Increased Pneumonia Risk Associated with Concomitant Use of Inhaled Corticosteroids and Benzodiazepines: A Pharmacovigilance Analysis.

BACKGROUND: Inhaled corticosteroids (ICS) are effective in managing asthma and chronic obstructive pulmonary disease (COPD) but increase the risk of pneumonia. Benzodiazepines (BZD), commonly prescribed for comorbid psychiatric disorders in asthma or COPD patients, are also associated with pneumonia. This study investigates the risk of pneumonia associated with the concomitant use of ICS and BZD. METHODS: Data from the FDA Adverse Event Reporting System from Q4 2013 to Q3 2023 were extracted. Reports involving asthma or COPD patients were included. Disproportionality analysis and logistic regression analysis were performed to assess the risk of pneumonia associated with the combined use of ICS and BZD. Additive and multiplicative models were used to further confirm the results. Additionally, subgroup analyses were conducted based on gender, age, and disease type. RESULTS: A total of 238,411 reports were included. The combined use of ICS and BZD was associated with a higher reporting of pneumonia (ROR: 2.41, 95% CI 2.25-2.58). Using additive and multiplicative methods, the results remained significant. The strongest risk signals were observed in specific drug combinations, such as mometasone with clonazepam, budesonide with temazepam, and mometasone with zopiclone. Subgroup analyses showed higher pneumonia risks in females, patients over 60 years old, and those with asthma. CONCLUSION: Our findings identified a significantly elevated pneumonia risk with the combined use of ICS and BZD. These results highlighted the necessity for cautious co-prescription of ICS and BZD and suggested the need for more comprehensive clinical studies to assess this interaction.

Physiologically based pharmacokinetic modeling of CYP2C8 substrate rosiglitazone and its metabolite to predict metabolic drug-drug interaction.

Rosiglitazone is an activator of nuclear peroxisome proliferator-activated (PPAR) receptor gamma used in the treatment of type 2 diabetes mellitus. The elimination of rosiglitazone occurs mainly via metabolism, with major contribution by enzyme cytochrome P450 (CYP) 2C8. Primary routes of rosiglitazone metabolism are N-demethylation and hydroxylation. Modulation of CYP2C8 activity by co-administered drugs lead to prominent changes in the exposure of rosiglitazone and its metabolites. Here, we attempt to develop mechanistic parent-metabolite physiologically based pharmacokinetic (PBPK) model for rosiglitazone. Our goal is to predict potential drug-drug interaction (DDI) and consequent changes in metabolite N-desmethyl rosiglitazone exposure. The PBPK modeling was performed in the PKSim® software using clinical pharmacokinetics data from literature. The contribution to N-desmethyl rosiglitazone formation by CYP2C8 was delineated using vitro metabolite formation rates from recombinant enzyme system. Developed model was verified for prediction of rosiglitazone DDI potential and its metabolite exposure based on observed clinical DDI studies. Developed model exhibited good predictive performance both for rosiglitazone and N-desmethyl rosiglitazone respectively, evaluated based on commonly acceptable criteria. In conclusion, developed model helps with prediction of CYP2C8 DDI using rosiglitazone as a substrate, as well as changes in metabolite exposure. In vitro data for metabolite formation can be successfully utilized to translate to in vivo conditions.

Pacritinib and concurrent azole antifungal therapy is deliverable in patients with hematologic malignancies.

OBJECTIVE: Pacritinib is a novel kinase inhibitor approved for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis. Strong and moderate CYP3A4 inhibitors, such as some azole antifungals, are contraindicated or recommended to be avoided in combination with pacritinib, respectively. We aim to report our experience in patients who received pacritinib with concurrent azole antifungal therapy. DATA SOURCES: We queried for patients with hematologic malignancies in the electronic medical record who received concurrent pacritinib and azole antifungal therapy. DATA SUMMARY: There were five cases of concurrent pacritinib and azole antifungal therapy in which none of the patients experienced grade 3 or higher non-hematologic toxicities. Some patients required dose modifications and/or interruptions in pacritinib therapy. CONCLUSION: This is the first clinical experience describing concurrent pacritinib and azole antifungals. Our experience shows that in the setting where this interaction cannot be avoided, concurrent administration is feasible with close monitoring and possible empiric dose reductions in select patients.

