Dolutegravir versus Atazanavir
^
Study Design
UGT1A1 inhibitors, such as atazanavir, have the potential to increase dolutegravir plasma concentrations. Conversely, ritonavir is a well-known inducer of the UGT1A1 pathway and thus has the potential to decrease dolutegravir plasma concentrations. A randomized, open-label, crossover study was conducted to assess the effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of dolutegravir. Twenty-four healthy volunteers received dolutegravir 30 mg daily for 5 days, followed by co-administration of dolutegravir and atazanavir 400 mg daily or atazanavir/ritonavir 300/100 mg daily for 14 days.
Study Results
Giving atazanavir alone increased plasma dolutegravir exposure by 50–180 %, whereas giving atazanavir/ ritonavir increased dolutegravir exposure by only 34–121 %. This diminished effect is likely related to ritonavir-mediated UGT1A1 induction, with ritonavir attenuating the inhibitory effect of atazanavir on this pathway. Co-administration of both atazanavir and atazanavir/ritonavir with dolutegravir did produce modest increases in dolutegravir exposure. Yet no increase in adverse effects was seen, and the mean AUC values (87.4 μg ml−1 h) were still lower than those achieved by a well-tolerated single dose of dolutegravir 100 mg in phase I studies (131 μg ml−1 h).
Study Conclusions
Thus, despite a modest increase in dolutegravir exposure, it was determined that no dose adjustment for dolutegravir is necessary when it is co-administered with atazanavir or atazanavir/ritonavir.
References
Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clinical Pharmacokinetics. 2013; 11: 981-994.
icon on your home screen.