European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Dried Blood Spots-A Platform for Therapeutic Drug Monitoring (TDM) and Drug/Disease Response Monitoring (DRM).","authors":"Nur Nabihah Binte Zailani,&nbsp;Paul Chi-Lui Ho","doi":"10.1007/s13318-023-00846-4","DOIUrl":"https://doi.org/10.1007/s13318-023-00846-4","url":null,"abstract":"<p><p>This review provides an overview on the current applications of dried blood spots (DBS) as matrices for therapeutic drug (TDM) and drug or disease response monitoring (DRM). Compared with conventional methods using plasma/serum, DBS offers several advantages, including minimally invasiveness, a small blood volume requirement, reduced biohazardous risk, and improved sample stability. Numerous assays utilising DBS for TDM have been reported in the literature over the past decade, covering a wide range of therapeutic drugs. Several factors can affect the accuracy and reliability of the DBS sampling method, including haematocrit (HCT), blood volume, sampling paper and chromatographic effects. It is crucial to evaluate the correlation between DBS concentrations and conventional plasma/serum concentrations, as the latter has traditionally been used for clinical decision. The feasibility of using DBS sampling method as an option for home-based TDM is also discussed. Furthermore, DBS has also been used as a matrix for monitoring the drug or disease responses (DRM) through various approaches such as genotyping, viral load measurement, assessment of inflammatory factors, and more recently, metabolic profiling. Although this research is still in the development stage, advancements in technology are expected to lead to the identification of surrogate biomarkers for drug treatment in DBS and a better understanding of the correlation between DBS drug levels and drug responses. This will make DBS a valuable matrix for TDM and DRM, facilitating the achievement of pharmacokinetic and pharmacodynamic correlations and enabling personalised therapy.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b7/78/13318_2023_Article_846.PMC10480258.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10178499","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":"First-in-Human Study of the Safety, Pharmacokinetics, and Pharmacodynamics of MHV370, a Dual Inhibitor of Toll-Like Receptors 7 and 8, in Healthy Adults.","authors":"Tamas Shisha,&nbsp;Maximilian G Posch,&nbsp;Jeanette Lehmann,&nbsp;Roland Feifel,&nbsp;Tobias Junt,&nbsp;Stuart Hawtin,&nbsp;Jens Schuemann,&nbsp;Alexandre Avrameas,&nbsp;Rambabu Danekula,&nbsp;Patrycja Misiolek,&nbsp;Richard Siegel,&nbsp;Peter Gergely","doi":"10.1007/s13318-023-00847-3","DOIUrl":"https://doi.org/10.1007/s13318-023-00847-3","url":null,"abstract":"<p><strong>Background and objective: </strong>MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370.</p><p><strong>Methods: </strong>This was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated.</p><p><strong>Results: </strong>MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.).</p><p><strong>Conclusion: </strong>The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0e/ff/13318_2023_Article_847.PMC10480294.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10531220","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":"Preclinical Pharmacokinetics and in vitro Metabolism of FHND5071, a Novel Selective RET Kinase Inhibitor.","authors":"Yiran Han,&nbsp;Tiantian Wen,&nbsp;Jia Wang,&nbsp;Jinmiao Shi,&nbsp;Yongqiang Zhu","doi":"10.1007/s13318-023-00844-6","DOIUrl":"https://doi.org/10.1007/s13318-023-00844-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that plays a crucial role in tumorigenesis. FHND5071, a potent and selective RET kinase inhibitor, could exert antitumor effects by inhibiting RET autophosphorylation. The present work aims to profile the pharmacokinetics of FHND5071 in in vivo and in vitro experiments as a ground work for further clinical research.</p><p><strong>Methods: </strong>The absorption, distribution, metabolism, and excretion properties of FHND5071 were examined, along with metabolite production and cytochrome P450 (CYP) phenotyping assay. Additionally, plasma protein binding and pharmacokinetics in mice were investigated.