Temporal Effect of CYP3A4/5 Induction on Ticagrelor's Pharmacodynamic Effects: A Case Series.

Ticagrelor is contraindicated in combination with cytochrome P450 3A4 and 3A5 enzyme (CYP3A4/5) inducers due to increased clearance, causing diminished antiplatelet effects. The emergent nature of acute coronary syndromes (ACS) may preclude scrutinization of home medications before P2Y12 inhibitor administration. The purpose of this case series is to establish the temporal impact of CYP3A4/5 enzyme induction on ticagrelor's pharmacodynamic effect by utilizing VerifyNow platelet aggregation studies. This was a retrospective case series of three patients who were taking a CYP3A4/5-inducing medication and loaded with ticagrelor for ACS. The duration of ticagrelor's antiplatelet effect was dramatically shortened in the presence of background CYP3A4/5 induction. The offset of antiplatelet effect, defined by platelet reactivity units (PRU), was 10-24 hours in the presence of CYP3A4/5 enzyme induction compared to the anticipated 36-48 hours. This was consistent across CYP3A4/5-inducing medications including carbamazepine, phenobarbital, and phenytoin. This study demonstrates rapid return of platelet function after a ticagrelor loading dose in the presence of CYP3A4/5-inducing medications. Monitoring of PRU every 6-12 hours with subsequent loading with clopidogrel or prasugrel should be considered. Larger scale studies are warranted to confirm these results.

Impact of lactoferrin supplementation on cotrimoxazole pharmacokinetics: A preliminary clinical investigation.

Background and purpose: Cotrimoxazole, a commonly prescribed antibiotic, has substantial resistance, especially in Indonesia, with its uropathogenic resistance reaching 67% in 2017. Although cotrimoxazole has been suggested to be co-administered with lactoferrin to enhance its antibacterial effectiveness and this practice has been widely adopted since the Covid-19 pandemic, the impact of lactoferrin on the pharmacokinetics of cotrimoxazole remains relatively unknown. This study aims to conduct a preliminary clinical investigation into the impact of lactoferrin supplementation on the pharmacokinetics of cotrimoxazole, focusing on the elimination rate and excretion of unchanged drug in urine. Experimental approach: This study employed a blinded, cross-over, single-dose pharmacokinetics investigation, which included five healthy volunteers as participants. In the initial period, the first group received cotrimoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) along with a lactoferrin-containing supplement, while the second group only received cotrimoxazole. Subsequently, after a washout period, the conditions were reversed. Urine sampling was conducted at intervals from 0 to 24 hours post-medication, and drug levels in the urine were determined using high-performance liquid chromatography. Key results: The population-based pharmacokinetic analysis revealed that the optimal model was the one-compartment model with first-order elimination and proportional residual error. Conclusion: The findings show that the administration of lactoferrin-containing supplements did not significantly influence the covariate model and, therefore, did not alter the pharmacokinetics parameter of cotrimoxazole in urine with a single administration, implying that lactoferrin did not cause drug interaction problems when given simultaneously.

Characteristics of CYP3A4-related potential drug-drug interactions in outpatients receiving prescriptions from multiple clinical departments.

