Slide 1: Deciphering the Clinical DDI Between Atazanavir and Rosuvastatin
Deciphering the Clinical DDI Between Atazanavir and Rosuvastatin Cyprotex, January 2024
Slide 2: Agenda
Agenda 1. Introduction to drug-drug interactions 2. Introduction for the DDI between rosuvastatin and protease inhibitors 3. DDI predictions 4. Summary PAGE 2
Slide 3: Drug-Drug Interactions Introduction
Drug-Drug Interactions Introduction • Polypharmacy • DDI occur when one drug affects • Pharmacokinetic DDI are − Aging population and the pharmacokinetics or mediated via mechanistic changes co-morbidities pharmacodynamics of a in the processes of absorption, co-administered drug distribution, metab
Slide 4: Drug-Drug Interactions: Transporters
Drug-Drug Interactions Transporters • Evaluating the DDI potential of an investigational Key questions to answer drug involves: • Victim: − Identifying principal routes of drug elimination − Is there potential for my drug to be a victim of a DDI? − Estimating contribution of transporters to drug − W
Slide 5: Human Immunodeficiency Virus (HIV)
Human Immunodeficiency Virus (HIV) Since the 1980’s >85 million people have been infected with HIV: >40 million people have died from AIDS1 Infection/Disease Treatment • Viral infection that is transmitted through the transfer • No cure - but several marketed drugs are able to slow of infected bodil
Slide 6: Protease Inhibitors
Protease Inhibitors • One of the main classes of HAART agents are protease inhibitors (PI) • PIs are analogues of substrates of the HIV aspartyl protease enzyme − Aspartyl protease enzyme is required for the processing of viral proteins. − Once bound to the protease active site the PI inhibits furth
Slide 7: Rosuvastatin
Rosuvastatin • Patients infected with HIV are at an increased risk from further conditions, a common comorbidity is dyslipidaemia (24% of patients)1 • Rosuvastatin is a statin used to manage lipid levels by inhibiting production of cholesterol in the liver – more effective in managing lipid levels i
Slide 8: Rosuvastatin & Atazanavir DDI
Rosuvastatin & Atazanavir DDI • Subjects dosed with 10mg of rosuvastatin – blood samples taken up to 24 hrs after dosing • 6 day wash out period Table 1: Pharmacokinetic Parameters (Mean ± SD) of Rosuvastatin when dose alone or in combination • Day 7 – Day 14 atazanavir / ritonavir 300mg / 100mg was
Slide 9: Rosuvastatin Disposition Pathway
Rosuvastatin Disposition Pathway Intestinal Lumen/ Rosuvastatin • Oral administration of rosuvastatin is 50% absorbed enterocyte Acid (RSV) − BCRP limiting absorption by 50% (e = 0.5) • Once in the hepatic portal vein and at the inlet to the liver it is taken up into hepatocytes by a process which
Slide 10: Quantitative Tools – Application of the Rowland Matin Equation
Quantitative Tools – Application of the Rowland Matin Equation Estimation 1 Adapted Rowland Matin mechanistic static equation and its derivatives can be used to quantitatively predict the extent of AUC changes of a victim drug due to DDI in the clinic 1. Maximum theoretical AUC change if an individu
Slide 11: Quantitative Prediction of Rosuvastatin-Atazanavir DDI
Quantitative Prediction of Rosuvastatin-Atazanavir DDI Estimation 1 continued 1. To decipher which pathways Assumptions • Mathematically close to the may be playing a crucial role in observed DDI, however not • Transporter is 100% inhibited by the rosuvastatin-atazanavir representative of a true cli
Slide 12: Quantitative Prediction Tools
Quantitative Prediction Tools Adapted Rowland Matin mechanistic static equation and its derivatives can be used to quantitatively predict the extent of AUC changes of a victim drug due to DDI in the clinic 1. Maximum theoretical AUC change if an individual 1 pathway is fully inhibited: Fold ∆ =…
Slide 13: Previously Published Predictions for the Clinical DDI: Prediction 1
Previously Published Predictions for the Clinical DDI Prediction 1 1. Predictions of rosuvastatin AUCR have been made integrating solely the critical pathways of BCRP and OATP1B’s: Rowland Matin equation, incorporating literature Ki values Assumptions • Max intestinal luminal conc used (I2 now terme
