Dolutegravir + Phenobarbital = Prohibited

Effect on Concentration

Dolutegravir
Decrease
Applies within class?
No
Phenobarbital
No change
Applies within class?
No

Pharmacologic Effects

Dolutegravir
Effect
N/A
Applies within class?
No
Phenobarbital
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 16-Jul-2018

Summary

Similar effects are expected when coadministering dolutegravir with phenytoin or phenobarbital.

Sources

Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation. ^

Study Design

This was a phase 1, single center, open-label, fixed sequence crossover study in healthy adult subjects to evaluate the effect of carbamazepine (CBZ) on the pharmacokinetics (PK) of dolutegravir (DTG). Study treatments were administered with a moderate fat meal as following: Period 1: DTG 50mg QD for 5 days; Period 2: CBZ 100mg Q 12H for 3 days, then 200mg Q 12H for 3 days, then 300mg Q 12H for 10 days; Period 3: DTG 50mg QD + CBZ 300mg Q 12H for 5 days. There were no washout intervals between treatments and subjects were inpatients except from the evening of Day 8 through the morning of Day 16 in period 2. Plasma samples for PK analysis were collected over 24 hours on day 5 of Period 1 and Period 3.

Study Results

Carbamazepine co-administration significantly reduced DTG exposure. Using 90% confidence intervals and least square means ratios, Cmax, AUC and Cmin were 0.66 (0.61-0.73), 0.51 (0.48-0.55) and 0.27 (0.24-0.31), respectively. 14 out of 16 participants completed the study; 1 subject withdrew on Day 4 due to Grade 1 fever and the other on Day 11 due to drug induced hypersensitivity syndrome.

Study Conclusions

The manufacturer states that co-administration with CBZ should be avoided due to insufficient data to make dosing recommendations. The change in DTG pharmacokinetic parameters in this study are similar to those seen when DTG is coadministered with efavirenz or rifampin. In which they recommend that in treatment-naïve or treatment-experienced, integrase strand inhibitor-naïve patients to increase DTG to 50 mg twice daily. The authors of the study presented here, Weller, et al. make the same recommendation for DTG and CBZ.

References

Song I, Weller S, Patel J, Borland J, Wynne B, Choukour M, Piscitelli S. Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation. European Journal Of Clinical Pharmacology. 2016; 6: 665-670.