Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling

Mao, Jialin; Doshi, Utkarsh; Wright, Matthew; Hop, Cornelis E. C. A.; Li, Albert P.; Chen, Yuan

doi:10.1002/psp4.12283

Cited by 21 publications

(18 citation statements)

References 28 publications

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“…The 4% BSA was used to mimic the physiologic amount of albumin and can be applied to various species. A similar phenomenon has been reported recently using plated human hepatocytes in human plasma, but the approach was only verified with pravastatin (Mao et al, 2018). In vitro hepatocyte systems supplemented with proteins appear to more closely mimic in vivo disposition, although the underlining mechanisms are not entirely clear.…”

Section: Discussionsupporting

confidence: 74%

A Novel Unified Approach to Predict Human Hepatic Clearance for Both Enzyme- and Transporter-Mediated Mechanisms Using Suspended Human Hepatocytes

et al. 2019

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The accurate prediction of human pharmacokinetics is critically important in modern drug discovery since it drives both pharmacological and toxicological effects. Although significant progress has been made in predicting drug disposition by hepatic drugmetabolizing enzymes, predicting transporter-mediated clearance is still highly uncertain. Furthermore, different approaches are often used to predict clearance with and without transporter involvement, hence the major clearance pathway for a compound must first be determined to know which approach to use. As a result of these challenges, a novel unified method has been developed using cryopreserved suspended human hepatocytes to predict human hepatic clearance for both enzyme-and transporter-mediated mechanisms. This method hypothesizes that, once in vitro metabolic stability is scaled by partition coefficients between hepatocytes and buffer with 4% bovine serum albumin, in vivo clearance can be better predicted. With this method, good in vitro-in vivo correlation of human hepatic clearance has been obtained for a set of 32 structurally diverse compounds, including such transporters as organic anion-transporting polypeptide substrates. The clearance predictions for most compounds are within 3-fold of observed values. This is the first time that multiple compounds result in good in vitro-in vivo extrapolation using an entirely "bottom-up" approach without any empirical scaling factor when transportermediated clearance is involved. Potential exceptions are compounds with significant biliary and/or extra-hepatic clearance. The method offers an alternative approach to more accurately predict human hepatic clearance when multiple complex mechanisms are involved.

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Section: Discussionsupporting

confidence: 74%

A Novel Unified Approach to Predict Human Hepatic Clearance for Both Enzyme- and Transporter-Mediated Mechanisms Using Suspended Human Hepatocytes

et al. 2019

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“…Furthermore, direct scaling of uptake clearance using primary hepatocytes to predict in vivo plasma clearance also typically results in several‐fold underprediction, which is not entirely explained by loss of transporter expression . Use of OATP transporter kinetic data generated using plateable human hepatocytes with human plasma showed improved in vitro ‐to‐ in vivo translation for human PK prediction, more substrates need to be tested using this approach.…”

Section: Challenges and Opportunitiesmentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug–Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations

Taskar

Reddy

Burt

et al. 2019

Clin Pharma and Therapeutics

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Physiologically-based pharmacokinetic (PBPK) modeling has been extensively used to quantitatively translate in vitro data and evaluate temporal effects from drug-drug interactions (DDIs), arising due to reversible enzyme and transporter inhibition, irreversible time-dependent inhibition, enzyme induction, and/or suppression. PBPK modeling has now gained reasonable acceptance with the regulatory authorities for the cytochrome-P450-mediated DDIs and is routinely used. However, the application of PBPK for transporter-mediated DDIs (tDDI) in drug development is relatively uncommon. Because the predictive performance of PBPK models for tDDI is not well established, here, we represent and discuss examples of PBPK analyses included in regulatory submission (the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA)) across various tDDIs. The goal of this collaborative effort (involving scientists representing 17 pharmaceutical companies in the Consortium and from academia) is to reflect on the use of current databases and models to address tDDIs. This challenges the common perceptions on applications of PBPK for tDDIs and further delves into the requirements to improve such PBPK predictions. This review provides a reflection on the current trends in PBPK modeling for tDDIs and provides a framework to promote continuous use, verification, and improvement in industrialization of the transporter PBPK modeling. ) † Venkatesh Pilla Reddy and Kunal S. Taskar equally contributed to this article and are joint first authors. REVIEW(1)) CL H,int = (PS inf ,act + PS inf,pas ) * (CL int,met + CL int,sec ) PS ef f,act + PS ef f,pas + CL int,met + CL int,sec (3) CL H,int = PS inf * REVIEW

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“…Briefly, the pravastatin absorption was predicted using the advanced dissolution, absorption and metabolism (ADAM) model with P eff,man predicted using a MechPeff model. A full-PBPK model with V ss predicted using the method of Rodgers and Rowland (2006) was used SCHEME 1 Overview of GDC-0810 PBPK modeling process to describe the pravastatin distribution (Mao et al, 2018). The total clearance of pravastatin was assigned to the metabolic (13%), the biliary (40%) and renal clearance (47%) based on the clinical data from a mass balance study (Singhvi et al, 1990).…”

Section: Pbpk Model For Pravastatinmentioning

confidence: 99%

Assessment of OATP transporter‐mediated drug–drug interaction using physiologically‐based pharmacokinetic (PBPK) modeling – a case example

Chen

Zhu

et al. 2018

Biopharm & Drug Disp

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GDC‐0810 was under development as an oral anti‐cancer drug for the treatment of estrogen receptor‐positive breast cancer as a single agent or in combination. In vitro data indicated that GDC‐0810 is a potent inhibitor of OATP1B1/1B3. To assess clinical risk, a PBPK model was developed to predict the transporter drug–drug interaction (tDDI) between GDC‐0810 and pravastatin in human. The PBPK model was constructed in Simcyp® by integrating in vitro and in vivo data for GDC‐0810. The prediction of human pharmacokinetics (PK) was verified using GDC‐0810 phase I clinical PK data. The Simcyp transporter DDI model was verified using known OATP1B1/1B3 inhibitors (rifampicin, cyclosporine and gemfibrozil) and substrate (pravastatin), prior to using the model to predict GDC‐0810 tDDI. The effect of GDC‐0810 on pravastatin PK was then predicted based on the proposed clinical scenarios. Sensitivity analysis was conducted on the parameters with uncertainty. The developed PBPK model described the PK profile of GDC‐0810 reasonably well. In the tDDI verification, the model reasonably predicted pravastatin tDDI caused by rifampicin and gemfibrozil OATP1B1/3 inhibition but under‐predicted tDDI caused by cyclosporine. The effect of GDC‐0810 on pravastatin PK was predicted to be low to moderate (pravastatin Cmax ratios 1.01–2.05 and AUC ratio 1.04–2.23). The observed tDDI (Cmax ratio 1.20 and AUC ratio 1.41) was within the range of the predicted values. This work demonstrates an approach using a PBPK model to prospectively assess tDDI caused by a new chemical entity as an OATP1B1/3 uptake transporter inhibitor to assess clinical risk and to support development strategy.

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Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling

Cited by 21 publications

References 28 publications

A Novel Unified Approach to Predict Human Hepatic Clearance for Both Enzyme- and Transporter-Mediated Mechanisms Using Suspended Human Hepatocytes

A Novel Unified Approach to Predict Human Hepatic Clearance for Both Enzyme- and Transporter-Mediated Mechanisms Using Suspended Human Hepatocytes

Physiologically‐Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug–Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations

Assessment of OATP transporter‐mediated drug–drug interaction using physiologically‐based pharmacokinetic (PBPK) modeling – a case example

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