Dolutegravir + Calcium = Precautionary

Effect on Concentration

Dolutegravir
Decrease
Applies within class?
No
Calcium
Decrease
Applies within class?
No

Pharmacologic Effects

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

Interaction History

N/A

Last Updated 13-Jul-2018

Summary

Findings of drug interaction studies are different if the agents are taken with food.

Sources

Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. ^

Study Design

This was an open-label, randomized, single dose, 4-period cross-over study in healthy adults (n=12). All treatment groups received 50mg of dolutegravir (DTG) and had a washout period of at least 7 days between them. There were four treatment sequences consisting of DTG alone under fasted conditions, DTG + calcium carbonate 1200mg given under fasted conditions, and then under fed conditions, and lastly DTG given under fasted conditions, 2 hours prior to administration of calcium carbonate 1200mg. Pharmacokinetic (PK) samples were collected at the end of each treatment. An earlier study similar to this was conducted to compare the PK of DTG co-administration with a calcium-containing multivitamin (MVI), versus DTG alone in the fasted state. The MVI contained 162mg of elemental calcium and 100mg of magnesium, as well as iron, zinc, and copper. This was an open-label, randomized, four-period, cross-over study (n=16), with a 7-day washout period between treatments.

Study Results

Co-administration with calcium carbonate reduced DTG exposure under fasted conditions. AUC of DTG + calcium carbonate given in the fasted state was 0.61 (90%CI; 0.47-0.80) and Cmax 0.63 (0.50-0.81) compared to DTG alone. However, when DTG was administered with calcium carbonate under fed conditions or given 2 hours prior to administration of calcium carbonate under fasted conditions, the AUC was 1.09 (90%CI; 0.84-1.43) and 0.94 (0.72-1.23) respectively, versus DTG alone under fasted conditions. Results from the earlier study were consitent with the above, showing a decrease in DTG exposure (AUC 0.67, 90%CI; 0.55-0.81) when co-administered with the calcium-containing MVI in the fasted state. Co-administration with the iron supplement reduced DTG exposure under fasted conditions. AUC of DTG + ferrous fumarate given in the fasted state was 0.46 (90%CI; 0.38-0.56) and Cmax 0.43 (0.35-0.52) compared to DTG alone. However, when DTG was administered with ferrous fumarate under fed conditions or given 2 hours prior to administration of ferrous fumarate under fasted conditions, the AUC was 0.98 (90%CI; 0.81-1.20) and 0.95 (0.77-1.15) respectively, versus DTG alone under fasted conditions. Results from the earlier study were consitent with the above, showing a decrease in DTG exposure (AUC 0.67, 90%CI; 0.55-0.81) when co-administered with the iron-containing MVI in the fasted state.

Study Conclusions

***In addition to previous labeling requirements that DTG be administered 2 hours before or 6 hours after taking medications containing polyvalent cations, the manufacturer revised labeling to include the alternative to co-administer DTG with calcium supplements if taken with food.

References

Song I, Borland J, Arya N, Wynne B, Piscitelli S. pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. Journal Of Clinical Pharmacology. 2015; 5: 490-496.