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Method for the classification of brain cancer treatment's responsiveness via physical parameters of DCE-MRI dataKanli, Georgia January 2015 (has links)
Tumors have several important hallmarks; anomalous and heterogeneous behaviors of their vascular structures, and high angiogenesis and neovascularization. Tumor tissue presents high blood flow (F) and extraction ratio (E) of contrast molecules. Consequently there is growing interest in non invasive methods for characterizing changes in tumor vasculature. Toft's model has been extensively used in the past in order to calculate Ktrans maps which take into consideration both F and E. However, in this thesis we argue that for accurate tumor characterization we need a model able to compute both F and E in tissue plasma. This project has been developed as part of a larger project, working toward building a Clinical Decision Support System (CDSS): an interactive expert computer software, that helps doctors and other health professionals make decisions regarding patient treatment progress. Using the Gamma Capillary Transit Time (GCTT) pharmacokinetic model we calculate F and E separately in a more realistic framework; unlike other models it takes into account the heterogeneity of the tumor, which depends on parameter a-1. a-1 is the width of the distribution of the capillary transit times within a tissue voxel. In more detail, a-1 expresses the heterogeneity of tissue microcirculation and microvasculature. We studied 9 patients pathologically diagnosed with glioblastoma multiforme (GBM), a common malignant type of brain tumor. Several physiological parameters including the blood flow and extraction ratio distributions were calculated for each patient. Then we investigated if these parameters can characterize early the patients' responsiveness to current treatment; we assessed the classification potential based on the actual therapy outcome. To this end, we present a novel analysis framework which exploits the new parameter a-1 and organizes each voxel into four sub-region. Our results indicate that early characterization of response based on GCCT can be significantly improved by focusing on tumor voxels from a specific sub-region.
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Physiologically-based Pharmacokinetic (PBPK) Models for the Description of Sequential Metabolism of Codeine to Morphine and Morphine 3-Glucuronide (M3G) in Man and RatChen, Shu 16 December 2010 (has links)
Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.
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Physiologically-based Pharmacokinetic (PBPK) Models for the Description of Sequential Metabolism of Codeine to Morphine and Morphine 3-Glucuronide (M3G) in Man and RatChen, Shu 16 December 2010 (has links)
Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.
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Development of a Software Code for Pharmacokinetic Analysis of PET Data.Shamas, Sofia 01 January 2006 (has links)
To improve efficacy in the field of drug discovery simpler in vivo, non invasive methods such as PET and SPECT are used. Pharmacokinetic analysis is the underlying method for analyzing the PET data. Imaging of tracer distribution is used to study a metabolic process. Using Matlab as the programming language, a software tool is developed to analyze the quantitative information from PET and to obtain an estimate of pharmacokinetic parameters, representing the bio- distribution of the radiotracer. A Graphical User Interface developed allows two types of analysis, depending upon the nature of the radiotracer: Compartmental Modeling and Logan Plot Analysis. Compartmental analysis gives us rate constants and blood volume where as Logan analysis gives us the distribution volume as the parameter of interest. Code validation is done for two radiotracers, 15O-water (Single compartment model) and FPAC (Logan Plot). Results from the code were compared with those obtained during a research work done to study MDR.
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Correlação in vitro - in vivo de comprimidos matriciais de furosemida complexada à hidroxipropil-β-ciclodextrina: métodos in vitro, in vivo e in silico / In vitro - in vivo correlation of matrix tablets of furosemide complexed with hidroxypropyl-β-cyclodextrin: in vitro, in vivo and in silico methodsSilva, Marina de Freitas 14 February 2014 (has links)
