There is an increase in AUC of Rivaroxaban in patients on Darunavir/Ritonavir. This increase is consistent across all age groups. Caution should exercised to prevent adverse drug events due to increased concentrations of Rivaroxaban in these patients.
Darunavir/Ritonavir versus Rivaroxaban
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Study Design
This study aimed to simulate the DDI magnitude between boosted darunavir (DRV/r) and rivaroxaban in young and elderly subjects using a physiologically based pharmacokinetic (PBPK) model. A whole-body PBPK model was built in Matlab® including age-dependent physiological changes for the simulation of elderly subjects. The DRV/r drug model was successfully verified against observed clinical data in young volunteers. The predictive performance of the rivaroxaban model was checked against observed clinical data in a) young, b) elderly and c) young individuals treated with ritonavir (600 mg BID at steady state) and rivaroxaban. The verified drug models were used to assess the effect of age on the DDI
magnitude between DRV/r (800/100 mg QD at steady state) and rivaroxaban
(10 mg single dose) in 100 virtual subjects considering 5 age groups: a) 20-49, b)
50-64, c) 65-74, d) 75-84 and e) 85-94 years.
Study Results
The developed PBPK model predicted the pharmacokinetics of
rivaroxaban in young and elderly correctly. Predicted versus observed mean
rivaroxaban AUC were 1148 and 1000 ng*h/mL for young and 1491 and 1839
ng*h/mL for elderly volunteers. The simulated versus observed rivaroxaban
AUC in the presence of ritonavir was 2655 ng*h/mL and 2529 ng*h/mL with
a resulting AUC ratio (rivaroxaban with / without ritonavir) of 2.31 and 2.53,
respectively. Age did not impact the DDI magnitude between rivaroxaban
and DRV/r, because all drugs are similarly affected by age-dependent
physiological changes. Virtual individuals aged 50-64 years
commonly defined as “elderly” in HIV medicine, showed only a 12% increase in
the AUC compared to younger subjects suggesting that this age cut-off is too
low for pharmacological studies.
Study Conclusions
The predictions showed an age-dependent increase in the AUC of rivaroxaban and an approximate 2-fold increase in AUC in patients on Rivaroxaban + DRV/r compared to Rivaroxaban alone across all ages suggesting a similar management of this DDI in the elderly.
References
Stader, F, Siccardi, M, Kinvig, H, Battegay, M, Penny, MA, Marzolini, C. Drug interaction magnitudes in young vs elderly: example of rivaroxaban–darunavir/r. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019.
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