of drugs that undergo oxidative metabolism. The activity of CYP2C9 exhibits marked inter-individual variability, which translates into prominent differences in the pharmacokinetics of CYP2C9 substrates, some of which are characterized by a narrow therapeutic window. Genetic polymorphisms in the gene encoding for CYP2C9 account for a fraction of the variability in CYP2C9 activity. The phenytoin metabolic ratio (PMR) is a marker of CYP2C9 activity in vivo, which correlates with CYP2C9 genetic polymorphisms. OBJECTIVE: The purpose of the current study was to evaluate the ability of the PMR to predict the oral clearance of (S)-warfarin (SWOCL) and its formation clearance towards its CYP2C9-mediated metabolites (SWCLf) [i.e., 6- and 7-hydroxy-(S)-warfarin]. METHODS: The study was conducted in 150 healthy non-smoker subjects (segment 1) and 60 patients treated with warfarin (segment 2). In the first segment, the participants received on two separate occasions a single 300-mg dose of phenytoin and at least 7 days later a single dose of warfarin (5 or 10 mg). The same PMR procedure was performed in the second segment, except that it was performed either before warfarin initiation or after the patients had reached stable anticoagulation. The PMR was derived from the ratio of 5-(4-hydroxyphenyl)-5-phenyl-hydantoin content in a 24-hour urine collection to plasma phenytoin concentration 12- (PMR24/12) or 24- (PMR24/24) post-dosing. In segment 1, SWOCL was calculated from the ratio of (S)-warfarin dose to the warfarin area under the plasma concentration-time curve extrapolated to infinity and the SWCLf from the ratio of urine content of 6- and 7-hydroxy-(S)-warfarin to (S)-warfarin area under the (S)-warfarin plasma concentration-time curve until the last measured timepoint. In segment 2, estimated SWOCL was derived from the ratio of (S)-warfarin dose to the mid-interval plasma concentration of (S)-warfarin. RESULTS: The PMR, SWOCL, and SWCLf varied significantly between carriers of different CYP2C9 genotypes in both healthy subjects (p < 0.001) and patients (p < 0.005). However, PMR and SWOCL values exhibited substantial intra-genotypic variability. PMR24/12 and PMR24/24 were significantly correlated with SWOCL both in healthy subjects (r = 0.62 and r = 0.67, respectively, p < 0.001) and in patients (r = 0.57 and r = 0.61, respectively, p < 0.001). In a multiple regression model that included all variables that correlated with SWOCL, PMR was the strongest predictor, explaining 44% and 38% of the variability in SWOCL among healthy subjects and patients, respectively, and accounting for 95.7% (44%/46%) and 90.5% (38%/42%) of the total explained variability in SWOCL among healthy subjects and patients, respectively. CONCLUSIONS: The PMR is the strongest predictor of SWOCL, and as such, it exhibits a significant advantage over the CYP2C9 genotype. The inclusion of PMR in future dosing algorithms of CYP2C9 substrates characterized by a narrow therapeutic window should be encouraged and further investigated.


Subject(s)
Cytochrome P-450 CYP2C9 , Warfarin , Anticoagulants/pharmacokinetics , Biomarkers , Cytochrome P-450 CYP2C9/genetics , Genotype , Humans , Phenytoin , Warfarin/pharmacokinetics
13.
Clin Pharmacol Ther ; 112(1): 156-163, 2022 07.
Article in English | MEDLINE | ID: mdl-35426132

ABSTRACT

Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)-warfarin. Single 300-mg phenytoin and 20-mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)-warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin in 24-hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)-warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no-function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti-inflammatory drugs, or siponimod.


