Amanda A Miller, Motohiro Nakajima, Briana N DeAngelis, Dorothy K Hatsukami, Mustafa al'Absi
{"title":"Nicotine addiction and the influence of life adversity and acute stress on PYY: Prediction of early smoking relapse.","authors":"Amanda A Miller, Motohiro Nakajima, Briana N DeAngelis, Dorothy K Hatsukami, Mustafa al'Absi","doi":"10.1002/prp2.70016","DOIUrl":"10.1002/prp2.70016","url":null,"abstract":"<p><p>Early life adversity (ELA) is associated with earlier initiation and maintenance of tobacco smoking and with a greater risk of subsequent relapse. There is growing evidence that appetite hormones, including peptide YY (PYY), which modulates craving and satiety responses, play a role in stress and addiction processes. This study employed a quasi-experimental design to examine the association between ELA and circulating PYY stress responses in smokers and nonsmokers (N = 152, ages 19-73 years) to examine the effects of nicotine addiction. Smokers initiated a quit attempt as part of the study and were classified as either abstinent smokers or relapsed smokers based on their nicotine use during the follow-up period. PYY levels were measured at five timepoints during three lab sessions and compared between nonsmokers and the two smoking groups (abstainers, relapsers): while smokers were using nicotine ad libitum, 24 h after smokers initiated a quit attempt, and 4 weeks after smokers initiated a quit attempt. Multivariate analyses showed the main effects of time on PYY, which decreased over time within each session. The main effects of ELA during the first (ad libitum smoking) and second (24-h post-cessation for smokers) sessions indicated that experiencing ELA was associated with lower PYY. No systematic effect of nicotine addiction or relapse was observed in this study. These findings suggest that adults with higher ELA may experience lower PYY. Additional research is needed to further explore the role of PYY in stress and addiction processes.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70016"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies.","authors":"Zhili Dong, Kensei Hashizume, Frauke Friedrichs, Pei Liu, Toshiaki Tanaka, Yuqin Liao","doi":"10.1002/prp2.70012","DOIUrl":"10.1002/prp2.70012","url":null,"abstract":"<p><p>The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single-blinded, placebo-controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1-3 h and 4-6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose-proportional pharmacokinetics for AUC but not C<sub>max</sub>; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1-4 h and 2-6 days after IV and SC administration, respectively. Anti-drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose-proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70012"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minakshi Sangwan, Hema Chaudhary, Sidharth Mehan, Zuber Khan, Ammar A Bahauddin, Bandar D Alrehaili, Hossein M Elbadawy, Mohannad A Almikhlafi, Acharan S Narula, Reni Kalfin, Hanna Wanas
{"title":"Effect of mitochondrial coenzyme-Q10 precursor solanesol in gentamicin-induced experimental nephrotoxicity: Evidence from restoration of ETC-complexes and histopathological alterations.","authors":"Minakshi Sangwan, Hema Chaudhary, Sidharth Mehan, Zuber Khan, Ammar A Bahauddin, Bandar D Alrehaili, Hossein M Elbadawy, Mohannad A Almikhlafi, Acharan S Narula, Reni Kalfin, Hanna Wanas","doi":"10.1002/prp2.70022","DOIUrl":"10.1002/prp2.70022","url":null,"abstract":"<p><p>Nephrotoxicity occurs when the body is exposed to certain drugs or toxins. When kidney damage occurs, the kidney fails to eliminate excess urine and waste. Solanesol (C45H74O) is a tri-sesquiterpenoid alcohol first isolated from tobacco, and it is widely distributed in plants of the Solanaceae family. Solanesol (SNL) is an intermediate in the synthesis of coenzyme Q10 (CoQ10), an antioxidant which protects nerve cells. This study investigated the protective effect of SNL at doses of 30 and 60 mg/kg in gentamicin-induced nephrotoxicity in Wistar albino rats. Animals were distributed into six groups and administered 100 mg/kg gentamicin-intraperitoneal injection for 14 days. Biochemical assessments were performed on kidney homogenate, blood, and serum. Treatment with SNL was shown as lower serum levels of creatinine, blood urea nitrogen (BUN), thiobarbituric acid reactive substances (TBARS), and Tumor necrosis factor alpha)TNF-α ((p < .001). It also restored reduced glutathione (GSH) and mitochondrial complex enzymatic activity as protective measures against gentamicin-induced nephrotoxicity. SNL were shown to reduce inflammation and oxidative stress markers (p < .001). Histological findings furtherly augmented the protective effects of SNL. Long-term SNL therapy also restored mitochondrial electron transport chain complex enzymes, such as complex-I (p < .001). In conclusion, these findings suggest that SNL can represent a protective therapeutic option for drug-induced nephrotoxicity, a long-term adverse effect of aminoglycoside antibiotics such as gentamicin.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70022"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Sofia Martins, Cristina Monteiro, Ana Paula Duarte