A correlação in vitro - in vivo (CIVIV) refere-se ao estabelecimento de uma relação racional entre uma propriedade in vitro de uma forma farmacêutica (FF) e uma característica biológica, ou parâmetros derivados destas, produzidas a partir da absorção do fármaco, liberado por uma FF. Para o desenvolvimento de uma CIVIV, são necessárias três ou mais formulações, as quais são avaliadas em relação ao comportamento de dissolução e à biodisponibilidade (BD), e por meio do cálculo de deconvolução, estimam-se as frações absorvidas. A furosemida, fármaco modelo, é um diurético usado no tratamento de hipertensão. Este fármaco é classificado como classe IV do sistema de classificação biofarmacêutico (SCB) (Amidon et al., 1995). O objetivo do presente trabalho foi estabelecer uma CIVIV para formas farmacêuticas (FFs) de liberação modificada contendo complexo de furosemida e hidroxipropil-β-ciclodextrina (HP-β-CD), a partir de ensaios de dissolução e estudos de BD. O complexo de furosemida e HP-β-CD foi obtido por liofilização e caracterizado por análise térmica, solubilidade e permeabilidade. A partir do complexo, foram produzidas cinco formulações de comprimidos de liberação modificada, com diferentes concentrações de hidroxipropilmetilcelulose (HPMC) (10-30%). Estas foram submetidas aos estudos de dissolução com o aparato II. Destas, foram selecionadas três formulações com perfis distintos e submetidas ao estudo com o aparato IV e posteriormente ao estudo de BD. A partir destes resultados foi estabelecida uma CIVIV e esta foi avaliada por meio da validação interna. Foi realizado o estudo in silico de previsão das curvas de decaimento plasmático com emprego dos programas, STELLA® e Simcyp®, a partir dos dados: solubilidade da furosemida; dissolução a partir das formulações e dados farmacocinéticos obtidos a partir da injeção intravenosa do medicamento referência. Quanto à caracterização do complexo, os ensaios termoanalíticos sugerem que a furosemida forme complexo de inclusão com a HP-β-CD pela técnica da liofilização. Observou-se o aumento da solubilidade em relação ao fármaco puro. Entretanto, quanto à permeabilidade, avaliada por meio do PAMPA (permeabilidade em membrana artificial paralela), os resultados foram semelhantes entre o fármaco puro e o complexo. Quanto ao comportamento de dissolução, avaliado com emprego dos aparatos II e IV, observou-se que as formulações apresentaram perfis de dissolução distintos. Os resultados do estudo de BD indicaram que a concentração do HPMC tem impacto relevante na absorção da furosemida. Foram obtidas correlações lineares a partir dos dados de fração absorvida e de dissolução, com coeficiente de determinação de 0,7662 para o aparato II e de 0,96017 para o IV. A validação interna da CIVIV empregando o aparato IV indicou que a correlação foi satisfatória. O estudo in silico de previsão das curvas de decaimento plasmático demonstrou que, nas condições empregadas, o modelo desenvolvido com o STELLA® foi mais preditivo do que o obtido pelo Simcyp®. / The in vitro - in vivo correlation (IVIVC) refers to the establishment of a rational relationship between a in vitro property of a pharmaceutical form (PF) and a biological characteristic or parameters derived from those, produced from the absorption of a drug released from a PF. For the development of an IVIVC, it is necessary three or more formulations, which are evaluated in relation to the dissolution behavior and for bioavailability (BA), calculating by deconvolution, an estimated absorbed fractions. Furosemide, a model drug, is a diuretic used in the treatment of hypertension. This drug is classified as class IV from biopharmaceutical classification system (BCS) (Amidon et al., 1995). The objective of this study was to establish an IVIVC for pharmaceutical forms (PFs) with modified release containing furosemide complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD), from dissolution tests and BA studies. The complex of furosemide and HP-β-CD was obtained by freeze-drying and characterized by thermal analysis, the solubility and the permeability. From the complex were produced five modified release tablet formulations, with different concentrations of hydroxypropylmethylcellulose (HPMC) (10-30%). These formulations were subjected to dissolution studies with the apparatus II. From these, three formulations with distinct profiles were selected and subjected to dissolution study with apparatus IV and subsequently to the BA study. From these results, an IVIVC was established and this was evaluated by internal validation. The in silico study was conducted to predict plasma decay curves with employment programs, STELLA® and Simcyp®, from the following data: furosemide solubility, dissolution from the formulations evaluated and pharmacokinetic data obtained from intravenous drug reference. From characterization of the complex, the thermoanalytical tests suggest that furosemide form inclusion complex with HP-β-CD by freeze-drying technique. It was observed an increased solubility compared to the pure drug. However, permeability results, as assessed by the PAMPA (Parallel artificial membrane permeability), were similar for both furosemide and the complex. As for the dissolution behavior, evaluated with apparatus II and IV, so it was observed that the formulations showed an distintict profile. it was observed that the formulations produced showed different dissolution profiles. The results form BA assays indicated that the HPMC concentration has an important impact on the furosemide absorption. It was obtained a linear correlation from absorption fraction and dissolution data, with the determination coefficient of 0.7662 to apparatus II and 0.96017 from apparatus IV. Internal validation, with the IVIVC obtainted from apparatus IV, indicated that the correlation obtained was satisfactory. The in silico study predicted plasma decay curves, showed that under the conditions used, the model developed with STELLA® was more predictive than the model obtained by Simcyp®.
