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Potential Interaction

Raltegravir (RAL)

Calcium supplements

Quality of Evidence: Very Low

Summary:

There are no studies of raltegravir and calcium supplements when given, for example, as an adjunct to specific therapies or to correct calcium deficiency. The daily dose of a calcium supplement may vary - often between 1 g and 3 g per day. It is known that raltegravir binds to divalent cations such as calcium and forms a complex at the level of the gastro-intestinal tract which results in less raltegravir being absorbed. A case report describes virological failure in a patient on raltegravir-containing regimen who was commenced on calcium carbonate (1 g vitamin D3 400 IU 3 times/day) for prevention of osteoporosis. Therapeutic drug monitoring at the time of virological failure showed lower than expected raltegravir concentrations at 5 hours post dose. However, coadministration of calcium carbonate antacids (1000 mg x 3 tabs) was not considered to have a clinically meaningful effect on twice daily raltegravir (raltegravir Cmax, AUC and Cmin decreased by 52%, 55% and 32%; n=24) and no dose adjustment is considered necessary. If possible, administration of raltegravir 400 mg twice daily should be separated by at least 4 hours from a calcium supplement (more important with higher doses). In addition, there was a more pronounced reduction in raltegravir Cmin when raltegravir was administered once daily with a calcium carbonate antacid compared to a twice daily regimen. A similar effect for calcium supplements cannot be excluded and, therefore, twice daily administration of raltegravir should be preferred. Note, for recommendations for calcium carbonate when used as an antacid, please search for interactions with "antacids".

Description:

No dose adjustment is required for raltegravir (400 mg twice daily) with calcium carbonate antacid; co-administration of raltegravir (1,200 mg once daily) and calcium carbonate antacid is not recommended. Simultaneous coadministration of raltegravir (400 mg twice daily) with a calcium carbonate antacid decreased raltegravir AUC, C12 and Cmax by 55%, 32% and 52%, respectively. Simultaneous coadministration of raltegravir (1,200 mg single dose) with a calcium carbonate antacid decreased raltegravir AUC, C12 and Cmax by 72%, 48% and 74%, respectively. Coadministration of the antacid 12 h after raltegravir decreased raltegravir AUC, C12 and Cmax by 10%, 57% and 2%.
Isentress Summary of Product Characteristics, Merck Sharp & Dohme Ltd, September 2021.

Calcium carbonate antacid decreases raltegravir concentrations. No dose adjustment is required with twice daily raltegravir; coadministration is not recommended with once daily raltegravir. Simultaneous coadministration of raltegravir (400 mg twice daily) with a calcium carbonate antacid (3000 mg single dose) decreased raltegravir Cmax, AUC and Cmin by 52%, 55% and 32% (n=24). Simultaneous coadministration of raltegravir (1200 mg single dose) with a calcium carbonate antacid (3000 mg single dose) decreased raltegravir Cmax, AUC and Cmin by 74%, 72% and 48% (n=19). Coadministration of the antacid 12 h after raltegravir (1200 mg single dose) decreased raltegravir Cmax, AUC and Cmin by 2%, 10% and 57% (n=19).
Isentress Prescribing Information, Merck & Co Inc, August 2021.

A case report describes a 39-year-old, HIV-1-infected man who experienced virologic failure while receiving a raltegravir-containing antiretroviral regimen with concomitant calcium administration. For drug interaction reasons, the patient was switched from a PI-based regimen to raltegravir/tenofovir/emtricitabine and calcium carbonate (1 g-vitamin D3 400 IU 3 times/day) was added for prevention of osteoporosis. After 10 months of an undetectable viral load and clinical evidence of a high level of adherence on this regimen, the patient developed detectable HIV-1 RNA levels with documented resistance to raltegravir His antiretroviral therapy was changed back to a protease inhibitor-based regimen, and his HIV-1 RNA level rapidly resuppressed. Therapeutic drug monitoring at the time of virologic failure showed lower than expected raltegravir concentrations at 5 hour post dose, but tenofovir and emtricitabine concentrations were within the expected range. The authors suggest that calcium binding to the divalent metal ion-chelating motif of raltegravir may have led to subtherapeutic raltegravir levels in this patient.
Virologic failure with a raltegravir-containing antiretroviral regimen and concomitant calcium administration. Roberts JL, et al. Pharmacother, 2011, 31(10): 298e-302e.

In vitro studies have shown raltegravir cellular permeativity was decreased in the presence of the divalent cations magnesium and calcium, but not in the presence of the monovalent cation potassium. Raltegravir may bind to the divalent metals and form a metal-drug complex which is unable to cross the cell membrane.
Divalent metals and pH alter raltegravir disposition in Vitro. Moss DM, Siccardi M, Murphy M, at al. Antimicrob Agents Chemother, 2012, 56(6): 3020-6.