DDI Study of Single Oral Dose of Acoziborole With Sequential Co-administration of Midazolam and Dextromethorphan
Condition: Trypanosomiasis, African
MeSH terms: Trypanosomiasis; Trypanosomiasis, African
Study type: Interventional
Phase: Phase 1

Summary: 
      To assess Drug drug interactions between Acoziborole and Dextromethorphan and Midazolam in
      healthy male volunteers.
    

Detailed description: 
      An in silico PB-PK model was developed within the simCYP software and qualified for
      acoziborole. This study suggested strong interactions with sensitive index substrates of
      CYP2D6 and CYP3A4.To validate these PB-PK model results, an open-label, non-randomised,
      three-treatment, one-sequence, two successive periods study with at least 3-day washout
      between periods was chosen to evaluate clinically the potential impact of acoziborole on
      plasma exposure of two different sensitive CYP substrates, DXM for CYP2D6 and midazolam for
      CYP3A4.

      Acoziborole will be administered as a single dose, due to the long t1/2 of 360 h in healthy
      participants.

      The SimCYP simulations showed that the best compromise to maximize the CYP2D6 inhibition and
      minimize the CYP3A4 induction is when DXM is given 24 to 60 h after acoziborole
      administration. Therefore, dextromethorphan will be given on Day 1 (in Period 1, without
      acoziborole) and on Day 14 in Period 2 i.e. 2 days following oral administration of
      acoziborole.

      Based on the PB-PK simulations, the interaction between acoziborole and midazolam should be
      maximal around Day 8 (due to the activity CYP3A4) following acoziborole administration and
      sustained for several weeks after. Thus, midazolam will be given on Day 8 (in Period 1
      without acoziborole) and on Day 21 in Period 2 i.e. 9 days following oral single
      administration of acoziborole.
    

Intervention name(s): Acoziborole; Midazolam; Dextromethorphan
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Acoziborole 960 mg (three tablets of 320 mg) for oral route in fasted condition Period 2: single oral administration on Day 12; • Midazolam 5 mg syrup in fasted condition Period 1: Single oral dose of 5 mg administered on Day 8 Period 2: Single oral dose of 5 mg administered on Day 21; • Dextromethorphan 15 mg syrup in fasted condition Period 1: Single oral dose of 15 mg administered on Day 1 Period 2: Single oral dose of 15 mg administered on Day 14
Intervention MeSH terms: Midazolam; Dextromethorphan
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: On Period 1, participants will receive: A single oral dose of Dextromethorphan on Day and of midazolam on Day 8.
On Period 2, participants will receive: A single oral dose of acoziborole on Day 12, of dextromethorphan on Day 14, and of midazolam on Day 21.
The study duration will be approximately 8 weeks:
Screening period before the first study drug administration, Period 1 with a hospitalisation period from the day before the first dose of dextromethorphan until 24 h after the first dose of midazolam, Wash-out period: 3 days, Period 2 with a hospitalisation period from the day before the single administration of acoziborole until 24 h after the last dose of midazolam .
End of study (EoS) visit between 7-10 days after last dose of midazolam on Period 2
Masking: None (Open Label)
Primary purpose: Other