Serum thromboxane B2 (TxB2) is a specific marker of platelet inhibition by aspirin. Yet, TxB2 levels differ by up to 10-fold between some aspirin-treated patient cohorts. This study aimed to identify factors responsible for differences in... more
Serum thromboxane B2 (TxB2) is a specific marker of platelet inhibition by aspirin. Yet, TxB2 levels differ by up to 10-fold between some aspirin-treated patient cohorts. This study aimed to identify factors responsible for differences in serum TxB2 between cohorts in the ADRIE study (n = 657) and the BOSTON study (n = 678) of aspirin-treated cardiovascular patients originally tested with different ELISA assays. TxB2 levels were assessed in representative subgroups of the two cohorts (34 samples in BOSTON and 39 in ADRIE) by both ELISAs, as well as liquid chromatography and tandem mass spectroscopy (MS). A multivariate analysis was performed on the whole cohort database to identify determinants of the difference of TxB2 levels between cohorts. There was no systematic bias between the original ELISA TxB2 values and the MS values and the median difference was small, 0.12 ng/ml, thus not explaining the difference between median TxB2 levels in the two study populations (7 and 0.6 ng/ml in the ADRIE and BOSTON studies, respectively). In the combined dataset of the ADRIE and BOSTON cohorts (n = 1342), body mass index, age, gender, aspirin dose, time from aspirin intake to blood draw, NSAID intake, platelet count and C-reactive protein were significantly associated with TxB2 levels. After adjustment for patient characteristics, the difference between cohorts did not decrease. Unexplained differences in serum TxB2 levels in different populations of aspirin-treated cardiovascular patients suggest that further studies are needed to confirm the role of serum TxB2 level as a prognostic factor or rather as a marker of therapeutic observance.
Research Interests: Biomarkers, Treatment Outcome, Medicine, Platelet, Humans, and 15 moreInternal Medicine, Platelets, Female, Male, Tandem Mass Spectrometry, Cohort, Aspirin, High Performance Liquid Chromatography, Clinical Sciences, Aged, Middle Aged, Cardiovascular Diseases, Enzyme Linked Immunosorbent Assay, Blood platelets, and Platelet Aggregation Inhibitors
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Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for... more
Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its Active Metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by Liquid-Liquid Extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.
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ABSTRACT Background The analgesic anti-NMDA effect of dextromethorphan (DEM) might result mainly from a central action of unchanged DEM rather than from its more active metabolite dextrorphan (DOR). This could be related to a weaker... more
ABSTRACT Background The analgesic anti-NMDA effect of dextromethorphan (DEM) might result mainly from a central action of unchanged DEM rather than from its more active metabolite dextrorphan (DOR). This could be related to a weaker interaction of DEM with the efflux drug transporter P-glycoprotein (P-gP) as compared with that of DOR.AimWe studied the involvement of P-gP in the transepithelial transport of DEM and DOR.Methods We used the human intestinal Caco-2 cell monolayer model. Bidirectional transport of 1, 5 and 10 μM DEM across the Caco-2 monolayers was investigated in the presence and absence of the P-gP inhibitor verapamil (100μM). DEM quantitation was performed using HPLC.ResultsWe found that: i) DEM showed no statistically significant differential transport rates between the basolateral-to-apical (B-A) and apical-to-basolateral (A-B) directions at 5 and 10μM (apparent permeability coefficient Papp: 17 vs 16.10−6 and 29 vs 31.10−6 cm/s respectively). However, at 1μM, the rate of transport A-B was greater (Papp: 5 vs 7.10−6 cm/s); ii) B-A transport of DEM was not affected by verapamil (Papp: 5 vs 5.10−6; 17 vs 16.10−6 and 29 vs 30.10−6 cm/s); iii) The transepithelial transport of DEM was concentration-dependant.Conclusion The data indicate that DEM is not a P-glycoprotein substrate at therapeutic concentrations and that the mechanism of diffusion is passive.Clinical Pharmacology & Therapeutics (2005) 77, P10-P10; doi: 10.1016/j.clpt.2004.11.039
