Physiologically based pharmacokinetic modeling of tacrolimus for food-drug and CYP3A drug-drug-gene interaction predictions

The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 and CYP3A5. For its pharmacokinetics (PK), high inter- and intra-individual variability can be observed. Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the CYP3A5 gene. Furthermore, tacrolimus is highly susceptible to drug–drug interactions, acting as a victim drug when coadministered with CYP3A perpetrators. This work describes the development of a whole-body physiologically based pharmacokinetic model for tacrolimus as well as its application for investigation and prediction of (i) the impact of food intake on tacrolimus PK (food–drug interactions [FDIs]) and (ii) drug–drug(−gene) interactions (DD[G]Is) involving the CYP3A perpetrator drugs voriconazole, itraconazole, and rifampicin. The model was built in PK-Sim® Version 10 using a total of 37 whole blood concentration–time profiles of tacrolimus (training and test) compiled from 911 healthy individuals covering the administration of tacrolimus as intravenous infusions as well as immediate-release and extended-release capsules. Metabolism was incorporated via CYP3A4 and CYP3A5, with varying activities implemented for different CYP3A5 genotypes and study populations. The good predictive model performance is demonstrated for the examined food effect studies with 6/6 predicted FDI area under the curve determined between first and last concentration measurements (AUClast) and 6/6 predicted FDI maximum whole blood concentration (Cmax) ratios within twofold of the respective observed ratios. In addition, 7/7 predicted DD(G)I AUClast and 6/7 predicted DD(G)I Cmax ratios were within twofold of their observed values. Potential applications of the final model include model-informed drug discovery and development or the support of model-informed precision dosing

Physiologically-based pharmacokinetic modeling of quinidine to establish a CYP3A4, P-gp, and CYP2D6 drug-drug-gene interaction network

The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) and is therefore recommended for use in clinical drug–drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P-gp, it is susceptible to DDIs involving these proteins. Physiologically-based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug–drug(–gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P-gp perpetrators as well as CYP2D6 and P-gp victims. The quinidine parent-metabolite model including 3-hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1–600mg). The model covers efflux transport via P-gp and metabolic transformation to either 3-hydroxyquinidine or unspecified metabolites via CYP3A4. The 3-hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two-fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two-fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is

Physiologically based pharmacokinetic modeling of tacrolimus for food–drug and CYP3A drug–drug–gene interaction predictions

Abstract The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 and CYP3A5. For its pharmacokinetics (PK), high inter‐ and intra‐individual variability can be observed. Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the CYP3A5 gene. Furthermore, tacrolimus is highly susceptible to drug–drug interactions, acting as a victim drug when coadministered with CYP3A perpetrators. This work describes the development of a whole‐body physiologically based pharmacokinetic model for tacrolimus as well as its application for investigation and prediction of (i) the impact of food intake on tacrolimus PK (food–drug interactions [FDIs]) and (ii) drug–drug(−gene) interactions (DD[G]Is) involving the CYP3A perpetrator drugs voriconazole, itraconazole, and rifampicin. The model was built in PK‐Sim® Version 10 using a total of 37 whole blood concentration–time profiles of tacrolimus (training and test) compiled from 911 healthy individuals covering the administration of tacrolimus as intravenous infusions as well as immediate‐release and extended‐release capsules. Metabolism was incorporated via CYP3A4 and CYP3A5, with varying activities implemented for different CYP3A5 genotypes and study populations. The good predictive model performance is demonstrated for the examined food effect studies with 6/6 predicted FDI area under the curve determined between first and last concentration measurements (AUClast) and 6/6 predicted FDI maximum whole blood concentration (Cmax) ratios within twofold of the respective observed ratios. In addition, 7/7 predicted DD(G)I AUClast and 6/7 predicted DD(G)I Cmax ratios were within twofold of their observed values. Potential applications of the final model include model‐informed drug discovery and development or the support of model‐informed precision dosing

Physiologically‐based pharmacokinetic modeling of quinidine to establish a CYP3A4, P‐gp, and CYP2D6 drug–drug–gene interaction network

Abstract The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P‐glycoprotein (P‐gp) and is therefore recommended for use in clinical drug–drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P‐gp, it is susceptible to DDIs involving these proteins. Physiologically‐based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug–drug(–gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P‐gp perpetrators as well as CYP2D6 and P‐gp victims. The quinidine parent‐metabolite model including 3‐hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1–600 mg). The model covers efflux transport via P‐gp and metabolic transformation to either 3‐hydroxyquinidine or unspecified metabolites via CYP3A4. The 3‐hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two‐fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two‐fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is