</p><p><strong>Results: </strong>Microsomal stability assay corroborated moderate to high clearance of FHND5071, and the use of UPLC-Q-TOF-MS identified a total of six metabolites and suggested a possible metabolic pathway involving oxidation, demethylation, and N-dealkylation. Primary contributors to the CYP-mediated metabolism of FHND5071 were found to be CYP2C8 and CYP3A4, and FHND5071 displayed low permeability and acted as a substrate for the P-glycoprotein (P-gp). FHND5071 had a moderate to high binding in plasma and exhibited a moderate absorption degree (absolute bioavailability > 60%) The distribution of FHND5071 in mouse tissues was rapid (mostly peaking at 1-4 h) and wide (detectable in almost all tissues and organs), with the highest exposure in the spleen. A small fraction of FHND5071 was excreted via the urine and feces, and a presumed metabolic pathway involving 20 metabolites in mice is proposed.</p><p><strong>Conclusion: </strong>Pharmacokinetic characteristics of FHND5071 were systemically profiled, which may lay the foundation for further clinical development as a drug candidate.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10158548","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":"Comparative Pharmacokinetics of Commercially Available Cannabidiol Isolate, Broad-Spectrum, and Full-Spectrum Products.","authors":"Erin C Berthold,&nbsp;Shyam H Kamble,&nbsp;Siva Rama Raju Kanumuri,&nbsp;Michelle A Kuntz,&nbsp;Alexandria S Senetra,&nbsp;Yi-Hua Chiang,&nbsp;Lance R McMahon,&nbsp;Christopher R McCurdy,&nbsp;Abhisheak Sharma","doi":"10.1007/s13318-023-00839-3","DOIUrl":"https://doi.org/10.1007/s13318-023-00839-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>A wide variety of products containing cannabidiol (CBD) are available on the commercial market. One of the most common products, CBD oil, is administered to self-treat a variety of conditions. These oils are available as CBD isolate, broad-spectrum [all terpenes and minor cannabinoids except Δ-9-tetrahydrocannabinol (THC)], or full-spectrum (all terpenes and minor cannabinoids with THC < 0.3% dried weight) products. A systematic pharmacokinetic study was performed to determine whether there are differences in the pharmacokinetic parameters and systemic exposure of CBD after oral dosing as an isolate, broad-spectrum, or full-spectrum product.</p><p><strong>Methods: </strong>Male and female Sprague Dawley rats were treated with a single, equivalent oral dose of CBD delivered as isolate, broad-spectrum, or full-spectrum product. An additional study using an in-house preparation of CBD isolate plus 0.2% THC was performed. A permeability assay was also conducted to investigate whether the presence of THC alters the intestinal permeability of CBD.</p><p><strong>Results: </strong>There was an increase in the oral bioavailability of CBD (12% and 21% in male and female rats, respectively) when administered as a full-spectrum product compared with the isolate and broad-spectrum products. There was no difference in the bioavailability of CBD between the commercially available full-spectrum formulation (3.1% CBD; containing 0.2% THC plus terpenes and other minor cannabinoids) versus the in-house preparation of CBD full-spectrum (CBD isolate 3.2% plus 0.2% THC isolate). In vitro permeability assays demonstrated that the presence of THC increases permeability of CBD while also decreasing efflux through the gut wall.</p><p><strong>Conclusions: </strong>The presence of 0.2% THC increased the oral bioavailability of CBD in male and female rats, indicating that full-spectrum products may produce increased effectiveness of CBD due to a greater exposure available systemically.