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Research Interests: Pharmacology and Medicine
The present study evaluates the influence of type 2 diabetes (T2D) on important CYP450 (CYP) isoforms and P‐glycoprotein (Pgp) transporter activities before and 3 months after an intensifying treatment regimen involving 40 patients.... more
The present study evaluates the influence of type 2 diabetes (T2D) on important CYP450 (CYP) isoforms and P‐glycoprotein (Pgp) transporter activities before and 3 months after an intensifying treatment regimen involving 40 patients. Results have been compared with 21 non‐T2D healthy participants (the control group). CYPs and Pgp activities were assessed after administering the Geneva cocktail. The mean metabolic ratios (MR) for CYP2B6 (1.81 ± 0.93 versus 2.68 ± 0.87), CYP2C19 (0.420 ± 0.360 versus 0.687 ± 0.558) and CYP3A4/5 (0.487 ± 0.226 versus 0.633 ± 0.254) significantly decreased in T2D patients compared to the control group (p < 0.05). CYP2C9 (0.089 ± 0.037 versus 0.069 ± 0.017) activities slightly increased in diabetic patients, and no difference was observed regarding CYP1A2 (0.154 ± 0.085 versus 0.136 ± 0.065), CYP2D6 (1.17 ± 0.56 versus 1.24 ± 0.83), and Pgp activities in comparison to the control group. Three months after the intensifying treatment regimen, MRs of CYP2C9 (0.080 ± 0.030) and CYP3A4/5 (0.592 ± 0.268) improved significantly and were not statistically different compared to the control group (P > 0.05). Several covariables, such as inflammatory markers (IL‐1β and IL‐6), genotypes, diabetes and demographic‐related factors, were considered in the analyses. The results indicate that chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform‐specific manner.
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Precision dosing strategies require accounting for between‐patient variability in pharmacokinetics together with subsequent pharmacodynamic differences. Liquid biopsy is a valuable new approach to diagnose disease prior to the appearance... more
Precision dosing strategies require accounting for between‐patient variability in pharmacokinetics together with subsequent pharmacodynamic differences. Liquid biopsy is a valuable new approach to diagnose disease prior to the appearance of clinical signs and symptoms, potentially circumventing invasive tissue biopsies. However, the possibility of quantitative grading of biomarkers, as opposed to simply confirming their presence or absence, is relatively new. In this study, we aimed to verify expression measurements of cytochrome P450 (CYP) enzymes and the transporter P‐glycoprotein (P‐gp) in liquid biopsy against genotype and activity phenotype (assessed by the Geneva cocktail approach) in 30 acutely ill patients with cardiovascular disease in a hospital setting. After accounting for exosomal shedding, expression in liquid biopsy correlated with activity phenotype for CYP1A2, CYP2B6, CYP2C9, CYP3A, and P‐gp (r = 0.44–0.70, P ≤ 0.05). Although genotype offered a degree of stratification, large variability (coefficient of variation (CV)) in activity (up to 157%) and expression in liquid biopsy (up to 117%) was observed within each genotype, indicating a mismatch between genotype and phenotype. Further, exosome screening revealed expression of 497 targets relevant to drug metabolism and disposition (159 enzymes and 336 transporters), as well as 20 molecular drug targets. Although there were no functional data available to correlate against these large‐scale measurements, assessment of disease perturbation from healthy baseline was possible. Verification of liquid biopsy against activity phenotype is important to further individualize modeling approaches that aspire to achieve precision dosing from the start of drug treatment without the need for multiple rounds of dose optimization.
