Simulation of Human Intravenous and Oral Pharmacokinetics of 21 Diverse Compounds Using Physiologically Based Pharmacokinetic Modelling

Jones, Hannah M.; Gardner, Iain; Collard, Wendy T.; Stanley, Phil; Oxley, Penny; Hosea, Natilie; Plowchalk, David R.; Gernhardt, Steve S.; Lin, Jing; Dickins, Maurice; Rahavendran, S Ravi; Jones, Barry; Watson, Kenny; Pertinez, Henry; Kumar, Vikas; Cole, Susan

doi:10.2165/11539680-000000000-00000

Cited by 106 publications

(96 citation statements)

References 37 publications

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“…Typically, generic PBPK models assume flow-limited distribution and well stirred tissue kinetics. Successful predictions using these PBPK models have been made for lipophilic compounds whose absorption and distribution are governed by passive processes (Jones et al, 2006(Jones et al, , 2011Rostami-Hodjegan and Tucker, 2007). However, these models would not be expected to provide reasonable predictions for compounds that are actively transported.…”

Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Ghosh

Maurer

et al. 2014

Drug Metab Dispos

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A previously developed physiologically based pharmacokinetic model for hepatic transporter substrates was extended to an organic anion transporting polypeptide substrate, telmisartan. Predictions used in vitro data from sandwich culture human hepatocyte and human liver microsome assays. We have developed a novel method to calibrate partition coefficients (Kps) between nonliver tissues and plasma on the basis of published human positron emission tomography (PET) data to decrease the uncertainty in tissue distribution introduced by in silico-predicted Kps. With in vitro data-predicted hepatic clearances, published empirical scaling factors, and PET-calibrated Kps, the model could accurately recapitulate telmisartan pharmacokinetic (PK) behavior before 2.5 hours. Reasonable predictions also depend on having a model structure that can adequately describe the drug disposition pathways. We showed that the elimination phase (2.5-12 hours) of telmisartan PK could be more accurately recapitulated when enterohepatic recirculation of parent compound derived from intestinal deconjugation of glucuronide metabolite was incorporated into the model. This study demonstrated the usefulness of the previously proposed physiologically based modeling approach for purely predictive intravenous PK simulation and identified additional biologic processes that can be important in prediction.

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Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Ghosh

Maurer

et al. 2014

Drug Metab Dispos

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“…These models use physiologically relevant parameters describing absorption, distribution, metabolism and excretion (ADME) to predict the overall pharmacokinetic (PK) profile of a compound. The use of PBPK models has increased significantly in recent years, and reports of successful retrospective application with large industrial data sets are forthcoming [5][6][7]. An important aspect of PBPK modeling for compounds cleared primarily by the liver is the application of IVIVE methods to predict in vivo clearance from in vitro metabolic data.…”

Section: Introductionmentioning

confidence: 99%

Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies

Chen¹,

Jin²,

Mukadam³

et al. 2012

Biopharm & Drug Disp

102

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Prospective simulations of human pharmacokinetic (PK) parameters and plasma concentration-time curves using in vitro in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) models are becoming a vital part of the drug discovery and development process. This paper presents a strategy to deliver prospective simulations in support of clinical candidate nomination. A three stage approach of input parameter evaluation, model selection and multiple scenario simulation is utilized to predict the key components influencing human PK; absorption, distribution and clearance. The Simcyp W simulator is used to illustrate the approach and four compounds are presented as case studies. In general, the prospective predictions captured the observed clinical data well. Predicted C max was within 2-fold of observed data for all compounds and AUC was within 2-fold for all compounds following a single dose and three out of four compounds following multiple doses. Similarly, t max was within 2-fold of observed data for all compounds. However, C last was less accurately captured with two of the four compounds predicting C last within 2-fold of observed data following a single dose. The trend in results was towards overestimation of AUC and C last , this was particularly apparent for compound 2 for which clearance was likely underestimated via IVIVE. The prospective approach to simulating human PK using IVIVE and PBPK modeling outlined here attempts to utilize all available in silico, in vitro and in vivo preclinical data in order to determine the most appropriate assumptions to use in prospective predictions of absorption, distribution and clearance to aid clinical candidate nomination.

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“…More complex disposition models could be utilized. A recent study found that physiologically based pharmacokinetic models (PBPK) were able to accurately predict the multiphasic shape of the pharmacokinetic profiles for many of the compounds tested (8). Since it is the shape of the unit input function that is most important (rather than the magnitude on the absorption axis), a PBPK simulated solution unit impulse might offer advantages over one derived from a one-compartment model when a more complex disposition is anticipated.…”

Section: Discussionmentioning

confidence: 99%

A Technique to Estimate In Vivo Dissolution Profiles Without Data from a Solution

Cook

2012

AAPS J

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Abstract. Dissolution tests are expected to ensure adequate in vivo product performance. Given the recent progress in the ability to predict of human permeability, it is possible to synthesize the plasma drug concentration-time profile from human permeability predictions and the results of the first-in-human trial and use these data to synthesize a pharmacokinetic profile for a solution and provide an initial estimate of the in vivo dissolution profile. This manuscript provides details of such a deconvolution methodology in order to provide an initial estimate of in vivo dissolution. Plasma metoprolol concentration-time data from a previously published study examining the pharmacokinetics of three metoprolol formulations (100 mg), slow, moderate, and fast releasing, and an oral solution (50 mg) were used to estimate in vitro dissolution profiles. A one-compartment unit impulse function was used, and the absorption rate was estimated from animal permeability data (synthetic solution method). The results were compared to those obtained using a unit impulse function estimated from the oral solution data. In vivo dissolution profiles estimated from animal permeability data were similar to those estimated from the oral solution data. Ratios of absorption rate constants (synthetic solution method/oral solution) ranged from 1 to 1.3. The synthetic solution method offers a way to estimate in vivo dissolution profile through deconvolution. It is applicable in cases where it is not possible or feasible to obtain data from a solution. It performs best in cases where dissolution is the rate-limiting step in the absorption process.

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Simulation of Human Intravenous and Oral Pharmacokinetics of 21 Diverse Compounds Using Physiologically Based Pharmacokinetic Modelling

Cited by 106 publications

References 37 publications

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies

A Technique to Estimate In Vivo Dissolution Profiles Without Data from a Solution

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