Subject(s)
Cytochrome P-450 CYP2C9 , Phenytoin , Warfarin , Alleles , Anticoagulants/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Genotype , Humans , Phenytoin/pharmacokinetics , Warfarin/pharmacokinetics
14.
Eur J Clin Pharmacol ; 78(1): 43-51, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34453556

ABSTRACT

PURPOSE: The purpose of this paper is to study the correlation between demographic and clinical factors and warfarin dose of patients in Chinese Han population taking warfarin and study gene polymorphisms impact of related gene loci (CYP2C9*3, VKORC1-1639G > A) on warfarin doses, to establish a model to predict initial standard dose and maintenance dose based on CYP2C9*3, VKORC1-1639G > A genotype. METHODS: The study collects the data of patients in our hospital and other subcenters which incorporates 2160 patients to establish the initial dose model and 1698 patients for the stable dose model, and sequences 26 multigene sites in 451 patients. Based on the patient's dosage, clinical data, and demographic characteristics, the genetic and non-genetic effects on the initial dose and stable dose of warfarin are calculated by using statistical methods, and the prediction model of initial standard dose and maintenance dose can be established via multiple linear regression. RESULTS: The initial dose of warfarin (mg/day) was calculated as (1.346 + 0.350 × (VKORC1-1639G > A) - 0.273 × (CYP2C9*3) + 0.245 × (body surface area) - 0.003 × (age) - 0.036 × (amine-iodine) + 0.021 × (sex))2. This model incorporated seven factors and explained 55.3% of the individualization differences of the warfarin drug dose. The maintenance dose of warfarin (mg/day) was calculated as (1.336 + 0.299 × (VKORC1-1639G > A) + 0.480 × (body surface area) - 0.214 × (CYP2C9*3) - 0.074 × (amine-iodine) - 0.003 × (age) - 0.077 × (statins) - 0.002 × (height))2. This model incorporated six factors and explained 42.4% of the individualization differences in the warfarin drug dose. CONCLUSION: The genetic and non-genetic factors affecting warfarin dose in Chinese Han population were studied systematically in this study. The pharmacogenomic dose prediction model constructed in this study can predict anticoagulant efficacy of warfarin and has potential application value in clinical practice.


Subject(s)
Anticoagulants/administration & dosage , Anticoagulants/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Warfarin/administration & dosage , Warfarin/pharmacokinetics , Adult , Age Factors , Aged , Asian People , Body Surface Area , China , Comorbidity , Dose-Response Relationship, Drug , Ethnicity , Female , Genotype , Health Behavior , Humans , International Normalized Ratio , Male , Middle Aged , Pharmacogenetics , Pharmacogenomic Variants , Polymorphism, Genetic , Sex Factors , Sociodemographic Factors
16.
Clin Transl Sci ; 15(4): 899-911, 2022 04.
Article in English | MEDLINE | ID: mdl-34877801

ABSTRACT

This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no-effect interval (0.80-1.25). When co-administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC0-last ) GMR (90% CIs) for midazolam was 0.734 (0.647-0.832). When co-administered with cenobamate 200 mg/day, AUC0-last GMRs (90% CI) for midazolam, bupropion, S-warfarin, and omeprazole were 0.277 (0.238-0.323), 0.615 (0.522-0.724), 1.14 (1.10-1.18), and 2.07 (1.44-2.98), respectively. Co-administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co-administration of cenobamate led to omeprazole values which were outside and above the no-effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co-administration of cenobamate with these probes drugs was well-tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose-dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.


Subject(s)
Cytochrome P-450 CYP3A , Midazolam , Bupropion/pharmacokinetics , Carbamates , Chlorophenols , Cytochrome P-450 CYP2B6/metabolism , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Healthy Volunteers , Humans , Midazolam/pharmacokinetics , Omeprazole/pharmacokinetics , Pharmaceutical Preparations , Tetrazoles , Warfarin/pharmacokinetics
17.
Evid. actual. práct. ambul ; 25(3): e002144, 2022. tab
Article in Spanish | LILACS, UNISALUD, BINACIS | ID: biblio-1398442