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BackgroundIn an observational study in Geneva (Switzerland), we found that administering a standardized THC/CBD oil was feasible, safe, and beneficial in an elderly polymedicated population with severe dementia, behavioral troubles, and... more
BackgroundIn an observational study in Geneva (Switzerland), we found that administering a standardized THC/CBD oil was feasible, safe, and beneficial in an elderly polymedicated population with severe dementia, behavioral troubles, and pain. Those findings need to be confirmed in a randomized clinical trial.ObjectivesThe MedCanDem trial is a randomized, double-blind cross-over placebo-controlled trial to study the efficacy of cannabinoids in improving painful symptoms during severe dementia disorders in patients living in long-term care facilities in Geneva. This manuscript describes the MedCanDem trial protocol.Materials and methodsParticipants will be patients suffering from severe dementia associated with pain and behavioral troubles and living in long-term care facilities. We selected five facilities specialized in caring for severely demented patients in Geneva (Switzerland). A total of 24 subjects will be randomized 1:1 to the sequence study intervention/placebo or the sequen...
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Available data have shown an association between direct oral anticoagulant (DOAC) plasma concentration and clinical, particularly bleeding, events. Factors that may influence DOAC plasma concentration are therefore the focus of particular... more
Available data have shown an association between direct oral anticoagulant (DOAC) plasma concentration and clinical, particularly bleeding, events. Factors that may influence DOAC plasma concentration are therefore the focus of particular attention. Population pharmacokinetic (PopPK) analyses can help in identifying such factors while providing predictive models. The main aim of the present study was to identify all the PopPK models to date for the four most frequently used DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban). The secondary aim was to use these models to simulate different DOAC plasma concentration–time profiles in relevant clinical scenarios. The results of our model‐based simulations confirm the clinical relevance of the known major factors influencing DOAC exposure and support the current approved dose adaptation, at least for atrial fibrillation. They also highlight how the accumulation of covariates, not currently considered for dose adaptation due to their ...
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AimsKetorolac is a nonsteroidal anti‐inflammatory racemic drug with analgesic effects only attributed to its S‐enantiomer. The aim of this study is to quantify enantiomer‐specific maturational pharmacokinetics (PK) of ketorolac and... more
AimsKetorolac is a nonsteroidal anti‐inflammatory racemic drug with analgesic effects only attributed to its S‐enantiomer. The aim of this study is to quantify enantiomer‐specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants.MethodsData were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry‐based enantiomer‐specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S‐ and R‐ketorolac exposure.ResultsS‐ and R‐ketorolac PK were best described with a 3‐ and a 2‐compartment model, respectively. The allometry‐based PK parameters accounted for changes between popul...
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The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at... more
The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late‐stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC. We identified low‐dose synergistic and selective ODCs for a panel of six human CRC cell lines also active in heterotypic 3D co‐culture models. Transcriptome sequencing and phosphoproteome analyses showed that the mechanisms of action of these ODCs converged toward MAP kinase signaling and cell cycle inhibition. Two cell‐specific ODCs were translated to in vivo mouse models. The ODCs reduced tumor growth by ~80%, outperforming standard chemotherapy (FOLFOX). No toxicity was observed for the ODCs, while significant side effects were induced in the group treated with FOLFOX ther...
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IntroductionKetorolac is a racemic drug with analgesic effects specific to its S-enantiomer. This study aimed to describe enantiomer-specific maturational pharmacokinetics (PK). Simulations were performed to describe how S-ketorolac... more
IntroductionKetorolac is a racemic drug with analgesic effects specific to its S-enantiomer. This study aimed to describe enantiomer-specific maturational pharmacokinetics (PK). Simulations were performed to describe how S-ketorolac exposure in infants differs from adults, and how this affects the adult racemic analgesic trough threshold EC50 (EC50thr-adult, 0.37 mg/L) in infants (EC50thr-infant)when the same S-target is applied.MethodsA population PK analysis (NONMEM 7.3) was performed based on 1020 plasma samples from 5 studies including 80 patients (adults, children, infants) following single intravenous ketorolac administration.ResultsS-ketorolac PK was best described with a 2-compartment model in infants and 3-compartment model in adults, while R-ketorolac PK was best described with a 2-compartment model in all. S-ketorolac clearance [mean population value: 3.45 L/h/56 kg] and central volume of distribution (V1) [4.27 L/56kg] increased exponentially with bodyweight (0.75, 0.59 ...