BACKGROUND: Drug-drug interactions (DDIs) increase the incidence of adverse drug reactions (ADRs). In a previous report, we revealed that the incidence of potential DDIs due to the same CYP molecular species in one prescription exceeds 90% among patients taking six or more drugs and that CYP3A4 markedly influences the increase in the number of potential DDIs in clinical practice. However, the factors contributing to an increased number of potential DDIs in prescriptions from multiple clinical departments remain poorly clarified. METHODS: This observational study was performed at five pharmacies in Okayama Prefecture, Japan. Patients who visited these pharmacies from 11 April 2022 to 24 April 2022 were included, except those who had prescriptions only from a single clinical department. A stratified analysis was performed to determine the incidence of CYP3A4-related potential DDIs according to the number of drugs taken. Additionally, factors associated with an increase in the number of drugs involved in CYP3A4-related potential DDIs were identified using multiple linear regression analysis. In this study, potential DDIs for the prescription data subdivided by clinical department, containing two or more drugs, were used as control data. RESULTS: Overall, 372 outpatients who received prescriptions from multiple clinical departments were included in the current study. The number of drugs contributing to CYP3A4-related potential DDIs increased with an increase in the number of clinical departments. Notably, in cases taking fewer than six drugs, prescriptions from multiple clinical departments had a higher frequency of CYP3A4-related potential DDIs than those in prescriptions subdivided by clinical department. Multiple regression analysis identified "Cardiovascular agents", "Agents affecting central nervous system", and "Urogenital and anal organ agents" as the top three drug classes that increase CYP3A4-related potential DDIs. CONCLUSION: Collectively, these results highlight the importance of a unified management strategy for prescribed drugs and continuous monitoring of ADRs in outpatients receiving prescriptions from multiple clinical departments even if the number of drugs taken is less than six.

Effect of chloroquine pre-treatment on the metoclopramide's pharmacokinetics after their co-administration.

BACKGROUND: This study evaluated the pharmacokinetic interactions of orally administered chloroquine and metoclopramide. METHODS: The study employed a randomized and two-phase cross-over design with 4-week washout plan. Twelve healthy male volunteers were shortlisted according to the set criteria and were administered with metoclopramide 10 mg PO and chloroquine (a total of 1500 mg) at different intervals which were (500 mg at 0, 6, and 24 h). The concentration of chloroquine and metoclopramide in the blood samples was estimated using a validated HPLC-UV technique to affirm the maximum concentration (Cmax), time to reach Cmax (Tmax), and area under the curve (AUC). RESULTS: Cmax, T1/2, and AUC of metoclopramide were increased up to 20, 10, and 47.8%, respectively, by the concomitantly administering Chloroquine. Chloroquine-treated phase showed increased values of Cmax (ng/ml), AUC (ng.h/ml), and T½ (h), i.e. 41.35 ± 1.61, 504.12 ± 66.25, and 5.72 ± 2.63, as compared to that reference phase i.e. 34.52 ± 4.92, 341.14 ± 112.8, and 5.19 ± 1.14, respectively. CONCLUSIONS: Chloroquine was found to attenuate CYP2D6 activity in healthy Pakistani male volunteers. Hence, patients that are prescribed with metoclopramide or other CYP2D6-substrate drugs require a dose adjustment when administered with chloroquine.

Evaluation of pharmacokinetic herb-drug interaction of diabecon and losartan by UHPLC-MS/MS.

The diabecon is an ayurvedic herbal formulation that contains a mixture of herbs traditionally used as antidiabetic which is reported in the ayurvedic pharmacopeia of India and Indian Materia medica. The diabetic population has a common co-morbidity of hypertension for which losartan drug is commonly used for the treatment of hypertension. However, there is a lack of research on the pharmacokinetics interaction between diabecon and losartan. This research aims to investigate the influence of diabecon on the pharmacokinetics of losartan drugs in rats by establishing a highly sensitive ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-MS/MS) method. The method was validated according to the USFDA guidelines and was applied for the pharmacokinetic study. The lowest concentration of losartan detection in rat plasma was found to be 1 ng/mL and the accuracy and precision were within the linear range (1-1500 ng/mL). The results revealed that after 28 days of dosing diabecon, it has altered the pharmacokinetic parameters like area under the curve (AUC0-t), drug clearance (Cl/F), and rate of elimination (Ke) of losartan, which may happen due to enzyme induction. Although there was a change in the pharmacokinetic parameters of losartan when administered in the presence of diabecon, it was found to be nonsignificant in rats (p > 0.05). According to the best of our knowledge, this is the first article that discusses the pharmacokinetic herb-drug interaction between diabecon and losartan.

