Application of permeability-limited physiologically-based pharmacokinetic models: Part I–digoxin pharmacokinetics incorporating P-glycoprotein-mediated efflux

Neuhoff, Sibylle; Yeo, Karen Rowland; Barter, Zoe; Jamei, Masoud; Turner, David B.; Rostami‐Hodjegan, Amin

doi:10.1002/jps.23594

Cited by 58 publications

(61 citation statements)

References 76 publications

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“…The impact of the laboratory-specific intestinal relative expression factor for P-glycoprotein (REF iP-gp ) and intestinal relative expression factor for breast cancer resistance protein (REF iBCRP ) in virtual healthy Caucasian volunteers (HVs) was assessed in a PBPK model (version 14.1; Simcyp, a Certara company, Sheffield, UK) containing the regional distribution of intestinal P-gp and BCRP and their population variability (Harwood et al, 2013). P-gp and BCRP transport in the model is driven by the unbound intracellular enterocyte concentration and is multiplied by REF and the regional-specific transporter expression to yield effective permeability (Yang et al, 2007;Neuhoff et al, 2013a).…”

Section: Methodsmentioning

confidence: 99%

“…The Impact of P-gp and BCRP REF in IVIVE (Troutman and Thakker, 2003b) on digoxin C max was investigated using identical digoxin parameter inputs as the previously reported digoxin IVIVE-PBPK model (Neuhoff et al, 2013a). Caco-2-derived J max and K m data (Troutman and Thakker, 2003a) were applied to intestinal and hepatic P-gp, assuming P-gp activity in vitro in healthy individuals corresponds to that in vivo, and that J max is related to P-gp protein expression.…”

Section: Methodsmentioning

confidence: 99%

“…To scale these data to in vivo, human and in vitro system transporter protein expression or activity data are also required in combination with physiologic, demographic, and genetic information (Rostami-Hodjegan, 2012). To date, intestinal transporter IVIVE scaling factors (Neuhoff et al, 2013a) have been generated based on Western blotting, a relative quantitative technique to quantify transport expression (Troutman and Thakker, 2003b). Yet, absolute transporter protein abundances quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) have recently been explored for hepatic application in IVIVE-PBPK (Vildhede et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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In Vitro–In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II. The Impact of Cross-Laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition

Harwood

Achour

Neuhoff

et al. 2016

Drug Metabolism and Disposition

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Relative expression factors (REFs) are used to scale in vitro transporter kinetic data via in vitro-in vivo extrapolation linked to physiologically based pharmacokinetic (IVIVE-PBPK) models to clinical observations. Primarily two techniques to quantify transporter protein expression are available, immunoblotting and liquid chromatographytandem mass spectrometry. Literature-collated REFs ranged from 0.4 to 5.1 and 1.1 to 90 for intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. The impact of using human jejunum-Caco-2 REFs for P-gp (REF iP-gp ) and BCRP (REF iBCRP ), generated from the same samples and using different proteomic methodologies from independent laboratories, on PBPK outcomes was assessed. A 5-fold decrease in REF iP-gp for a single oral dose of digoxin resulted in a 1.19-and 1.31-fold higher plasma area under the curve and C max , respectively. All generated REF iP-gp values led to simulated digoxin C max values within observed ranges; however, combining kinetic data generated from a different laboratory with the 5-fold lower REF iP-gp could not recover a digoxin-rifampicin drug-drug interaction, emphasizing the necessity to obtain transporter-specific kinetic estimates and REFs from the same in vitro system. For a theoretical BCRP compound, with absorption taking place primarily in the jejunum, a decrease in the REF iBCRP from 2.22 (University of Manchester) to 1.11 (Bertin Pharma) promoted proximal intestinal absorption while delaying t max 1.44-fold. Laboratory-specific differences in REF may lead to different IVIVE-PBPK outcomes. To understand the mechanisms underlying projected pharmacokinetic liabilities, it is important to assess the potential impact of bias on the generation of REFs on an interindividual basis within a target population.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vitro–In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II. The Impact of Cross-Laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition

Harwood

Achour

Neuhoff

et al. 2016

Drug Metabolism and Disposition

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“…This is, in part, based on a lack of high quality data accurately representing transporter abundance levels in a variety of organs. This is pertinent given that whole body PBPK models require the incorporation of organ-specific transporter expression including the intestine, that are typically based on gene expression (i.e., mRNA) or immunoblotting analyses [4,5].…”