ABSTRACT

Lograr un adecuado nivel de anticoagulación con antagonistas orales de la vitamina K suele ser un desafío frecuente en la práctica clínica, dado que su estrecho rango terapéutico suele verse afectado por diversas interacciones farmacológicas,alimentos y condiciones clínicas. A partir de un caso de un paciente anticoagulado que presenta una hemorragia gastro-intestinal posterior a realizar un tratamiento antibiótico, la autora de este artículo revisó la evidencia sobre el riesgo desangrado secundario a la interacción entre este tipo de anticoagulantes y antibióticos orales. Su conclusión tras realizar una búsqueda bibliográfica y seleccionar la mejor evidencia disponible, es que existe un aumento del riesgo relativo desangrado en pacientes anticoagulados que reciben antibióticos, por lo que deberían evitarse aquellos antibióticos con conocido potencial de interacción. Si ello no fuera posible, se recomienda monitorizar el estado de anticoagulación con dosaje de la razón internacional normatizada (RIN) posterior a la introducción del antibiótico. (AU)


Achieving an adequate level of anticoagulation with oral vitamin K antagonists is often a frequent challenge in clinical practice, given that their narrow therapeutic range is often affected by various drug interactions, food, and clinical conditions. Based on a case of an anticoagulated patient who presented gastrointestinal bleeding after antibiotic treatment, the authorof this article reviewed the evidence on the risk of secondary bleeding due to the interaction between this type of anticoagulants and oral antibiotics. Their conclusion, after performing a literature search and selecting the best available evidence, is that there is an increased relative risk of bleeding in anticoagulated patients receiving antibiotics, so antibiotics with known potential for interaction should be avoided. If it weren't possible, it is recommended to monitor the anticoagulation status with International Normalized Ratio (INR) dosing after the introduction of the antibiotic. (AU)


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Vitamin K/antagonists & inhibitors , Warfarin/adverse effects , Hemorrhage/chemically induced , Acenocoumarol/adverse effects , Anti-Bacterial Agents/adverse effects , Anticoagulants/adverse effects , Warfarin/pharmacology , Warfarin/pharmacokinetics , Risk Factors , Risk Assessment , International Normalized Ratio , Drug Interactions , Acenocoumarol/pharmacology , Acenocoumarol/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anticoagulants/pharmacology , Anticoagulants/pharmacokinetics
18.
Sci Rep ; 11(1): 24060, 2021 12 15.
Article in English | MEDLINE | ID: mdl-34912021

ABSTRACT

Due to large dosage variation, a variety of warfarin prescription regimens are utilized for specific doses such as tablet splitting, or pill strength alternating. The clinical comparison between the two is lacking. We hypothesize that both approaches result in different times in therapeutic range. We randomized patients with specific warfarin dosage and stable INR for 6 months or longer to receive the whole tablet, alternate-day dosing or the split tablet, same daily-dosing regimen without initial dose change and followed them every 6 weeks for 6 months. The primary outcome was a time in therapeutic range of 2.0-3.0. The secondary outcomes included dosage, compliance, INR, anticoagulant-related events. A total of 66 patients were enrolled, 32 randomly assigned to the split tablet regimen (group S) and 34 to the alternate-day regimen (group A) with two withdrawers. The mean age was 58.6 ± 8.5 years. All baseline characteristics of both groups were similar. The average time in therapeutic range was 72.8 ± 25.4% in group S and 74.9 ± 22.0% in group A (p = 0.72). There were no significant differences in warfarin dosage, compliance, INR and, complications between the two groups. Both warfarin prescription methods, the split tablet and the alternate-day had comparable time in the therapeutic range.


Subject(s)
Anticoagulants/administration & dosage , Tablets , Warfarin/administration & dosage , Aged , Anticoagulants/pharmacokinetics , Clinical Decision-Making , Disease Management , Drug Administration Schedule , Female , Humans , International Normalized Ratio , Male , Middle Aged , Tablets/administration & dosage , Treatment Outcome , Warfarin/pharmacokinetics
19.
Curr Drug Metab ; 22(12): 989-995, 2021.
Article in English | MEDLINE | ID: mdl-34802403