[Renal failure and drug-drug interactions]. / Bei Niereninsuffizienz auf Arzneimittel-Interaktionen achten!

Renal failure is common and comes with a steep increasing prevalence in older patients. It is a frequent aspect in multimorbidity and associated with polypharmacia. Based on available literature an overview is given concerning important drug-drug interactions and how to avoid or manage them. Among a large variety of possible interactions anticoagulation and diuretic therapy still represent the highest clinical relevance.

Clinical Significance and Patterns of Potential Drug-Drug Interactions in Cardiovascular Patients: Focus on Low-Dose Aspirin and Angiotensin-Converting Enzyme Inhibitors.

Objective: This study assessed the patterns and clinical significance of potential drug-drug interactions (pDDIs) in patients with diseases of the cardiovascular system. Methods: Electronic health records (EHRs), established in 2018-2023, were selected using the probability serial nested sampling method (n = 1030). Patients were aged 27 to 95 years (65.0% men). Primary diagnosis of COVID-19 was present in 17 EHRs (1.7%). Medscape Drug Interaction Checker was used to characterize pDDIs. The Mann-Whitney U test and chi-square test were used for statistical analysis. Results: Drug numbers per record ranged from 1 to 23 in T-List and from 1 to 20 in P-List. In T-List, 567 drug combinations resulted in 3781 pDDIs. In P-List, 584 drug combinations resulted in 5185 pDDIs. Polypharmacy was detected in 39.0% of records in T-List versus 65.9% in P-List (p-value < 0.05). The rates of serious and monitor-closely pDDIs due to 'aspirin + captopril' combinations were significantly higher in P-List than in T-List (p-value < 0.05). The rates of serious pDDIs due to 'aspirin + enalapril' and 'aspirin + lisinopril' combinations were significantly lower in P-List compared with the corresponding rates in T-List (p-value < 0.05). Serious pDDIs due to administration of aspirin with fosinopril, perindopril, and ramipril were detected less frequently in T-List (p-value < 0.05). Conclusions: Obtained data may suggest better patient adherence to 'aspirin + enalapril' and 'aspirin + lisinopril' combinations, which are potentially superior to the combinations of aspirin with fosinopril, perindopril, and ramipril. An abundance of high-order pDDIs in real-world clinical practice warrants the development of a decision support system aimed at reducing pharmacotherapy-associated risks while integrating patient pharmacokinetic, pharmacodynamic, and pharmacogenetic information.

Effect of Itraconazole, a CYP3A4 Inhibitor, and Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of Vatiquinone.

Vatiquinone is a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich's ataxia. The objective of this analysis was to determine the effect of a cytochrome P450 isoform 3A4 (CYP3A4) inhibitor and inducer on vatiquinone pharmacokinetics (PKs). The coadministration of 400 mg of vatiquinone with 200 mg of itraconazole (a CYP3A4 inhibitor) resulted in increased maximum observed concentration (Cmax) of vatiquinone and systemic exposure (AUC0-inf) by approximately 3.5- and 2.9-fold, respectively. The coadministration of 400 mg of vatiquinone with 600 mg of rifampin (a CYP3A4 inducer) resulted in decreased vatiquinone Cmax and AUC0-inf by approximately 0.64- and 0.54-fold, respectively. The terminal half-life of vatiquinone was not affected by itraconazole or rifampin. These clinical study results confirm the in vitro reaction phenotyping data that shows that CYP3A4 plays an important role in vatiquinone metabolism. The result of this analysis together with phase 3 efficacy and safety data, population PK analysis, and the exposure-response relationship will determine if the extent of vatiquinone changes in the presence of CYP3A4 inhibitors and inducers are considered clinically relevant.