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To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo... more
To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo studies were done to confirm safety and investigate fucoidan-mediated immune modulation. Cytochrome P450 (CYP450) 3A4, 2C8, 2C9, and 2D6 inhibition experiments were conducted in vitro followed by an ex vivo human hepatocytes model to evaluate the CYP450 induction potential of each fucoidan at highest theoretical concentrations. Four hepatic metabolism phase II pathways-glutathione S transferase (GST), quinone oxidoreductase (QOR), catechol-O-methyltransferases (COMT), and uridine di-phosphate (UDP)-glucuronosyltransferase (UGT)-were evaluated with validated immunoassays. Growth inhibition assays were performed with each fucoidan alone and in combination with chemotherapy agents in a panel of human cancer cell lines. In vivo studies evaluated safety ...
Research Interests: Pharmacology, Complementary and Alternative Medicine, Biology, Drug interactions, Polysaccharides, and 15 moreMedicine, Humans, Mice, Female, Animals, Fucus, In Vivo, HeLa cells, Hepatocytes, Fucoidan, Glutathione Transferase, Cell Proliferation, Undaria, Antineoplastic Agents, and glucuronosyltransferase
Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity.... more
Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is however relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This manuscript highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration of MIPD in healthcare. Considerations are brought up herein that will need addressing to see MIPD become 'widespread clinical practice': amongst those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implicatio...
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Genetic variation in cytochrome P450 (CYP) 2C9 is known to cause significant inter-individual differences in drug response and adverse effects. The frequencies of CYP2C9*2 and CYP2C9*3, both of which are responsible for the low activity... more
Genetic variation in cytochrome P450 (CYP) 2C9 is known to cause significant inter-individual differences in drug response and adverse effects. The frequencies of CYP2C9*2 and CYP2C9*3, both of which are responsible for the low activity of the enzyme, are not known in the Pakistani population. Therefore, we screened various ethnic groups residing in Pakistan for these polymorphisms. A total of 467 healthy human volunteers were recruited from six major ethnicities of Pakistan after written informed consent. Our results indicate that about 20% of the Pakistani population has a genotype containing at least one low activity allele. Ethnic Punjabi and Pathan populations had the highest frequencies of wild type genotypes while Urdu, Seraiki, and Sindhi populations showed higher rates of both low activity genotypes. The Baloch population showed the highest rates of low activity genotypes with less than 50% of the samples showing wild type genotypes, suggesting that more than half of the Ba...
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Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of several drugs that are currently in clinical use. The gene encoding CYP2C19 is polymorphic with the existence of different alleles resulting in altered enzyme activity. In... more
Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of several drugs that are currently in clinical use. The gene encoding CYP2C19 is polymorphic with the existence of different alleles resulting in altered enzyme activity. In addition, CYP2C19 activity is also dependent on its basal expression levels determined by the transcriptional regulation. Genetic variations located in the CYP2C19 promoter region may alter the interaction of promoter with transcription factors causing variable transcription. Genetic variants may also influence the induction, inhibition of CYP2C19 and may as well affect drug-drug interactions involving CYP2C19 substrates. The role of various transcription factors and genetic variants in the promoter region of CYP2C19 regulating its expression are discussed in this review. Furthermore, induction and inhibition of CYP2C19 by various drugs in clinically meaningful drug interactions are also discussed.
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Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a... more
Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione‐s‐transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model‐based, first‐dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu‐based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age‐dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based onGSTA1polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first‐dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, −0.5%; 95% confidence interval [CI], −3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%–20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence ofGSTA1polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.