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10174942","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":"In Vitro Assessment of the Metabolic Stability of Two Novel Endomorphin-2 Analogs, CYX-5 and CYX-6, in Rat Liver Microsomes.","authors":"Mohammad Zafar Imam,&nbsp;Sussan Ghassabian,&nbsp;Andy Kuo,&nbsp;Yunxin Cai,&nbsp;Yajuan Qin,&nbsp;Tingyou Li,&nbsp;Maree T Smith","doi":"10.1007/s13318-023-00828-6","DOIUrl":"https://doi.org/10.1007/s13318-023-00828-6","url":null,"abstract":"","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9956962","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":"Monitoring Salivary Concentrations of Tedizolid and Linezolid Using Rats.","authors":"Yuki Inoue,&nbsp;Yuki Sato,&nbsp;Hitoshi Kashiwagi,&nbsp;Shunsuke Nashimoto,&nbsp;Mitsuru Sugawara,&nbsp;Yoh Takekuma","doi":"10.1007/s13318-023-00836-6","DOIUrl":"https://doi.org/10.1007/s13318-023-00836-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Therapeutic drug monitoring (TDM) is an effective tool for the management of patients who are administered linezolid. The use of saliva for TDM has potential advantages over the use of plasma; however, only a few reports have compared drug concentrations in the saliva and plasma. Moreover, there are no reports on the salivary concentration of tedizolid, an oxazolidinone antibiotic similar to linezolid. In the present study, the concentrations of tedizolid and linezolid in rat submandibular saliva were compared with those measured in the plasma.</p><p><strong>Methods: </strong>Tedizolid (10 mg/kg, n = 6) and linezolid (12 mg/kg, n = 5) were administered via the rat tail vein. Submandibular saliva and plasma samples were collected for up to 8 h after the initiation of drug administration, and assayed for the concentrations of tedizolid and linezolid.</p><p><strong>Results: </strong>A strong correlation was found between the saliva and plasma concentrations of tedizolid (r = 0.964, p < 0.001) and linezolid (r = 0.936, p < 0.001). The value of tedizolid maximum concentration of drug (C_max) was 0.99 ± 0.08 µg/mL in the saliva and 14.46 ± 1.71 µg/mL in the plasma. Meanwhile, the C_max of linezolid was 8.01 ± 1.42 µg/mL in the saliva and 13.00 ± 1.90 µg/mL in the plasma. According to these results, the saliva/plasma concentration ratios of tedizolid and linezolid in rats were 0.0513 ± 0.0080 and 0.6341 ± 0.0339, respectively.</p><p><strong>Conclusions: </strong>Considering the correlation between saliva and plasma concentrations of tedizolid and linezolid, as well as the characteristics of saliva, the results of this study suggest that saliva is a useful matrix for TDM.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10158433","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":"Re-examining Naloxone Pharmacokinetics After Intranasal and Intramuscular Administration Using the Finite Absorption Time Concept.","authors":"Athanasios A Tsekouras,&nbsp;Panos Macheras","doi":"10.1007/s13318-023-00831-x","DOIUrl":"https://doi.org/10.1007/s13318-023-00831-x","url":null,"abstract":"<p><strong>Background and objectives: </strong>Naloxone for opioid overdose treatment can be administered by intravenous injection, intramuscular injection, or intranasal administration. Published data indicate differences in naloxone pharmacokinetics depending on the route of administration. The aim of this study was to analyze pharmacokinetic data in the same way that we recently successfully applied the concept of the finite absorption time in orally administered drug formulations.</p><p><strong>Methods: </strong>Using the model equations already derived, we performed least squares analysis on 24 sets of naloxone concentration in the blood as a function of time.</p><p><strong>Results: </strong>We found that intramuscular and intranasal administration can be described more accurately when considering zero-order absorption kinetics for finite time compared with classical first order absorption kinetics for infinite time.</p><p><strong>Conclusions: </strong>One-compartment models work well for most cases. Two-compartment models provide better details, but have higher parameter uncertainties. The absorption duration can be determined directly from the model parameters and thus allow an easy comparison between the ways of administration. Furthermore, the precise site of injection for intramuscular delivery appears to make a difference in terms of the duration of the drug absorption.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10171505","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":"Early At-Home Measurement of Adalimumab Concentrations to Guide Anti-TNF Precision Dosing: A Pilot Study.","authors":"Paul A G de Klaver,&nbsp;Ron J Keizer,&nbsp;Rob Ter Heine,&nbsp;Lisa Smits,&nbsp;Paul J Boekema,&nbsp;Inge Kuntzel,&nbsp;Tiny Schaap,&nbsp;Annick de Vries,&nbsp;Karien Bloem,&nbsp;Theo Rispens,&nbsp;Frank Hoentjen,&nbsp;Luc J J Derijks","doi":"10.1007/s13318-023-00835-7","DOIUrl":"https://doi.org/10.1007/s13318-023-00835-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy.</p><p><strong>Methods: </strong>Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE).</p><p><strong>Results: </strong>Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was -2.6% and normalised RMSE 24.0%. Concordance between predicted and measured adalimumab serum concentrations falling within or outside the therapeutic window was 75%. Three patients (8.3%) developed detectable concentrations of anti-adalimumab antibodies.</p><p><strong>Conclusion: </strong>This prospective study demonstrates that adalimumab concentrations at steady state can be predicted from early samples during the induction phase.</p><p><strong>Clinical trial registration: </strong>The trial was registered in the Netherlands Trial Register with trial registry number NTR 7692 ( www.trialregister.nl ).</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10174378","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":"Hydrolytic Metabolism of Withangulatin A Mediated by Serum Albumin Instead of Common Esterases in Plasma.","authors":"Yu Zhuang,&nbsp;Yuxiao Wang,&nbsp;Ning Li,&nbsp;Haitao Meng,&nbsp;Zhiyu Li,&nbsp;Jianguang Luo,&nbsp;Zhixia Qiu","doi":"10.1007/s13318-023-00834-8","DOIUrl":"https://doi.org/10.1007/s13318-023-00834-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>The oral bioavailability of withangulatin A (WA) is low and may undergo first-pass metabolism because of the presence of two esters bonds. This study aimed to identify the hydrolysis behavior and mechanism of WA, thus enriching its structure-pharmacokinetic relationship.</p><p><strong>Methods: </strong>The in vivo pharmacokinetic studies of WA in rats were first investigated, followed by in vitro assays including metabolic stability, phenotyping identification and metabolic kinetics assays. After screening out the responsible enzymes with higher catalytic capacity, molecular docking study was performed to demonstrate the interaction mode between WA and metabolic enzymes. Then, metabolites in human serum albumin (HSA) were identified by LC-TOF-MS/MS.</p><p><strong>Results: </strong>In rats, the oral bioavailability of WA was only 2.83%. In vitro, WA was hydrolyzed in both rat and human plasma and could not be inhibited by selective esterase inhibitors. Physiologic concentration of HSA not recombinant human carboxylesterases (rhCES) could significantly hydrolyze WA, and it had a similar hydrolytic capacity with human plasma to WA. Furthermore, WA could stably bind to HSA by forming hydrogen bonds with Lys199 and Arg410, accompanied by the metabolic reaction of the lactone ring opening.</p><p><strong>Conclusion: </strong>The study showed that WA underwent obvious hydrolysis in rat and human plasma, which implied a strong first-pass effect. Serum albumin rather than common esterases primarily contributed to the hydrolytic metabolism of WA in plasma.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10175495","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":"Management of Drug Interactions with Inducers: Onset and Disappearance of Induction on Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyltransferase 1A1 Substrates.","authors":"Sara Bettonte,&nbsp;Mattia Berton,&nbsp;Felix Stader,&nbsp;Manuel Battegay,&nbsp;Catia Marzolini","doi":"10.1007/s13318-023-00833-9","DOIUrl":"https://doi.org/10.1007/s13318-023-00833-9","url":null,"abstract":"<p><strong>Background: </strong>People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized.</p><p><strong>Objective: </strong>The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling.</p><p><strong>Methods: </strong>The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers.</p><p><strong>Results: </strong>The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1.</p><p><strong>Conclusions: </strong>Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6c/b0/13318_2023_Article_833.PMC10322778.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9798742","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}