Raltegravir Pharmacokinetic Variability Not Impacted by All Antacids

MARCH 07, 2018
Matt Hoffman
Helen Reynolds, PGDip, MSc, MS
While it was previously debated whether antacids or gastrointestinal pH has the predominant effect on the pharmacokinetic variability of raltegravir (Isentress, Merck), an HIV-1 therapy, new data reveals that not all antacids influence the of drug’s absorption.

The study found that the absorption of raltegravir is influenced positively increased by antacids without divalent cations, such as sodium bicarbonate, which the authors, led by Helen Reynolds, PGDip, MSc, MS, noted is likely related to the ‘boosting’ effect of elevated pH during absorption and the pH-dependent solubility of raltegravir.

In the open-label, triple-arm, 5-phase controlled healthy volunteer study, Reynolds, a research nurse at the Royal Liverpool University Hospital, and colleagues randomized 15 healthy volunteers—although 1 withdrew consent and 4 did not complete the study due to adverse events (AEs; n = 3) and inability to follow-up (n = 1).

Patients were administered a single, 400 mg dose of oral raltegravir (n = 14), followed by either raltegravir plus 30 mL Maalox Plus (n = 11), 1 g sodium bicarbonate (n = 11), a single capsule multivitamin (n = 10), or 30 mL Maalox Plus alone (n =10) for the course of 4 days, without food.

Patients underwent intensive pharmacokinetic sampling pre-dose and at hours 1, 2, 3, 4, 6, 8, 10, and 12 post-dose. The plasma concentrations of raltegravir were quantified by High-performance liquid chromatography-mass spectrometry (HPCL-MS/MS), “with a lower and upper limit of quantification of 5 and 5000 ng/L, respectively,” the authors wrote.

The geometric mean (GM) of maximum concentrations (Cmax) of raltegravir alone were recorded at 1586 ng/mL (coefficient of variation [CV], 96%), with the concentration post-dose (C12) and time to maximum concentration (Tmax) recorded as 27.92 ng/mL (CV, 71%) and 2.46 hours (CV, 33%), respectively. The area under the concentration-time curve over 12 hours (AUC0-12) was measured as 5150 ng.h/mL (CV, 85%).

Raltegravir concentrations and pharmacokinetic parameters for the 12-hour dosing interval were impacted most greatly by sodium bicarbonate. The 1-g dose increased the Cmax by 1669 ng/mL (CV, 66%; GM ratio, 2.07; 95% CI, 1.00–4.30), the C12 by 11.9 ng/mL (CV, 90%; GM ratio, 1.35; 95% CI, 0.95–1.91), and the AUC0-12 by 4814 ng.h/mL (CV, 61%; GM ratio, 1.96; 95% CI, 1.04–3.72). The Tmax was lowered by 0.31 hours (CV, 35%; GM ratio, 0.83; 95% CI, 0.66–1.04).

All other combinations—the multivitamin, Maalox Plus alone, and Maalox Plus with raltegravir—negatively impacted the absorption of raltegravir in most measurements. Maalox Plus alone did increase the Cmax by 42 ng/mL (CV, 91%; GM ratio, 0.95; 95% CI, 0.53–1.69) and lowered the Tmax by 1.04 hours (CV, 44%; GM ratio, 0.58; 95% CI, 0.43–0.78), but did not impact AUC0-12 or C12 positively. Both the multivitamin and the Maalox Plus with raltegravir also decreased time to max concentration by 0.35 hours (CV, 49%; GM ratio, 0.85; 95% CI, 0.68–1.05) and 0.14 (CV, 45%; GM ratio, 0.93; 95% CI, 0.68–1.28), respectively.

“Surprisingly, vitamins did not significantly affect the PK of RAL even though multivitamins and iron-containing supplements are known to reduce the bioavailability of other integrase inhibitors,” Reynolds and colleagues wrote. “Further study into the effect of multivitamins on raltegravir is warranted.”

“Assuming a gastric retention time of 2-4 h, 3 arms (sodium bicarbonate, Maalox Plus +/- 2 h) achieved the optimal gastric pH (6-8) for RAL solubility 2 whereas this was only achieved later (more distally) in the RAL alone or RAL + vitamins arms,” they added.

Levels of ­­pH were higher in all arms compared to raltegravir save for sodium bicarbonate at hour 8 and the multivitamin at hours 1–8. By hour 12, pH levels were higher with all arms compared to raltegravir.

“In conclusion, not all antacids influence the pharmacokinetics of raltegravir in the same way,” they wrote. “Raltegravir exposure was approximately doubled by sodium bicarbonate, whereas aluminum/magnesium hydroxide did not exhibit this effect.”

The study, “The Effect of Antacids and Multivitamins on Raltegravir,” was presented in a poster at the 25th Conference on Retroviruses and Opportunistic Infections (CROI), in Boston, Massachusetts.

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