Paleobotanical features of Tyumen and Naunak formations (middle-upper jurassic of the south-east of West Siberia)

Актуальность. Традиционное использование данных геофизических исследований скважин при стратиграфическом расчленении и корреляции стратонов юго-востока Западной Сибири не всегда позволяет уверенно провести границы между литологически схожими отложениями. В связи с этим возникают сложности при построении геологической модели месторождений, что в конечном итоге может привести к неэффективному освоению и удорожанию разработки залежей углеводородного сырья. Цель исследования заключается в выделении комплексов растений, которые являются характерными для тюменской и наунакской свит, для проведения биостратиграфического расчленения и корреляции нефтепродуктивных отложений на площадях (месторождениях) Снежная и Двойная в Томской области на юго-востоке Западной Сибири. Объекты: палеоботанические остатки из керна скважин площадей Снежная и Двойная, а также опубликованный материал предыдущих исследований. Методы. Для определения отпечатков растений применялись сравнительно-морфологический и эпидермально-кутикулярный методы. Отпечатки ископаемых растений изучались под бинокулярным микроскопом МБС-1 и ЛОМО. Для стратиграфического расчленения и корреляции отложений применялся метод комплексного анализа органических остатков. Результаты. Изучен палеоботанический материал из средне-верхнеюрских отложений юго-востока Западной Сибири (площади Снежная и Двойная). Установлена приуроченность растительных таксонов к определенным свитам (тюменской и наунакской). Выяснено, что для тюменской свиты характерными являются папоротники Raphaelia diamensis и Coniopteris vialovae, а также голосеменные чекановскиевые Phoenicopsis mogutchevae, Czekanowskia rigida и Cz. irkutensis. Для наунакской свиты характерными являются эндемичные папоротники Coniopteris latilobus и голосеменные чекановскиевые Czekanowskia tomskiensis, а также широко распространенные хвойные Podozamites eichwaldii. Эндемичный состав флоры наунакского комплекса растений вполне обоснованно указывает на специфические условия формирования наунакской свиты. Проведено расчленение однотипных по литологическому составу стратонов. Создана надежная база для стратиграфического расчленения и корреляции средневерхнеюрских отложений, которая станет основой для построения достоверной геологической модели месторождений, что приведет к более эффективному проведению геологоразведочных работ на юго-востоке Западной Сибири.The relevance. Traditional use of data of geophysical researches of wells for stratigraphic subdivision and correlation of stratigraphicunits of the South'East of Western Siberia is not always possible to confidently draw boundaries between lithological similar deposits. In this relation the difficulties in constructing geological models of fields occur, that can result in inefficient exploration and increase in cost of development of deposits of hydrocarbon raw materials. The aim of the research is to form complexes of plants typical for the Tyumen and Naunak formations for biostratigraphic subdivision and correlation of oil-productive deposits of the South-East of Western Siberia (areas Snezhnaya and Dvoinaya). Objects: paleobotanical remains from the core of boreholes in Snezhnaya and Dvoinaya areas, as well as the published material from previous studies. Methods. To determine the imprints of plants the authors have used the comparative morphological and epidermal-cuticular methods. Imprints of fossil plants were studied under binocular microscope MBS-1 and LOMO. For stratigraphic division and correlation of sediments the method of complex analysis of organic residues was applied. Results. The authors studied paleobotanical material from the middle-upper-Jurassic deposits of southeastern West Siberia (Snezhnaya and Dvoinaya) and determined distribution of plant taxa to certain strata (the Tyumen and Naunak). It was found out that ferns Coniopteris and Raphaelia diamensis vialovae and gymnosperms Czekanowskiales Phoenicopsis mogutchevae, Czekanowskia rigida and Cz. irkutensis are typical for the Tyumen formation. The endemic ferns Coniopteris latilobus and gymnosperms Czekanowskiales Czekanowskia tomskiensis and widespread coniferous Podozamites eichwaldii are typical for Naunak formation. Endemic structure of Naunak plant complex flora points to the specific conditions of Naunak strata formation. The stratigraphic units similar in lithological composition were separated. The authors developed the reliable base for stratigraphic division and correlation, which will be the base for construction of reliable geological model of deposits. This will result in more effective exploration in the South-East of Western Siberia