Slide 14: Previously Published Predictions for the Clinical DDI: Prediction 2
Previously Published Predictions for the Clinical DDI Prediction 2 2. When the assumption was made that atazanavir was an inhibitor of the 3 hepatic clearance routes, (OATP1B1, OATP1B3 and NTCP giving the combined e of 0.7) did the prediction in AUC change of rosuvastatin fall in line with the clin
Slide 15: Improving on Predictions of the Clinical DDI
Improving on Predictions of the Clinical DDI Existing predictions used several assumptions to predict the AUCR of rosuvastatin when co-dosed with atazanavir, can these be improved further? • Generate IC50 (Ki) values for all transporters that contribute to the critical disposition pathways of rosuva
Slide 16: Impact of Atazanavir on Rosuvastatin Disposition: BCRP Inhibition
Impact of Atazanavir on Rosuvastatin Disposition Intestinal Lumen/ Rosuvastatin BCRP Inhibition enterocyte Acid (RSV) In vitro experiments showed BCRP transport of [3H]-estrone 3-sulfate (surrogate for rosuvastatin) to be inhibited by atazanavir with an IC50 of 42.2 µM Renal Proximal Tubule Using th
Slide 17: Impact of Atazanavir on Rosuvastatin Disposition: SLC Inhibition
Impact of Atazanavir on Rosuvastatin Disposition Intestinal Lumen/ Rosuvastatin SLC Inhibition enterocyte Acid (RSV) In vitro experiments showed atazanavir to inhibit OATP1B1, OATP1B3 and NTCP mediated transport with IC50’s of 0.734 µM, 1.86 µM and 65.6 µM respectively, but not against OAT3 Renal Pr
Slide 18: Quantitative Prediction: Application of Determined In Vitro Parameters (3a)
Quantitative Prediction: Application of Determined In Vitro Parameters Prediction 3a 3a) Theoretical AUCR if an individual pathway is inhibited, or the combined AUCR for these four pathways Transporter 𝒇e Ki Equation AUCR Overall AUCR OATP1B1 0.38 0.734 1.49 1 [1.44-1.56] 𝑓𝑒 2.43 𝐼 +(1−𝑓𝑒)…
Slide 19: Quantitative Prediction: Application of Determined In Vitro Parameters (3b)
Quantitative Prediction: Application of Determined In Vitro Parameters Prediction 3b 3b) Theoretical AUCR if an individual pathway is inhibited, or the combined AUCR for these four pathways Transporter 𝒇e Ki Equation AUCR Equation AUCR Overall AUCR OATP1B1 0.38 0.734 1.49 [1.44-1.56] 1 OATP1B3 0.11
Slide 20: Comparison of Predictions for the Rosuvastatin-Atazanavir DDI
Comparison of Predictions for the Rosuvastatin-Atazanavir DDI • Using the various prediction tools and associated assumptions the fold change in AUC ranges from 2.43 to 3.25 compared to the clinically observed value of 3.1 • Mechanistic theoretical maximum equation in the absence of [I]/Ki can mathe
Slide 21: Accuracy of Predictions
Accuracy of Predictions Predicted Accuracy of prediction Mechanistic static model for 28 statin DDIs Predictive tool AUCR (%) [95% CI] (6 statin victim drugs) Mechanistic theoretical maximum equation 3.22 +12 [22-68] for e (BCRP + OATP1B1) BCRP and combined OATP from literature 3.2 + 10 [20-70] in
Slide 22: Summary of Predictions
Summary of Predictions Method AUCR Prediction Assumptions Calculations Variances Reference Transporters are 100% inhibited Estimate 1 Combination of individual e 3.22 e only Only 2 pathways at play Max luminal conc used (I2) [dose/250mL] Complete inhibition when I2/Ki > 10 Combined OATP e for BCR
Slide 23: Rosuvastatin Drug Label
Rosuvastatin Drug Label • Due to the observed clinical DDI interaction seen between protease inhibitors and rosuvastatin this has been incorporated into the drug label • When administering this combination, the dosages of each drug must be considered to ensure a safe and efficacious dose is achieved
Slide 24: Summary
Summary 1. Prediction methods have developed over time as the understanding of DDI and biological parameters improves 2. The correct in vitro parameters and the correct victim model (critical disposition route(s) and associated fe values and assumptions) are required for mechanistic models for succe
Slide 25: Questions and Answers