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Biopharmaceutical considerations and in vitro-in vivo correlations (IVIVCs) for orally administered amorphous formulationsLong, Chiau Ming January 2014 (has links)
Dissolution testing and physiological based pharmacokinetic modeling are the essential methods during drug development. However, there is a lack of a sound approach and understanding of the parameter that controls dissolution and absorption of amorphous formulations. Robust dissolution conditions and setup and PBPK models that have a predictability of in vivo results will expedite and facilitate the drug development process. In this project, cefuroxime axetil, CA (Zinnat® as the amorphous formulations); itraconazole, ITR (Sporanox® as the amorphous formulation) and a compound undergoing clinical trial, Compound X, CX (CX tablet as the amorphous formulation) were chosen. The design of experiments for the in vitro dissolution studies using different apparatus, media and setup which closely simulate the physiological condition of humans (CA and ITR) and dogs (CX) were implemented. The dissolution of CA, ITR and CX formulations was successfully characterised using different dissolution apparatus, setting and media (compendial, biorelevant and modified media) to simulate the changes of pH, contents, hydrodynamic conditions (flow rate and rotation speed) in human gastrointestinal tract (fasted and fed state). The change of hydrodynamics combined with media change that corresponded to the physiological conditions created with USP apparatus 4 and biorelevant dissolution media were able to mimic the in vivo performance of the tested formulations. Furthermore, surface UV dissolution imaging methodology that could be used to understand the mechanism of CA and ITR (Active compounds and their amorphous formulations) dissolution were developed in this project. The UV images developed using surface UV imaging apparatus provided a visual representation and a means for the qualitative as well as quantitative assessment of the differences in dissolution rates and concentration for the model compounds used. In this project, validated PBPK models for fasted state (CA, ITR) and fed state (CA, ITR and CX) were developed. These models incorporated in vitro degradation, particle size distribution, in vitro solubility and dissolution data as well as in vivo human/ dog pharmacokinetics data. Similarly, the results showed that level A IVIVCs for all three model compounds were successfully established. Dissolution profiles with USP apparatus 4 combined with biorelevant media showed close correlation with the in vivo absorption profiles. Overall, this project successfully provides a comprehensive biorelevant methodology to develop PBPK models and IVIVCs for orally administered amorphous formulations.
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Correlação in vitro - in vivo de comprimidos matriciais de furosemida complexada à hidroxipropil-β-ciclodextrina: métodos in vitro, in vivo e in silico / In vitro - in vivo correlation of matrix tablets of furosemide complexed with hidroxypropyl-β-cyclodextrin: in vitro, in vivo and in silico methodsMarina de Freitas Silva 14 February 2014 (has links)
A correlação in vitro - in vivo (CIVIV) refere-se ao estabelecimento de uma relação racional entre uma propriedade in vitro de uma forma farmacêutica (FF) e uma característica biológica, ou parâmetros derivados destas, produzidas a partir da absorção do fármaco, liberado por uma FF. Para o desenvolvimento de uma CIVIV, são necessárias três ou mais formulações, as quais são avaliadas em relação ao comportamento de dissolução e à biodisponibilidade (BD), e por meio do cálculo de deconvolução, estimam-se as frações absorvidas. A furosemida, fármaco modelo, é um diurético usado no tratamento de hipertensão. Este fármaco é classificado como classe IV do sistema de classificação biofarmacêutico (SCB) (Amidon et al., 1995). O objetivo do presente trabalho foi estabelecer uma CIVIV para formas farmacêuticas (FFs) de liberação modificada contendo complexo de furosemida e hidroxipropil-β-ciclodextrina (HP-β-CD), a partir de ensaios de dissolução e estudos de BD. O complexo de furosemida e HP-β-CD foi obtido por liofilização e caracterizado por análise térmica, solubilidade e permeabilidade. A partir do complexo, foram produzidas cinco formulações de comprimidos de liberação modificada, com diferentes concentrações de hidroxipropilmetilcelulose (HPMC) (10-30%). Estas foram submetidas aos estudos de dissolução com o aparato II. Destas, foram selecionadas três formulações com perfis distintos e submetidas ao estudo com o aparato IV e posteriormente ao estudo de BD. A partir destes resultados foi estabelecida uma CIVIV e esta foi avaliada por meio da validação interna. Foi realizado o estudo in silico de previsão das curvas de decaimento plasmático com emprego dos programas, STELLA® e Simcyp®, a partir dos dados: solubilidade da furosemida; dissolução a partir das formulações e dados farmacocinéticos obtidos a partir da injeção intravenosa do medicamento referência. Quanto à caracterização do complexo, os ensaios termoanalíticos sugerem que a furosemida forme complexo de inclusão com a HP-β-CD pela técnica da liofilização. Observou-se o aumento da solubilidade em relação ao fármaco puro. Entretanto, quanto à permeabilidade, avaliada por