Lack of pharmacokinetic interaction between the oral anti-influenza neuraminidase inhibitor prodrug oseltamivir and antacids.
OBJECTIVE
Oseltamivir is an oral ester prodrug of its active metabolite Ro 64-0802, a potent and selective neuraminidase inhibitor of the influenza virus. The object of this study was to evaluate whether the oral absorption of oseltamivir was reduced in the presence of two main classes of antacid, Maalox(R) suspension (containing magnesium hydroxide and aluminium hydroxide) and Titralac(R) tablets (containing calcium carbonate).


METHODS
Twelve healthy volunteers completed a randomized, single dose, three-period crossover study. Each volunteer received in a fasted state, 150 mg oseltamivir alone (Treatment A), 150 mg oseltamivir with a 20 ml Maalox suspension (Treatment B), and 150 mg oseltamivir with four Titralac tablets (Treatment C), with 7-10 days washout in between treatments. Plasma and urine concentrations of oseltamivir and Ro 64-0802 were measured using a validated h.p.l.c./MS/MS assay. Pharmacokinetic parameters were calculated for oseltamivir and Ro 64-0802. Since antacids are locally acting drugs and generally not expected to be absorbed substantially into the systemic system, no plasma or urine concentrations of antacids were measured.


RESULTS
Bioequivalence was achieved for the primary pharmacokinetic parameters Cmax and AUC(0, infinity ) of Ro 64-0802 following administration of oseltamivir with either Maalox suspension or Titralac(R) tablets vs administration of oseltamivir alone. The bioavailability (90% confidence intervals) of Ro 64-0802 following administration of oseltamivir together with Maalox suspension vs administration of oseltamivir alone, was 90% (83.6, 96.9%) for C(max) and 94.1% (91.4, 96.9%) for AUC(0, infinity); similarly, for Titralac tablets, the equivalent values were 95.1% (88.3, 102%) for C(max) and 94.7% (91.9, 97.5%) for AUC(0, infinity).


CONCLUSIONS
The coadministration of either Maalox suspension or Titralac tablets with oseltamivir has no effect on the pharmacokinetics of either oseltamivir or Ro 64-0802, and conversely, there is no evidence that coadministration with oseltamivir has an effect on the safety and tolerability of either Maalox suspension or Titralac tablets. There was no pharmacokinetic interaction between oseltamivir with either antacid, demonstrating that the oral absorption of oseltamivir was not impaired in the presence of antacids containing magnesium, aluminium or calcium.
Snell
Paul
P
Department of Research and Development, Roche Products Ltd, Welwyn Garden City, Hertfordshire, UK. paul.snell@roche.com
Oo
Charles
C
Dorr
Al
A
Barrett
Joanne
J
D000081:Acetamides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000328:Adult; D000536:Aluminum Hydroxide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D000863:Antacids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002119:Calcium Carbonate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy / Q000378:metabolism; D008276:Magnesium Hydroxide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D053139:Oseltamivir; D011355:Prodrugs; D013607:Tablets; D013810:Therapeutic Equivalency
D000081:Acetamides; D000863:Antacids; D000998:Antiviral Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011355:Prodrugs; C403132:Ro 64-0802; D013607:Tablets; D053139:Oseltamivir; C013591:aluminum hydroxide, magnesium hydroxide, drug combination; D000536:Aluminum Hydroxide; D002119:Calcium Carbonate; D008276:Magnesium Hydroxide