The anti-COVID-19 drug nirmatrelvir crosses the blood‒brain barrier and exhibits herb-drug pharmacokinetic interactions with Scutellaria baicalensis formulations.

Aim of the study: Our hypothesis is that nirmatrelvir can penetrate the blood‒brain barrier and reach effective concentrations in the brain. Furthermore, herbal formulations can help maintain nirmatrelvir levels in the body, suggesting potential interactions between these medications. Materials and methods: To investigate this hypothesis, an animal model combining multisite microdialysis, ultrahigh-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS) methods was developed to monitor nirmatrelvir levels in the blood and brain of rats. Results: The pharmacokinetic results showed that the area under the curve (AUC) of nirmatrelvir in the blood and brain was 798.3 ± 58.56 and 187.2 ± 23.46 min µg/mL, respectively, after the administration of nirmatrelvir alone (15 mg/kg, iv). When the Scutellaria baicalensis formulations were administered for five consecutive days prior to drug administration, the AUC of nirmatrelvir in the blood increased. Conclusions: These results provide constructive preclinical information that the concentrations of nirmatrelvir in the blood and brain were greater than the effective concentration (EC90) for more than 6 h, and the Scutellaria baicalensis formulations had synergistic pharmacokinetic effects by increasing the concentration of nirmatrelvir in the blood.

Drug-induced enzyme activity inhibition and CYP3A4 genetic polymorphism significantly shape the metabolic characteristics of furmonertinib.

This study aimed to elucidate the impact of variations in liver enzyme activity, particularly CYP3A4, on the metabolism of furmonertinib. An in vitro enzyme incubation system was established for furmonertinib using liver microsomes and recombinant CYP3A4 baculosomes, with analytes detected by LC-MS/MS. The pharmacokinetic characteristics of furmonertinib were studied in vivo using Sprague-Dawley rats. It was found that telmisartan significantly inhibited the metabolism of furmonertinib, as demonstrated by a significant increase in the AUC of furmonertinib when co-administered with telmisartan, compared to the furmonertinib-alone group. Mechanistically, it was noncompetitive in rat liver microsomes, while it was mixed competitive and noncompetitive in human liver microsomes and CYP3A4. Considering the genetic polymorphism of CYP3A4, the study further investigated its effect on the kinetics of furmonertinib. The results showed that compared to CYP3A4.1, CYP3A4.29 had significantly increased activity in catalyzing furmonertinib, whereas CYP3A4.7, 9, 10, 12, 13, 14, 18, 23, 33, and 34 showed markedly decreased activity. The inhibitory activity of telmisartan varied in CYP3A4.1 and CYP3A4.18, with IC50 values of 8.56 ± 0.90 µM and 27.48 ± 3.52 µM, respectively. The key loci affecting the inhibitory effect were identified as ARG105, ILE301, ALA370, and LEU373. Collectively, these data would provide a reference for the quantitative application of furmonertinib.

Hyperkalemic effect of drug-drug interaction between esaxerenone and trimethoprim in patients with hypertension: a pilot study.

BACKGROUND: We examined whether the pharmacodynamic drug-drug interaction between esaxerenone and trimethoprim enhances the hyperkalemic effect. METHODS: A retrospective observational study was conducted to identify patients >18 years undertaking esaxerenone alone or esaxerenone plus trimethoprim at Mie University Hospital from May 2019 to December 2022. We performed propensity score-matching (1:1) to compare between-group differences in the maximum change in serum potassium levels (ΔK) using the Mann-Whitney U test. For esaxerenone plus trimethoprim, Spearman's correlation coefficients were used to examine correlations between ΔK and variables, including changes in blood urea nitrogen (ΔBUN), serum creatinine levels (ΔCr), and weekly trimethoprim cumulative dose. RESULTS: Out of propensity score-matched groups (n=8 each), serum potassium levels significantly increased after administration of esaxerenone alone (4.4 [4.2 to 4.7] meq/L to 5.2 [4.7 to 5.4] meq/L, p=0.008) and esaxerenone plus trimethoprim (4.2 [4.0 to 5.1] meq/L to 5.4 [4.7 to 5.5] meq/L, p=0.023). ΔK did not significantly differ between the groups (esaxerenone alone; 0.6 [0.3 to 0.9] meq/L vs. esaxerenone plus trimethoprim; 1.0 [0.4 to 1.3] meq/L, p=0.342). ΔK positively correlated with ΔBUN (r=0.988, p<0.001) or ΔCr (r=0.800, p=0.017). There was a trend of correlation of ΔK with a weekly cumulative trimethoprim dose (r=0.607, p=0.110). CONCLUSIONS: The hyperkalemic effect of the drug-drug interaction between esaxerenone and trimethoprim is not notable and related to renal function and trimethoprim dosage.

