Raltegravir (RAL) absorption is influenced by antacids and gastrointestinal pH but it is unclear which of these mechanisms has the predominant effect on pharmacokinetic (PK) variability. We sought to characterise the effect of separate metals on the PK of RAL in healthy volunteers, and to determine the role of intestinal pH in this interaction.
Open label, randomised, 3 arm, 5 phased controlled healthy volunteer study. Participants received a single dose (sd) of RAL (400 mg tablet), followed by RAL plus Maalox Plus (30 ml), sodium bicarbonate (1 g), Forceval (1tablet) or Maalox Plus (30 ml) 2 h prior to dosing without food, for 4 study days. The Heidelberg pH diagnostic system was used to collect gastrointestinal pH data. Blood samples and pH measurements were collected at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h post dose. Plasma RAL concentrations were determined by validated LC-MS/MS, and PK parameters were estimated (WinNonLin). The primary endpoint was a change in AUC, C12h, CMAX, or TMAX. Secondary endpoints were safety and tolerability of combinations, and correlation of pH with RAL PK.
Of fifteen participants randomised, three withdrew due to adverse events and two withdrew consent. All combinations were well-tolerated with one serious clinical event reported. A significant increase in RAL GMR (90 % CI) AUC0-12 (1.96; 1.04 – 3.72) and CMAX (2.07; 1.00 – 4.30) when RAL was administered with sodium bicarbonate was observed. A significant decrease in TMAX (GMR 0.58; 90 % CI 0.43 – 0.78) was seen when Maalox Plus was administered at the same time as RAL which was not observed when the antacid was taken 2 h prior to RAL. The multivitamin, Forceval, did not significantly affect the PK of RAL. PK data shown below are in keeping with previous studies. Optimal pH (6 to 8) for RAL solubility was achieved on administration of sodium bicarbonate or Maalox Plus (+/- 2 h).
A significant increase in absorption of RAL in the presence of antacid lacking divalent cations (sodium bicarbonate) was observed which is likely to relate to the unopposed ‘boosting’ effect of a raised pH upon absorption and the known pH-dependent solubility of RAL. In conclusion, not all antacids influence the PK of RAL in the same way. RAL exposure was approximately doubled by sodium bicarbonate, whereas aluminium/magnesium hydroxide did not exhibit this effect.