meio do PAMPA (permeabilidade em membrana artificial paralela), os resultados foram semelhantes entre o fármaco puro e o complexo. Quanto ao comportamento de dissolução, avaliado com emprego dos aparatos II e IV, observou-se que as formulações apresentaram perfis de dissolução distintos. Os resultados do estudo de BD indicaram que a concentração do HPMC tem impacto relevante na absorção da furosemida. Foram obtidas correlações lineares a partir dos dados de fração absorvida e de dissolução, com coeficiente de determinação de 0,7662 para o aparato II e de 0,96017 para o IV. A validação interna da CIVIV empregando o aparato IV indicou que a correlação foi satisfatória. O estudo in silico de previsão das curvas de decaimento plasmático demonstrou que, nas condições empregadas, o modelo desenvolvido com o STELLA® foi mais preditivo do que o obtido pelo Simcyp®. / The in vitro - in vivo correlation (IVIVC) refers to the establishment of a rational relationship between a in vitro property of a pharmaceutical form (PF) and a biological characteristic or parameters derived from those, produced from the absorption of a drug released from a PF. For the development of an IVIVC, it is necessary three or more formulations, which are evaluated in relation to the dissolution behavior and for bioavailability (BA), calculating by deconvolution, an estimated absorbed fractions. Furosemide, a model drug, is a diuretic used in the treatment of hypertension. This drug is classified as class IV from biopharmaceutical classification system (BCS) (Amidon et al., 1995). The objective of this study was to establish an IVIVC for pharmaceutical forms (PFs) with modified release containing furosemide complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD), from dissolution tests and BA studies. The complex of furosemide and HP-β-CD was obtained by freeze-drying and characterized by thermal analysis, the solubility and the permeability. From the complex were produced five modified release tablet formulations, with different concentrations of hydroxypropylmethylcellulose (HPMC) (10-30%). These formulations were subjected to dissolution studies with the apparatus II. From these, three formulations with distinct profiles were selected and subjected to dissolution study with apparatus IV and subsequently to the BA study. From these results, an IVIVC was established and this was evaluated by internal validation. The in silico study was conducted to predict plasma decay curves with employment programs, STELLA® and Simcyp®, from the following data: furosemide solubility, dissolution from the formulations evaluated and pharmacokinetic data obtained from intravenous drug reference. From characterization of the complex, the thermoanalytical tests suggest that furosemide form inclusion complex with HP-β-CD by freeze-drying technique. It was observed an increased solubility compared to the pure drug. However, permeability results, as assessed by the PAMPA (Parallel artificial membrane permeability), were similar for both furosemide and the complex. As for the dissolution behavior, evaluated with apparatus II and IV, so it was observed that the formulations showed an distintict profile. it was observed that the formulations produced showed different dissolution profiles. The results form BA assays indicated that the HPMC concentration has an important impact on the furosemide absorption. It was obtained a linear correlation from absorption fraction and dissolution data, with the determination coefficient of 0.7662 to apparatus II and 0.96017 from apparatus IV. Internal validation, with the IVIVC obtainted from apparatus IV, indicated that the correlation obtained was satisfactory. The in silico study predicted plasma decay curves, showed that under the conditions used, the model developed with STELLA® was more predictive than the model obtained by Simcyp®.
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Risk assessment for drug degradation products using physiologically-based pharmacokinetic modelsNguyen, Quynh Hoa 01 December 2014 (has links)
Degradation product toxicity is a critical quality issue for a small group of useful drug products--e.g. lidocaine, isoniazid, chlorhexidine, gabapentin. In the traditional risk assessment approaches, a no-observed-adverse-effect level (NOAEL) derived from animal data is determined with the use of generic (and arbitrary) uncertainty factors to obtain an acceptable daily intake. The effects of compound-specific biological complexities and pharmacokinetics are typically not part of the risk calculations. The selection of uncertainty factors that account for interspecies or intraspecies difference concerning biokinetics and biodynamics has also generally failed to consider chemical-specific mechanism information or pharmacokinetics data. The use of combining in-vitro biopharmaceutical characterization methods and physiologically-based pharmacokinetic modeling has undergone extensive study and validation for predicting clinical drug blood level time profiles. The rationale for the proposed research is that a PBPK modeling utilizing rat to human scaling for target tissue toxicity in combination with the Monte Carlo method for estimating human target exposure distributions provides a rational basis for assessing drug stability safety issues for drug substances that potentially degrade to toxic compounds.