Development of UPLC-MS/MS method for studying the pharmacokinetic interactions of fuzuloparib with curcumin in rats.

Fuzuloparib is a novel orally bioactive poly-ADP-ribose polymerase inhibitor (PARPi), which was approved by the Chinese Regulatory Agency (CRA) in 2020 for the treatment of platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancers. This study firstly presents a rapid and accurate ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for analyzing the levels of fuzuloparib and its major metabolite (SHR165202), and to investigate drug-drug interaction between fuzuloparib and curcumin in vitro and in vivo studies. After protein precipitation with acetonitrile, mobile phase consisted of acetonitrile and 0.1 % formic acid with a gradient elution was used to successfully separate fuzuloparib, SHR165202 and talazoparib (internal standard, IS). The results indicated that fuzuloparib and SHR165202 had good linearity over the calibration range of 2-50 ng/mL and 1-20 ng/mL, respectively. The precision, accuracy, stability, matrix effect, and extraction recovery required for methodological validation all complied with the requirements of the Bioanalytical Method Validation Guidelines. In vitro microsome incubation experiments, curcumin exhibited inhibitory effect on fuzuloparib in both rat liver microsomes (RLM) and human liver microsomes (HLM) with half-maximal inhibitory concentration (IC50) value of 10.54 µM and 47.64 µM, respectively, and the corresponding mechanism was non-competitive. Furthermore, the inhibitory mechanism of curcumin on fuzuloparib was validated through molecular docking. In pharmacokinetic experiments in rats, curcumin significantly altered the plasma exposure of fuzuloparib, resulting in significant increases in AUC(0-t) and Cmax of fuzuloparib and a significant decrease in CLz/F. Moreover, the metabolite SHR165202 showed significant increases in AUC(0-t), AUC(0-∞), Tmax and Cmax and a significant decrease in CLz/F. This further supports the notion that curcumin could inhibit the metabolism of fuzuloparib. Therefore, when co-administering fuzuloparib and curcumin in clinic, it is recommended to monitor plasma levels of fuzuloparib and pay close attention to adverse effects. If necessary, the dose of fuzuloparib needs to be reduced.

Ovicidal activity of diaryl dichalcogenides and ivermectin on Fasciola hepatica: A novel candidate for a blending-based therapeutic strategy.

Fasciolosis is a food and waterborne disease caused by Fasciola spp., representing a global health burden to various hosts, including humans and other animals. This study investigates the in vitro activity of tellurium- and selenium-containing diaryl dichalcogenides: diacetal ditelluride (LQ07), diacetal diselenide (LQ62), and diacetyl diselenide (LQ68) alone and in combination with ivermectin (IVM) against eggs of Fasciola hepatica. The eggs were exposed for 12 h with each organochalcogen (OC) (0.1 - 2 mmol l-1) and IVM (0.01 - 2 mmol l-1) following an incubation of 15 days, allowing embryonation. The inhibitory concentration of 50 % (IC50) of each OC or IVM was tested with the IC10, IC30, and IC50 of IVM or each OC, respectively. LQ07, LQ62, and LQ68, as well as IVM, demonstrated a concentration-dependent ovicidal activity. The peak ovicidal activity of 99.74 % was achieved when IVM was tested at 2.0 mmol l-1. LQ62 and LQ68 demonstrated greater ovicidal activity, having an IC50 < 0.32 mmol l-1 being 6.25-fold more toxic than IVM alone. The percentage of dead eggs was significantly higher in the IVM group (early mortality), as Se-containing OCs led to the (miracidia) embryonation of the eggs with no hatching (late mortality). Blending Se-containing OCs and IVM showed an additive effect of up to 27 % against F. hepatica eggs. The present data contribute to the potential use of blending-based therapeutic strategies to combat F. hepatica infections in eradication programs worldwide. The combinations may also act against multidrug-resistant strains, reinstating drug-based parasite control.