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Research Interests: Earth Sciences, Chemistry, Chromatography, Medicine, Linear models, and 15 moreBiological Sciences, Therapeutic drug monitoring, Humans, Child, Calibration, Tandem Mass Spectrometry, High Pressure Liquid Chromatography, CHEMICAL SCIENCES, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Repeatability, Reproducibility of Results, Dried Blood Spot, Drug Stability, SELECTED REACTION MONITORING, and Busulfan
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ABSTRACT La variabilité interindividuelle dans la réponse médicamenteuse est un problème clinique majeur. La polymédication et les polymorphismes génétiques modulant l’activité des enzymes du métabolisme médicamenteux tels que les... more
ABSTRACT La variabilité interindividuelle dans la réponse médicamenteuse est un problème clinique majeur. La polymédication et les polymorphismes génétiques modulant l’activité des enzymes du métabolisme médicamenteux tels que les cytochromes P450 (CYP) sont une source de variabilité dans la réponse médicamenteuse. De nouvelles techniques diagnostiques rendues plus sûres et plus simples à réaliser ont été développées afin de diagnostiquer les variations dans l’activité métabolique des CYP (tests de phénotypage) ou de rechercher des variantes alléliques spécifiques (génotypage). Alors que le génotypage des CYP offre la possibilité de prédire le phénotype en fonction des allèles identifiés pour autant que le lien entre génotype et phénotype soit établi, le phénotypage apporte des informations sur l’activité réelle (in vivo) des CYP et est le reflet d’une combinaison de facteurs génétiques, environnementaux et endogènes. Le génotypage et le phénotypage pourraient ainsi être considérés de manière prospective afin d’identifier la molécule idéale ou la dose adéquate à administrer chez un patient donné, ou de manière rétrospective pour expliquer une réponse médicamenteuse anormale (toxicité ou inefficacité).
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Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used drugs, either on prescription or over-thecounter (OTC). Their daily dosage is based on randomised controlled trials and an empirical clinical assessment of their... more
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used drugs, either on prescription or over-thecounter (OTC). Their daily dosage is based on randomised controlled trials and an empirical clinical assessment of their efficacy and toxicity that allows dose adjustment. The individual response can however be altered by environmental and genetic pharmacokinetic and pharmacodynamic factors. This review summarizes the available pharmacogenetic data that explains part of the variability in response and occurrence of adverse drug reactions to NSAIDs treatment, with a thorough focus on CYP2C9, uridine diphosphate glucuronosyltransferases (UGTs) and cyclooxygenases (COX1 and COX2). Other polymorphisms that are currently being studied and could also explain the interindividual variability in the efficacy and safety of NSAIDs will also be considered.
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Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug–drug interactions, but CYPs can also contribute to drug–disease interactions, especially in the case of inflammation, which downregulates CYP activities through... more
Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug–drug interactions, but CYPs can also contribute to drug–disease interactions, especially in the case of inflammation, which downregulates CYP activities through pretranscriptional and posttranscriptional mechanisms. Interleukin‐6 (IL‐6), a key proinflammatory cytokine, is mainly responsible for this effect. The aim of our study was to develop a physiologically based pharmacokinetic (PBPK) model to foresee the impact of elevated IL‐6 levels in combination with drug interactions with esomeprazole on CYP3A and CYP2C19. Data from a cohort of elective hip surgery patients whose CYP3A and CYP2C19 activities were measured before and after surgery were used to validate the accurate prediction of the developed models. Successive steps were to fit models for IL‐6, esomeprazole, and omeprazole and its metabolite from the literature and to validate them. The models for midazolam and its metabolite were obtained from the literature. When appropriate, a correction factor was applied to convert drug concentrations from whole blood to plasma. Mean ratios between simulated and observed areas under the curve for omeprazole/5‐hydroxy omeprazole, esomeprazole, and IL‐6 were 1.53, 1.06, and 0.69, respectively, indicating an accurate prediction of the developed models. The impact of IL‐6 and esomeprazole on the exposure to CYP3A and CYP2C19 probe substrates and respective metabolites were correctly predicted. Indeed, the ratio between predicted and observed mean concentrations were <2 for all observations (ranging from 0.51 to 1.7). The impact of IL‐6 and esomeprazole on CYP3A and CYP2C19 activities after a hip surgery were correctly predicted with the developed PBPK models.