Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate + Carbamazepine = Precautionary

Effect on Concentration

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate
Decrease
Applies within class?
No
Carbamazepine
Increase
Applies within class?
No

Pharmacologic Effects

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate
Effect
N/A
Applies within class?
No
Carbamazepine
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 13-Jul-2018

Summary

Sources

Pharmacokinetics and drug interaction profile of cobicistat-boosted elvitegravir with carbamazepine [abstract H-1011]. ^

Study Design

This was an open-label, single center, fixed sequence, multiple dose study, conducted in 14 healthy patients to evaluate the pharmacokinetics (PK) and drug interaction profile of cobicistat (COBI) boosted-elvitegravir (EVG) with carbamazepine (CBZ). Treatment was given sequentially over 41 days as follows: EVG/COBI 150/150mg QD for 10 days, followed by CBZ 100mg BID for 3 days then CBZ 200mg BID for 18 days, followed by EVG/COBI 150/150mg QD + CBZ 200mg BID for 10 days. PK assessments were performed on days 10, 31 and 41.

Study Results

12 participants completed the study. EVG and COBI exposures (AUC) were outside the no-effect boundary of 70-143% when co-administered with CBZ. Results showed a 69% (90%CI, 28.2-33.4) and 84% (14.3-18.3) lower exposure for EVG and COBI respectively compared to EVG/COBI alone. PK analyses also found that EVG Ctau was below the limit of quantitation (BLQ: <20ng/ml) in 8 out of 12 subjects following administration of EVG/COBI + CBZ. It was also found to be below the protein-binding adjusted IC95 (45ng/ml) for HIV-1 in 11 out of 12 participants. Lower exposures of COBI as a result of CYP3A induction by CBZ, resulted in weaker inhibition of CYP3A by COBI. COBI Ctau was BLQ (<5ng/ml) in 8 out of 12 subjects following administration of EVG/COBI + CBZ. Results also showed that the AUC of CBZ was 43% (136-152) higher, and that of CYP3A metabolite CBZ-10,11-epoxide was 35% 63.1-66.5) lower when co-administered with EVG/COBI, relative to CBZ alone. All adverse effects were mild or moderate in severity, and no deaths or serious adverse effects were reported.

Study Conclusions

These results are consistent with induction of CYP3A and UGT by CBZ, as well as the labelling of Stribild (EVG/COBI + Tenofovir + Emtricitabine) which contraindicates its use with potent CYP3A inducers.

References

Custodio JM, Shao Y, Begley R. Pharmacokinetics and drug interaction profile of cobicistat-boosted elvitegravir with carbamazepine [abstract h-1011]. Icaac: Interscience Conference On Antimicrobial Agents And Chemotherapy. Washington DC, USA. 54; September 2014.