AIM:

Evaluate the drug-drug interaction between pimodivir, a novel, non-nucleoside polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A virus polymerase complex, and oseltamivir, to assess the feasibility of this combination therapy. Furthermore, single- and multiple-dose pharmacokinetics and safety of pimodivir in healthy volunteers were assessed.

METHODS:

In Part 1 of this open-label phase 1 study, healthy volunteers (n=18) were randomized to 1 of 6 cross-over treatment sequences, each comprising of oseltamivir 75-mg or pimodivir 600-mg or combination administered twice-daily on days 1-4, followed by a single morning dose on day 5. Between each treatment session, there was a minimum 5-day washout period. In Part 2, healthy volunteers (n=16) randomly received pimodivir 600-mg or placebo (3:1) twice-daily on days 1-9, followed by a single morning dose on day 10. Pharmacokinetics of pimodivir, oseltamivir and oseltamivir carboxylate; and safety were assessed.

RESULTS:

In Part 1, co-administration of pimodivir with oseltamivir increased the Cmax of pimodivir by 31% (90%CI: 0.92-1.85) with no change in Cmin orAUC12h . Pimodivir had no effect on oseltamivir or oseltamivir carboxylate pharmacokinetics. In Part 2, after single- and multiple-dose administration of pimodivir, there was a 1.2- and 1.8-fold increase in Cmax and AUC12h , respectively, between day 1 and 10. The most frequently reported treatment-emergent adverse event was diarrhea (n=7 each in Part 1 and 2).

CONCLUSION:

Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug-drug interactions. No safety concerns were identified with pimodivir 600-mg twice-daily alone or in combination with oseltamivir 75-mg twice-daily.