PBPK models for rats and humans were developed to simulate drug exposure time profiles after oral administration of model compounds including aniline, p-chloroaniline, 2,6-dimethylaniline, o-toluidine and p-aminophenol. The PBPK models were parameterized using a combination of literature values, computational models and standard in vitro experiments. Microsomal and hepatocyte metabolism studies were used to estimate the metabolic constants, and ultrafiltration was used to measure protein binding. Intestinal permeability was predicted using a set of related compound data to correlate measured Caco-2 permeability with molecular descriptors by multivariate regression. Sensitivity analyses were conducted to evaluate the impact of PBPK model parameters on plasma level predictions. To evaluate patient population effects on exposure profiles, the PBPK model parameters were varied in meaningful ways using Monte Carlo methods. Based on population PBPK models, distributions of target tissue exposure in rats and humans were simulated and compared to derive human safe dose.
As results, rat PBPK model-predicted aniline concentration time profiles were in reasonable agreement with published profiles. Distributions of target tissue exposure in rats and humans were generated and compared based on a criterion. A human reference dose was then selected at a value of 1% criteria. This approach was compared to traditional risk assessment calculations. In conclusion, the PBPK modeling approach resulted in drug degradation product risk specifications that were less stringent than those estimated by conventional risk assessment approach. The PBPK modeling approach provides a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.
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Exposure to Perfluoroalkyl Compounds and Resultant Effects on Cholesterol in the Mid Ohio River ValleyHerrick, Robert L. 10 June 2019 (has links)
No description available.
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USING SEMIPHYSIOLOGICALLY-BASED PHARMACOKINETIC (SEMI-PBPK) MODELING TO EXPLORE THE IMPACT OF DIFFERENCES BETWEEN THE INTRAVENOUS (IV) AND ORAL (PO) ROUTE OF ADMINISTRATION ON THE MAGNITUDE AND TIME COURSE OF CYP3A-MEDIATED METABOLIC DRUG-DRUG INTERACTIONS (DDI) USING MIDAZOLAM (MDZ) AS PROTOTYPICAL SUBSTRATE AND FLUCONAZOLE (FLZ) AND ERYTHROMYCIN (ERY) AS PROTOTYPICAL INHIBITORSLi, Mengyao 01 January 2016 (has links)
The purpose of the project was to investigate the impact of IV and PO routes difference for MDZ, a prototypical CYP3A substrate, and two CYP3A inhibitors (CYP3AI) -FLZ and ERY-, on the magnitude and time course of their inhibitory metabolic DDI.
Individual semi-PBPK models for MDZ, FLZ and ERY were developed and validated separately, using pharmacokinetic (PK) parameters from clinical/in-vitro studies and published physiological parameters. Subsequently, DDI sub-models between MDZ and CYP3AIs incorporated non-competitive and mechanism-based inhibition (MBI) for FLZ and ERY, respectively, on hepatic and gut wall (GW) CYP3A metabolism of MDZ, using available in-vitro/in-vivo information. Model-simulated MDZ PK profiles were compared with observed data from available clinical PK and DDI studies, by visual predictive check and exposure metrics comparison. DDI magnitude and time course for CYP3AI (IV vs. PO) followed by MDZ (IV vs. PO) at various time points were predicted by the validated semi-PBPK-DDI models. Two hypothetical CYP3A substrates and four CYP3AI (derived from MDZ, FLZ and ERY, with GW metabolism removed, hepatic metabolism reduced, or oral bioavailability (Foral) and/or elimination half-life (t1/2) modified) were also simulated to generalize conclusions.
The final semi-PBPK-DDI models predict well the PK profiles for IV/PO MDZ in absence/presence of IV/PO CYP3AI, with deviations between model-predicted and observed exposure metrics within 30%. Prospective simulations demonstrate that:
1) CYP3A substrates, e.g., MDZ, are consistently more sensitive to metabolic inhibition after PO than after IV administration, due to pre-systemic hepatic and/or GW metabolism. For substrates without GW metabolism and limited hepatic metabolism, only a marginal route difference for substrate administration is observed.
2) For high-Foral CYP3AIs, e.g., FLZ, no inhibitor IV-PO route DDI differences are expected, unless they are given simultaneously with PO MDZ.
3) For low-Foral CYP3AIs, e.g., ERY, greater inhibition is expected after IV than after PO administration for IV MDZ, but is difficult to predict for PO MDZ.
4) In addition to Foral and plasma t1/2 of CYP3AIs, the DDI onset, peak and duration are determined by their oral absorption rate and by the resulting hepatic and/or GW concentration profiles relative to Ki for noncompetitive CYP3AIs, but by CYP3A kinetics (synthesis, degradation rate) for MBI CYP3AIs.
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