Prediction of Transporter-Mediated Rosuvastatin Hepatic Uptake Clearance and Drug Interaction in Humans Using Proteomics-Informed REF Approach

Abstract

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Improving the Translation of Organic Anion Transporting Polypeptide Substrates using HEK293 Cell Data in the Presence and Absence of Human Plasma via PBPK Modeling

“…For the two compounds with lower protein binding, pravastatin and rosuvastatin, comparable transporter kinetics were generated in plasma and buffer incubations.. For pravastatin, the sum of the OATP1B1/3 uptake CL int,T was relatively similar between the plasma, buffer, and base models. For rosuvastatin, the OATP1B1/3 uptake CL int,T in the plasma and buffer models were lower than the fitted OATP1B1/3 uptake CL int of the base model, which agrees with the recent work of Kumar et al (2020) who found that in vitro systems underpredicted rosuvastatin's uptake clearance, and suggested endogenous factors were missing.…”

“…The uptake clearance measured with this in vitro data is compared to the previously fitted uptake clearance values from PBPK models, and predictions of pharmacokinetic parameters and concentration-time profiles are examined. While many have used hepatocytes for transporter IVIVE (Izumi et al, 2017), using transporter overexpressing cells may be preferable due to information about specific transporter contributions, lack of lot variability, and cost (Kumar et al, 2020). Finding an appropriate in vitro system and incubation conditions is crucial for more accurate prospective PK predictions, and may avoid the previously needed compound-specific empirical scaling factors.…”

Successful Prediction of Human Steady‐State Unbound Brain‐to‐Plasma Concentration Ratio of P‐gp Substrates Using the Proteomics‐Informed Relative Expression Factor Approach

“…Such underprediction has been reduced when using the REF approach. For example, using this approach, we have successfully predicted metformin (an OCT substrate) hepatic uptake CL as well renal secretory CL, 41 , 42 and hepatic uptake CL of rosuvastatin (an OATP and NTCP substrate) 43 within twofold of the observed values; however, these predictions (except for metformin hepatic uptake CL) were close to the lower twofold boundary, indicating that IVIVE of CLs, using the REF approach, needs further refinement. 43 …”

“…For example, using this approach, we have successfully predicted metformin (an OCT substrate) hepatic uptake CL as well renal secretory CL, 41,42 and hepatic uptake CL of rosuvastatin (an OATP and NTCP substrate) 43 within twofold of the observed values; however, these predictions (except for metformin hepatic uptake CL) were close to the lower twofold boundary, indicating that IVIVE of CLs, using the REF approach, needs further refinement. 43 There are a few limitations to our approach, First, due to sparse availability of human PET imaging data we could not include other P-gp-transported drugs in our verification data set nor could we extend our approach to drugs transported by other transporters such as BCRP. However, when such PET imaging data are available, our REF approach could be extended to these drugs, using data from both BCRP and P-gp-transfected cell lines.…”

Estimation of Fetal-to-Maternal Unbound Steady-State Plasma Concentration Ratio of P-Glycoprotein and/or Breast Cancer Resistance Protein Substrate Drugs Using a Maternal-Fetal Physiologically Based Pharmacokinetic Model

“…From these profiles, the K p,uu,fetal of nelfinavir and efavirenz was estimated. Such predictions for imatinib were not possible as the fraction of imatinib transported by P-gp or BCRP is unknown and will need to be determined as we have described previously (Kumar et al, 2021).…”