Single- and multiple-dose pharmacokinetics and safety of pimodivir, a novel, non-nucleoside polymerase basic protein 2 subunit inhibitor of the influenza A virus polymerase complex, and interaction with oseltamivir: a Phase 1 open-label study in healthy volunteers

Abstract

Aims: The aim of this study was to 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 one of six cross-over treatment sequences, each comprising administration of oseltamivir 75 mg or pimodivir 600 mg or combination thereof 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 C_max of pimodivir by 31% (90% CI: 0.92-1.85) with no change in C_min or AUC_12h . 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 C_max and AUC_12h , respectively, between Day 1 and Day 10. The most frequently reported treatment-emergent adverse event was diarrhoea (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.

Keywords: combination; drug-drug interaction; oseltamivir; pharmacokinetics; pimodivir; safety.

Figure 1

Study design SEQ, Sequence.Treatment A: Pimodivir 600 mg b.i.d. on Days 1–4, followed by a single dose in the morning on Day 5; Treatment B: Oseltamivir 75 mg b.i.d. on Days 1–4, followed by a single dose in the morning on Day 5; Treatment C: Pimodivir 600 mg b.i.d. + oseltamivir 75 mg b.i.d. on Days 1–4, followed by a single dose of both the drugs in the morning on Day 5

Figure 2

Mean ± standard deviation plasma concentration‐time profile of pimodivir after administration of pimodivir 600 mg twice daily alone and in combination with oseltamivir 75 mg twice daily on Day 5 (Part 1)

Figure 3

Mean ± standard deviation plasma concentration‐time profiles of pimodivir on Day 1 and on Day 10 after administration of pimodivir 600 mg b.i.d. on Days 1–9, followed by a single dose of pimodivir 600 mg on Day 10 (Part 2)

Figure 4

Mean ± standard deviation plasma concentration‐time profile of A) oseltamivir and B) oseltamivir carboxylate after administration of oseltamivir 75 mg twice daily alone and in combination with pimodivir 600 mg twice daily on Day 5 (Part 1)