Significant increases in detection capability for assessment of organic anion transporting polypeptide-mediated drug-drug interaction in cynomolgus monkeys by modifying pretreatment of Coproporphyrin I and III, and glycochenodeoxycholate-3-sulfate in plasma.

BACKGROUND: Coproporphyrin I (CP-I), Coproporphyrin III (CP-III), and glycochenodeoxycholate-3-sulfate (GCDCA-S) act as endogenous substrates of Organic Anion Transporting Polypeptide (OATP) 1B and have been considered for application in OATP1B-mediated drug‒drug interaction (DDI) risk assessments. Prior assays of the endogenous OATP substrates might exhibit reduced DDI detection capability and possibly overlook low DDI risk. We pioneered a simultaneous assay of the three substrates in monkey plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) and applied it to monkey studies to identify lower DDI risk. RESULTS: The methodology development indicated that precursors of CP-I/III were oxidized to form CP-I/III, diminishing the detection capability in DDI risk assessments. A precursor eliminated analytical (PEA) method was developed to eliminate the precursors through solid-phase extraction. This method aimed to prevent the oxidation of CP-I/III precursors by incorporating edaravone. For comparison, a precursor oxidized analytical (POA) method was also developed, wherein the precursors of CP-I/III were fully oxidized to CP-I/III. The PEA method achieved high sensitivity for CP-I/III and GCDCA-S, with lower quantification limits of 0.01 ng mL-1 and 0.5 ng mL-1, respectively. Both methods ensured that the validation parameters met the acceptance criteria. The two methods were applied to a monkey study, with CP-I/III showcasing notably enhanced DDI detection capabilities through the novel PEA method in comparison to the POA method. SIGNIFICANCE: This study's methodology has future implications for OATP-mediated DDI risk assessment using endogenous substrates. The novel PEA method can identify lower OATP-mediated DDI risks for drugs that the current methods cannot detect. Our method is likely applicable in clinical settings, and its utility should be assessed in clinical trials.

The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice.

This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.

Grace periods and exposure misclassification in self-controlled case-series studies of drug-drug interactions.

The self-controlled case-series (SCCS) research design is increasingly used in pharmacoepidemiologic studies of drug-drug interactions (DDIs), with the target of inference being the incidence rate ratio (IRR) associated with concomitant exposure to the object plus precipitant drug versus the object drug alone. While day-level drug exposure can be inferred from dispensing claims, these inferences may be inaccurate, leading to biased IRRs. Grace periods (periods assuming continued treatment impact after days' supply exhaustion) are frequently used by researchers, but the impact of grace period decisions on bias from exposure misclassification remains unclear. Motivated by an SCCS study examining the potential DDI between clopidogrel (object) and warfarin (precipitant), we investigated bias due to precipitant or object exposure misclassification using simulations. We show that misclassified precipitant treatment always biases the estimated IRR toward the null, whereas misclassified object treatment may lead to bias in either direction or no bias, depending on the scenario. Further, including a grace period for each object dispensing may unintentionally increase the risk of misclassification bias. To minimize such bias, we recommend 1) avoiding the use of grace periods when specifying object drug exposure episodes; and 2) including a washout period following each precipitant exposed period.