Physiologically Based Pharmacokinetic Modeling of Rosuvastatin to Predict Transporter-Mediated Drug-Drug Interactions

Pharm Res. 2021 Oct;38(10):1645-1661. doi: 10.1007/s11095-021-03109-6. Epub 2021 Oct 18.

Abstract

Purpose: To build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated drug-drug interactions (DDIs).

Methods: The Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002-80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model.

Results: The carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUClast ratios (AUClast during DDI/AUClast without co-administration) and DDI Cmax ratios (Cmax during DDI/Cmax without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values.

Conclusions: A whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).

Keywords: Drug-drug interactions (DDIs); Model-informed drug discovery and development (MID3); Organic anion transporting polypeptide 1B1/1B3 (OATP1B1/1B3); Physiologically based pharmacokinetic modeling (PBPK); Rosuvastatin.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Adult
  • Age Factors
  • Area Under Curve
  • Biological Transport
  • Body Height
  • Body Weight
  • Drug Interactions*
  • Ethnicity
  • Feces / chemistry
  • Gemfibrozil / metabolism
  • Humans
  • Liver
  • Liver-Specific Organic Anion Transporter 1 / metabolism
  • Male
  • Models, Biological*
  • Neoplasm Proteins / metabolism
  • Probenecid / metabolism
  • Rifampin / metabolism
  • Rosuvastatin Calcium / blood
  • Rosuvastatin Calcium / pharmacokinetics*
  • Rosuvastatin Calcium / urine
  • Sex Factors
  • Software
  • Solute Carrier Organic Anion Transporter Family Member 1B3 / metabolism

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Rosuvastatin Calcium
  • Probenecid
  • Gemfibrozil
  • Rifampin