ABSTRACT

BACKGROUND: Warfarin is primarily metabolized by cytochrome P450 2C9 (CYP2C9) enzyme, which is encoded by the CYP2C9 gene. CYP2C9*2 and CYP2C9*3 variants significantly influence warfarin metabolism and subsequently the required dose of warfarin. OBJECTIVES: The current retrospective study was aimed to determine the influence of CYP2C9 variants on warfarin metabolic ratio (MR, warfarin/7-hydroxy warfarin) and warfarin maintenance therapy in 210 patients (mean age 44.6±11.6 (SD) years; male to female ratio 81:129). METHODS: High-performance liquid chromatography (HPLC) with UV detector was used to measure plasma concentrations of warfarin and 7-hydroxy warfarin. Plasma samples were collected 12 h after the previous dose of warfarin was administered. CYP2C9 variants (rs1799853 and rs1057910) were identified using real-time polymerase chain reaction allele-discrimination method. RESULTS: The mean daily maintenance dose of warfarin was 4.6±1.8 (SD) mg. The mean plasma warfarin and 7-hydroxy warfarin concentrations were 3.7±1.6 (SD) µg/mL and 1.1±0.54 (SD) µg/mL, respectively. Patients carrying other CYP2C9 variants required 39% lower warfarin maintenance dose 3.3±1.2(SD)mg than CYP2C9*1*1 carrier 4.9±1.8(SD)mg, (p<0.0001). MRs differed significantly between CYP2C9 variant carriers (8.1±5.1) and normal genotype carriers (4.8±3.9) (p<0.0001). Probit analysis identified an MR value of 7.6 as the anti-mode (sensitivity of 84% and specificity of 55%) to differentiate poor and intermediate metabolizers (carriers of any CYP2C9*2 or CYP2C9*3 variants) from normal metabolizers (CYP2C9*1*1 genotype). CONCLUSION: The present study results provide, insights on the effect of CYP2C9 genetic polymorphisms on inter-individual variability in warfarin metabolism and emphasizes utility of phenotyping in a setting of genotype-guided dosing of warfarin in South Indian population.


Subject(s)
Cytochrome P-450 CYP2C9/genetics , Warfarin/analogs & derivatives , Anticoagulants/blood , Anticoagulants/pharmacokinetics , Asian People/genetics , Biological Variation, Population/genetics , Chromatography, High Pressure Liquid/methods , Dose-Response Relationship, Drug , Female , Humans , India , Male , Middle Aged , Pharmacogenomic Testing/methods , Polymorphism, Single Nucleotide , Retrospective Studies , Warfarin/blood , Warfarin/pharmacokinetics
20.
Genes (Basel) ; 12(10)2021 09 28.
Article in English | MEDLINE | ID: mdl-34680932

ABSTRACT

The genotypes of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) can influence therapeutic warfarin doses. Conversely, nongenetic factors, especially renal function, are associated with warfarin maintenance doses; however, the optimal algorithm for considering genes and renal dysfunction has not been established. This single-center prospective cohort study aimed to evaluate the factors affecting warfarin maintenance doses and develop pharmacogenetics-guided algorithms, including the factors of renal impairment and others. To commence, 176 outpatients who were prescribed warfarin for thromboembolic stroke prophylaxis in the stroke center, were enrolled. Patient characteristics, blood test results, dietary vitamin K intake, and CYP2C9 and VKORC1 (-1639G>A) genotypes were recorded. CYP2C9 and VKORC1 (-1639G>A) genotyping revealed that 80% of the patients had CYP2C9 *1/*1 and VKORC1 mutant AA genotypes. Multiple linear regression analysis demonstrated that the optimal pharmacogenetics-based model comprised age, body surface area, estimated glomerular filtration rate (eGFR), genotypes, vitamin K intake, aspartate aminotransferase levels, and alcohol intake. eGFR exercised a significant impact on the maintenance doses, as an increase in eGFR of 10 mL/min/1.73 m2 escalated the warfarin maintenance dose by 0.6 mg. Reduced eGFR was related to lower warfarin maintenance doses, independent of VKORC1 and CYP2C9 genotypes in Japanese patients.


Subject(s)
Anticoagulants/administration & dosage , Drug Dosage Calculations , Glomerular Filtration Rate , Pharmacogenomic Variants , Warfarin/administration & dosage , Aged , Aged, 80 and over , Anticoagulants/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Female , Humans , Kidney/metabolism , Male , Vitamin K Epoxide Reductases/genetics , Warfarin/pharmacokinetics
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