Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir.
OBJECTIVE
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once-daily regimen (QD) at a dose of 1200 mg is under development. The effect of calcium carbonate and magnesium/aluminium hydroxide antacids on the pharmacokinetics of a 1200 mg dose of raltegravir was assessed in this study.


METHODS
An open-label, four-period, four-treatment, fixed-sequence study in 20 HIV-infected patients was performed. Patients needed to be on raltegravir as part of a stable treatment regimen for HIV, and upon entry into the trial received 5 days of 1200 mg raltegravir as pretreatment, before they entered the four-period study: 1200 mg of raltegravir alone (period 1), calcium carbonate antacid as TUMS®Ultra Strength (US) 1000 and 1200 mg raltegravir given concomitantly (Period 2), magnesium/aluminium hydroxide antacid as 20 ml MAALOX®Maximum Strength substitute MS given 12 h after administration of 1200 mg raltegravir (period 3), and calcium carbonate antacid as TUMS®US 1000 given 12 h after administration of 1200 mg raltegravir (period 4). Patients received their dose of 1200 mg QD raltegravir during the intervals between periods to re-establish steady state. AUC0-24, C24, Cmaxand Tmaxwere calculated from the individual plasma concentrations of 1200 mg QD raltegravir after administration alone or with a calcium carbonate antacid or with a staggered dose of a calcium carbonate antacid or magnesium/aluminium hydroxide antacid. Adverse events, in addition to laboratory safety tests (haematology, serum chemistry and urinalysis), 12-lead electrocardiograms and vital signs were assessed.


RESULTS
All treatments were well tolerated in the study. Metal-cation antacids variably affected the pharmacokinetics of 1200 mg QD raltegravir. When calcium carbonate antacid was given with 1200 mg raltegravir concomitantly, the geometric mean ratio (GMR) and its associated 90% confidence interval (90% CI) for AUC0-24, Cmaxand C24 hwere 0.28 (0.24, 0.32), 0.26 (0.21, 0.32) and 0.52 (0.45, 0.61), respectively. When calcium carbonate antacid and magnesium/aluminium hydroxide were given 12 h after raltegravir 1200 mg QD dosing, the GMR (90% CI) values for AUC0-24and Cmaxwere 0.90 (0.80, 1.03), 0.98 (0.81, 1.17), and 0.86 (0.73, 1.03), 0.86 (0.65, 1.15), respectively. However, significant reduction in the trough concentrations of raltegravir was observed: C24 h0.43 (0.36, 0.51) in the presence of calcium carbonate antacids and 0.42 (0.34, 0.52) in presence of magnesium/aluminium hydroxide, respectively.


CONCLUSIONS
Overall, the use of metal-cation antacids with 1200 mg QD raltegravir is not recommended.
Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA. rajesh_krishna@merck.com.
Rajesh
R
Krishna
Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
Lilly
L
East
Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
Patrick
P
Larson
Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
Chandni
C
Valiathan
Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
Kristin
K
Butterfield
QPS MRA (Miami Clinical Research), Miami, FL, USA.
Yang
Y
Teng
QPS MRA (Miami Clinical Research), Miami, FL, USA.
Martha
M
Hernandez-Illas
D000284:Administration, Oral; D000328:Adult; D000536:Aluminum Hydroxide / Q000008:administration & dosage* / Q000009:adverse effects; D000863:Antacids / Q000008:administration & dosage* / Q000009:adverse effects; D019540:Area Under Curve; D002119:Calcium Carbonate / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008274:Magnesium / Q000008:administration & dosage* / Q000009:adverse effects; D008276:Magnesium Hydroxide / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D019338:Polypharmacy; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000863:Antacids; D004338:Drug Combinations; D019428:HIV Integrase Inhibitors; C036487:aluminium hydroxide, magnesium carbonate drug combination; D000068898:Raltegravir Potassium; D000536:Aluminum Hydroxide; D002119:Calcium Carbonate; D008274:Magnesium; D008276:Magnesium Hydroxide
aluminium and magnesium hydroxide; calcium carbonate; interaction; once-daily; pharmacokinetics