Tissue Distribution of Basic Drugs: Accounting for Enantiomeric, Compound and Regional Differences Amongst β-Blocking Drugs in Rat

Rodgers, Trudy; Leahy, David E.; Rowland, Malcolm

doi:10.1002/jps.20323

Cited by 121 publications

(109 citation statements)

References 43 publications

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“…In addition, as extra information on the formulation and solubility for this compound was available, a third scenario was simulated using the ADAM model in which the immediate release solid formulation was simulated with an experimentally determined pH-solubility profile, super-saturation ratio and precipitation rate. V ss was predicted to be moderate using method 2 (Rodgers et al [27]) and was similar to that from allometric scaling. The plasma concentration-time profile was therefore simulated using the predicted V ss and the minimal PBPK model.…”

Section: Models and Modeling Parameters Used In The Four Case Studiesmentioning

confidence: 63%

“…Two different scenarios were therefore simulated using the first-order absorption model with either the f a calculated from permeability data or estimated from preclinical studies. A moderate V ss predicted using method 2 (Rodgers et al [27]) was comparable to that obtained from allometric scaling and was used in the minimal PBPK model. The CL int determined in HHs was used for clearance prediction.…”

Section: Models and Modeling Parameters Used In The Four Case Studiesmentioning

confidence: 81%

See 1 more Smart Citation

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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Section: Models and Modeling Parameters Used In The Four Case Studiesmentioning

confidence: 63%

Section: Models and Modeling Parameters Used In The Four Case Studiesmentioning

confidence: 81%

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

View full text Add to dashboard Cite

show abstract

“…and Rodgers and Rowland4 are listed in Table 2 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40…”

Section: Resultsmentioning

confidence: 99%

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

Pilari

Gaub

Block

et al. 2017

CPT Pharmacometrics Syst. Pharmacol.

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We extended a generic whole‐body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems (i.e., the testes and the thyroid gland). An extensive literature search was performed, first, to determine the most generic organ model structures for testes and thyroid across species, and, second, to identify the corresponding anatomic and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK‐Sim and MoBi. The capability of the PBPK approach to simulate the testes and thyroid tissue concentration data was demonstrated using a series of test compounds. The presented organ model structures and parameterization yielded a close agreement between observed and simulated tissue concentrations over time. The organ models are ready to be used to predict the pharmacokinetics of passively entering drugs in the testes and thyroid tissue in a generic PBPK modeling framework.

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“…This assumption was based on the fact that OXY, a strong base (pKa > 7), is predominantly bound to α 1 -acidglycoprotein (AGP), which is mainly located in the circulating plasma. Thus, the impact of OXY's binding to AGP within tissues was assumed to be minimal (82,90). Consequently, differences in OXY's volume of distribution can be mainly attributed to plasma protein-binding differences between the enantiomers (and racemic mixture), rather than to tissue binding (75,82,90).…”

Section: Discussionmentioning

confidence: 99%

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

Olivares‐Morales

Ghosh

Aarons

et al. 2016

AAPS J

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Abstract.A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

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Tissue Distribution of Basic Drugs: Accounting for Enantiomeric, Compound and Regional Differences Amongst β-Blocking Drugs in Rat

Cited by 121 publications

References 43 publications

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

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

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

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