{"title":"Risks of oral anticoagulants: Analysis of adverse drug reactions reported to the Portuguese National Pharmacovigilance System","authors":"Ana Sofia Martins, Cristina Monteiro, Ana Paula Duarte","doi":"10.1002/prp2.1235","DOIUrl":"https://doi.org/10.1002/prp2.1235","url":null,"abstract":"Cardiovascular diseases are the leading cause of death globally, making the use of oral anticoagulants for prevention increasingly important. Historically, warfarin has played a significant role in this context. In recent years, introduction of new oral anticoagulants, such as rivaroxaban, apixaban, dabigatran, and edoxaban, has been seen. This study evaluates the risk associated with the use of oral anticoagulants by analyzing spontaneous adverse drug reactions reported to the Portuguese Pharmacovigilance System from 2012 to 2021. The study includes 951 adverse drug reactions reports, with the majority (<jats:italic>n</jats:italic> = 770; 80.97%) classified as serious. Of the 770 serious adverse drug reactions reports, the most commonly reported seriousness criterion was “Clinically Important” (<jats:italic>n</jats:italic> = 350; 45.45%). In terms of demographics, there was a higher reporting rate among the elderly population, with a greater prevalence of females. The System Organ Class group with the highest number of adverse drug reactions was “Gastrointestinal disorders,” with the most commonly reported Preferred Term being “Gastrointestinal hemorrhage,” and dabigatran was the most frequently reported drug. In summary, oral anticoagulants have adverse drug reactions that require continuous monitoring. Accurate identification and monitorization of adverse drug reactions is an important starting point to improve drug safety in population.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"33 1","pages":"e1235"},"PeriodicalIF":2.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adeladlew Kassie Netere, Tony Hughes, Anna‐Marie Babey, Martin Hawes, Janet Mifsud, John P. Kelly, Willmann Liang, Mark Hernandez, Kelly Karpa, Hesham Al‐Sallami, Lynette B. Fernandes, Patrik Aronsson, Carolina Restini, Fabiana Caetano Crowley, Elvan Djouma, Tina Hinton, Johnson J. Liu, Fatima Mraiche, Paul J. White
{"title":"Evaluating the quality of multiple‐choice question pilot database: A global educator‐created tool for concept‐based pharmacology learning","authors":"Adeladlew Kassie Netere, Tony Hughes, Anna‐Marie Babey, Martin Hawes, Janet Mifsud, John P. Kelly, Willmann Liang, Mark Hernandez, Kelly Karpa, Hesham Al‐Sallami, Lynette B. Fernandes, Patrik Aronsson, Carolina Restini, Fabiana Caetano Crowley, Elvan Djouma, Tina Hinton, Johnson J. Liu, Fatima Mraiche, Paul J. White","doi":"10.1002/prp2.70004","DOIUrl":"https://doi.org/10.1002/prp2.70004","url":null,"abstract":"The Core Concepts of Pharmacology (CCP) initiative is developing educational resources to transform pharmacology education into a concept‐based approach. This study evaluated the quality of global educator‐created MCQs in generating items for the pharmacology concept inventory (PCI) instrument and developed as a resource for learning pharmacology fundamental concepts. A panel of 22 global pharmacology experts recruited from the CCP initiative research team participated in the MCQ pilot database design and evaluation. The quality analysis framework of the MCQs in the pilot database included four assessment tools: item writing guidelines (IWGs), Bloom's taxonomy, the CCP, and the MCQ design format. A two‐phase evaluation process was involved, including inter‐rater agreement on item quality, followed by resolving conflicts that occurred in quality assessment. The chi‐square (<jats:italic>χ</jats:italic><jats:sup>2</jats:sup>) test of independence and Cramer's V correlation tests were utilized to measure the relationship among quality assessment attributes. About 200 MCQs were gathered and 98% underwent expert evaluation. Nearly 80% addressed one or more CCP, with 52% designed using a context‐dependent format. However, only 40% addressed higher levels of Bloom's cognitive domain and 10% adhered to all IWGs. A strong positive correlation was observed between the context‐based item format and its effectiveness in assessing the higher cognitive domain, the main CCP and improved IWGs adherence. Context‐based item construction can assess the higher cognitive skills and fundamental pharmacology concepts, showing potential for rigorous PCI development. The pilot database will store items to create the PCI, aiding the development of a concept‐based pharmacology curriculum.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"101 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An improvement of the safety profile of SARS‐CoV‐2 vaccines is desirable","authors":"Josef Finsterer","doi":"10.1002/prp2.70008","DOIUrl":"https://doi.org/10.1002/prp2.70008","url":null,"abstract":"","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"4 1","pages":"e70008"},"PeriodicalIF":2.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Donghong Xu, Punag Divanji, Adrienne Griffith, Rajaa Sukhun, Kathleen Cheplo, Jianlin Li, Polina German