Section: Introductionmentioning

confidence: 99%

Application of an LC–MS/MS method for the simultaneous quantification of human intestinal transporter proteins absolute abundance using a QconCAT technique

Harwood

Achour

Russell

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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Transporter proteins expressed in the gastrointestinal tract play a major role in the oral absorption of some drugs, and their involvement may lead to drug-drug interaction (DDI) susceptibility when given in combination with drugs known to inhibit gut wall transporters. Anticipating such liabilities and predicting the magnitude of the impact of transporter proteins on oral drug absorption and DDIs requires quantification of their expression in human intestine, and linking these to data obtained through in vitro experiments. A quantitative targeted absolute proteomic method employing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) together with a quantitative concatenation (QconCAT) strategy to provide proteotypic peptide standards has been applied to quantify ATP1A1 (sodium/potassium-ATPase; Na/K-ATPase), CDH17 (human peptide transporter 1; HPT1), ABCB1 (P-glycoprotein; P-gp), ABCG2 (breast cancer resistance protein; BCRP), ABCC2 (multidrug resistance-associated protein 2; MRP2) and SLC51A (Organic Solute Transporter subunit alpha; OST-α), in human distal jejunum (n=3) and distal ileum (n=1) enterocyte membranes. Previously developed selected reaction monitoring (SRM) schedules were optimised to enable quantification of the proteotypic peptides for each transporter. After harvesting enterocytes by calcium chelation elution and generating a total membrane fraction, the proteins were subjected to proteolytic digestion. To account for losses of peptides during the digestion procedure, a gravimetric method is also presented. The linearity of quantifying the QconCAT from an internal standard (correlation coefficient, R(2)=0.998) and quantification of all target peptides in a pooled intestinal quality control sample (R(2)≥ 0.980) was established. The assay was also assessed for within and between-day precision, demonstrating a <15% coefficient of variation for all peptides across 3 separate analytical runs, over 2 days. The methods were applied to obtain the absolute abundances for all targeted proteins. In all samples, Na/K-ATPase, HPT1, P-gp and BCRP were detected above the lower limit of quantitation (i.e., >0.2 fmol/μg membrane protein). MRP2 abundance could be quantified in distal jejunum but not in the distal ileum sample. OST-α was not detected in 2 out of 3 jejunum samples. This study highlights the utility of a QconCAT strategy to quantify absolute transporter abundances in human intestinal tissues.

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“…The IVIVE approach is well established for many drug metabolizing enzymes [31,32]; however, the integration of drug transporters into PBPK models is lacking, with few positive examples reported [33][34][35][36]. IVIVE-PBPK models link in vitro systems to the in vivo system through algorithms and scaling factors [37,38]. Therefore, for an effective IVIVE-PBPK model to predict the behavior of a drug in vivo, accurate and relevant in vitro data in conjunction with the model system parameters of passive permeability and transporter-mediated flux are necessary.…”

Section: Ivive-pbpkmentioning

confidence: 99%

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

Mallick

2017

ADMET DMPK

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<p class="ADMETabstracttext">In vitro-in vivo extrapolation (IVIVE) integrated in physiologically-based pharmacokinetic (PBPK) models have been increasingly used during drug discovery and development processes to predict human pharmacokinetic (PK) parameters. Drug transporters can influence drug pharmacokinetics and are key aspects contributing to the development of a successful drug. This review provides a snapshot of challenges or shortcomings of in vitro and in vivo techniques for understanding the contribution of drug transporters to a drug’s pharmacokinetics. The paper also describes the potential of IVIVE-PBPK models as prospective approaches to predict the role of drug transporters in drug discovery and development.</p>

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Application of permeability-limited physiologically-based pharmacokinetic models: Part I–digoxin pharmacokinetics incorporating P-glycoprotein-mediated efflux

Cited by 58 publications

References 76 publications

In Vitro–In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II. The Impact of Cross-Laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition

In Vitro–In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II. The Impact of Cross-Laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition

Application of an LC–MS/MS method for the simultaneous quantification of human intestinal transporter proteins absolute abundance using a QconCAT technique

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

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