Grazoprevir (Single Agent) + Darunavir/Ritonavir = Precautionary

Effect on Concentration

Grazoprevir (Single Agent)
Increase
Applies within class?
No
Darunavir/Ritonavir
No change
Applies within class?
No

Pharmacologic Effects

Grazoprevir (Single Agent)
Effect
N/A
Applies within class?
No
Darunavir/Ritonavir
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 24-Apr-2019

Summary

Ritonavir does not inhibit OATP1B1- mediated transport in the range of physiologically relevant concentrations. However, darunavir which produced a moderate inhibition of OATP1B1 leading to increased concentration of Grazoprevir. Close monitoring of patients on DRV/r and Grazoprevir may be recommended.

Sources

GZR Vs. DRV/r ^

Study Design

Pooled human cryopreserved hepatocytes were suspended in Krebs-Henseleit buffer in 24-well cell culture plates and incubated with GZR (0.1μM) and either DRV or RTV (0.01-33μM) for 2 minutes at 37°C. Transporter uptake was terminated using ice cold phosphate buffered saline (PBS) followedby immediate centrifugation, washing with ice cold PBS and freeze thaw for cell lysis. GZR concentrations were quantified using LC-MS/MS and IC50 were calculated. The abundance of OATP1B1 in pooled human cryopreserved hepatocytes aged 18-60 years old and three individual elderly donors aged 74-80 years old were quantified using a sandwich ELISA. Statistical significance was assessed using an unpaired t-test.

Study Results

DRV reduced OATP1B1-mediated uptake of GZR by 35% (maximal inhibition at 0.01μM; IC50 of 4.4×10-8μM) whilst RTV decreased uptake by 40% (maximal inhibition at 10μM; IC50 of 9.4μM) (see figure). When compared to pooled hepatocytes from donors aged 18-60 years old, abundance of OATP1B1 in three individual elderly donors aged 74-80 years old were between 35% and 56% lower with P values between 0.005 and 0.032.

Study Conclusions

The authors concluded that in vitro model identified that RTV does not inhibit OATP1B1- mediated transport in the range of physiologically relevant concentrations, unlike DRV which produced a moderate inhibition of OATP1B1. Furthermore, the lower expression of OATP1B1 in hepatocytes from elderly donors provides a plausible mechanistic basis for the increased GZR AUC reported in this sub-population and justifies further investigation.

References

Stader, F, Roberts, O, Owen, A, Marzolini, C, Siccardi, M. The role of oatp1b1 in grazoprevir drug-drug interactions and the elderly. Conference On Retroviruses And Opportunistic Infections. 2019; : .