{"title":"Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans","authors":"Donghong Xu, Punag Divanji, Adrienne Griffith, Rajaa Sukhun, Kathleen Cheplo, Jianlin Li, Polina German","doi":"10.1002/prp2.70006","DOIUrl":"https://doi.org/10.1002/prp2.70006","url":null,"abstract":"Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median t<jats:sub>max</jats:sub> of 2.0 h postdose. The median t<jats:sub>1/2</jats:sub> of aficamten was 99.6 h with similar t<jats:sub>1/2</jats:sub> observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK‐3834282) and M1b (CK‐3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median t<jats:sub>max</jats:sub> of 5 h. The other major plasma metabolite was M5 (an oxygen‐linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a t<jats:sub>max</jats:sub> of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at >10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"8 1","pages":"e70006"},"PeriodicalIF":2.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura Saint-Lary, Isabelle Lacroix, Valériane Leroy, Agnès Sommet
{"title":"Integrase inhibitor drugs during pregnancy and congenital anomalies: A case/non-case study from the global pharmacovigilance database VigiBase®.","authors":"Laura Saint-Lary, Isabelle Lacroix, Valériane Leroy, Agnès Sommet","doi":"10.1002/prp2.1247","DOIUrl":"10.1002/prp2.1247","url":null,"abstract":"<p><p>In 2018, a significant neural tube defects (NTD) signal was reported after pre-conceptional exposure to dolutegravir, but was not confirmed in further analysis. Since 2019, dolutegravir-based regimen, an integrase inhibitor (INI), is recommended by WHO as the most-effective first-line therapy in all patients living with HIV. To explore the potential INI-related teratogenic effect, we searched disproportionate signals between exposure to INI-class drugs and congenital anomalies, compared to non-INI drugs, using the international pharmacovigilance database, VigiBase®. We selected all the reports registered in VigiBase® between 01/01/2007 and 30/03/2021 on any antiretroviral drug-related fetal or neonatal adverse drug reactions, declared either in children (<2 years) exposed in utero or in pregnant women (12-50 years). A case/non-case study was conducted to detected signals between congenital anomalies and prenatal exposure to any INI-class drug, compared to non-INI drugs, by estimating adjusted reporting odds ratios (aROR) with 95% confidence intervals (95%CI). We identified 2521 unique reports, among which 664 (26.3%) were related to INI-class use. Overall, 520 congenital anomalies were cited from 327 unique reports, of whom 31.0% were INI-related. Compared to non-INI drugs, no significant disproportionate reporting signal between prenatal exposure to INI-class drugs and congenital anomalies was found (aROR 1.13; 95% CI:0.85-1.51). However, specific significant signals were reported for raltegravir/elvitegravir/dolutegravir drug exposure and urinary malformations (aROR 2.43; 95%CI:1.08-5.43), digestive malformations (aROR 3.09; 95%CI:1.22-7.84), and NTDs (aROR 3.02; 95%CI:1.09-8.37). Although specific congenital anomalies signals associated with raltegravir/elvitegravir/dolutegravir exposure were notified, causal relationship needs to be further investigated in prospective studies.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 4","pages":"e1247"},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dung Nguyen, Xiusheng Miao, Kunal Taskar, Mindy Magee, Pete Gorycki, Katy Moore, Guoying Tai
{"title":"No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches.","authors":"Dung Nguyen, Xiusheng Miao, Kunal Taskar, Mindy Magee, Pete Gorycki, Katy Moore, Guoying Tai","doi":"10.1002/prp2.1238","DOIUrl":"10.1002/prp2.1238","url":null,"abstract":"<p><p>Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 4","pages":"e1238"},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11237172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An open-label study to explore the optimal design of CYP3A drug-drug interaction clinical trials in healthy Chinese people.","authors":"Jingcheng Chen, Jiangshuo Li, Jingxuan Wu, Yuqin Song, Lijun Li, Jianxiong Zhang, Ruihua Dong","doi":"10.1002/prp2.1252","DOIUrl":"10.1002/prp2.1252","url":null,"abstract":"<p><p>A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (C<sub>max</sub>), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC<sub>0-t</sub>), and 11.22-fold based on area under the curve from zero to infinity (AUC<sub>0-∞</sub>). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on C<sub>max</sub>, ~0.18-fold based on AUC<sub>0-t</sub>, and ~0.18-fold based on AUC<sub>0-∞</sub>. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 4","pages":"e1252"},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}