A Phase 1 interventional study of Acoziborole and Midazolam in Trypanosomiasis, African, sponsored by Drugs for Neglected Diseases. Completed at 1 site in Malaysia. Open to male participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-07-17.
Sponsored by Drugs for Neglected Diseases · Phase 1, Interventional, and Other
To assess Drug drug interactions between Acoziborole and Dextromethorphan and Midazolam in healthy male volunteers.
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.
Exclusion Criteria:
Drug drug interaction Dextromethorphan and Midazolam administrations * Dextromethorphan 15 mg syrup in fasted condition Period 1: Single oral dose of 15 mg administered on Day 1 * Midazolam 5 mg syrup in fasted condition Period 1: Single oral dose of 5 mg administered on Day 8
Drug: Midazolam · Drug: Dextromethorphan
Drug drug interaction Acoziborole, Dextromethorphan and Midazolam administrations * Acoziborole 960 mg (three tablets of 320 mg) for oral route in fasted condition Period 2: single oral administration on Day 12 * Dextromethorphan 15 mg syrup in fasted condition Period 2: Single oral dose of 15 mg administered on Day 14 * Midazolam 5 mg syrup in fasted condition Period 2: Single oral dose of 5 mg administered on Day 21
Drug: Acoziborole · Drug: Midazolam · Drug: Dextromethorphan
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
To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (Cmax) of midazolam as a probe substrate for CYP3A4 (induction)
Midazolam Cmax, plasma concentration
Time frame: Up to 72 hours post drug administration
To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (Cmax) of dextromethorphan as a probe substrate for CYP2D6 (inhibition).
Dextromethorphan Cmax, plasma concentration
Time frame: Up to 72 hours post drug administration
To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters ( AUC0-t) of midazolam as a probe substrate for CYP3A4 (induction)
Midazolam AUC0-t (plasma concentration) of Period 1 and Period 2.
Time frame: Up to 72 hours post drug administration
To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters ( AUC0-t) of dextromethorphan as a probe substrate for CYP2D6 (inhibition).
Dextromethorphan AUC0-t (plasma concentration) of Period 1 and Period 2.
Time frame: Up to 72 hours post drug administration
To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (AUC0-24) of midazolam as a probe substrate for CYP3A4 (induction)
Midazolam AUC0-24 (plasma concentration) of Period 1 and Period 2
Time frame: Up to 72 hours post drug administration
To assess the effect of single dose of acoziborole on pharmacokinetics (PK) parameters (AUC0-24) of dextromethorphan as a probe substrate for CYP2D6 (inhibition).
Dextromethorphan AUC0-24 of Period 1 and Period 2.
Time frame: Up to 72 hours post drug administration
To evaluate the clinical and laboratory safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Frequency and cumulative incidence of treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) from time of first IMP administration (dextromethorphan on Day 1 in Period 1) to EoS visit.
Time frame: Up to End of Study Visit, Day 31
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: Height
Vital signs for safety monitoring: Height (cm)
Time frame: Baseline
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: weight
Vital signs for safety monitoring: Weight (Kgs)
Time frame: Baseline and End of Study (Day 28 to Day 31)
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: Sistolic and Diastolic BP
Vital signs for safety monitoring: Sistolic BP and Diastolic BP (mmHg)
Time frame: Up to End of Study (Day 28 to Day 31)
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: respiratory rate
Vital signs for safety monitoring: respiratory rate (breaths/minute)
Time frame: Up to End of Study (Day 28 to Day 31)
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: ear body temperature
Vital signs for safety monitoring: ear body temperature (°C).
Time frame: Up to End of Study (Day 28 to Day 31)
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: 12-lead ECG Heart Rate
12-lead electrocardiogram (ECG) Heart Rate for safety monitoring purpose. ECGs for safety purpose will be performed using the internationally recognized 12 leads with devices recorder after 10 min rest in supine position and before any blood draws. ECG will be recorded at a standard paper speed of 25 mm/s and gain of 10 mm/mV. Print-outs for each ECG will include: date, time, initials of the Investigator or its deputy. The ECGs will be performed in 6 × 2 leads during this study. The corresponding source data will consist of the ECG recorder paper print-outs. The ECGs will be read and analysed by the Investigator.
Time frame: Up to Day 22
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: 12-lead ECG RR Interval
12-lead electrocardiogram (ECG) RR Interval for safety monitoring purpose. ECGs for safety purpose will be performed using the internationally recognized 12 leads with devices recorder after 10 min rest in supine position and before any blood draws. ECG will be recorded at a standard paper speed of 25 mm/s and gain of 10 mm/mV. Print-outs for each ECG will include: date, time, initials of the Investigator or its deputy. The ECGs will be performed in 6 × 2 leads during this study. The corresponding source data will consist of the ECG recorder paper print-outs. The ECGs will be read and analysed by the Investigator.
Time frame: Up to Day 22
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: 12-lead ECG QRS duration
12-lead electrocardiogram (ECG) QRS duration for safety monitoring purpose. ECGs for safety purpose will be performed using the internationally recognized 12 leads with devices recorder after 10 min rest in supine position and before any blood draws. ECG will be recorded at a standard paper speed of 25 mm/s and gain of 10 mm/mV. Print-outs for each ECG will include: date, time, initials of the Investigator or its deputy. The ECGs will be performed in 6 × 2 leads during this study. The corresponding source data will consist of the ECG recorder paper print-outs. The ECGs will be read and analysed by the Investigator.
Time frame: Up to Day 22
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: 12-lead ECG QT-interval
12-lead electrocardiogram (ECG) QT-interval for safety monitoring purpose. ECGs for safety purpose will be performed using the internationally recognized 12 leads with devices recorder after 10 min rest in supine position and before any blood draws. ECG will be recorded at a standard paper speed of 25 mm/s and gain of 10 mm/mV. Print-outs for each ECG will include: date, time, initials of the Investigator or its deputy. The ECGs will be performed in 6 × 2 leads during this study. The corresponding source data will consist of the ECG recorder paper print-outs. The ECGs will be read and analysed by the Investigator.
Time frame: Up to Day 22
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: 12-lead ECG QTcF-interval
12-lead electrocardiogram (ECG) QTcF-interval for safety monitoring purpose. ECGs for safety purpose will be performed using the internationally recognized 12 leads with devices recorder after 10 min rest in supine position and before any blood draws. ECG will be recorded at a standard paper speed of 25 mm/s and gain of 10 mm/mV. Print-outs for each ECG will include: date, time, initials of the Investigator or its deputy. The ECGs will be performed in 6 × 2 leads during this study. The corresponding source data will consist of the ECG recorder paper print-outs. The ECGs will be read and analysed by the Investigator.
Time frame: Up to Day 22
To evaluate the clinical safety of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone: 12-lead ECG PR Interval
12-lead electrocardiogram (ECG) PR Interval for safety monitoring purpose. ECGs for safety purpose will be performed using the internationally recognized 12 leads with devices recorder after 10 min rest in supine position and before any blood draws. ECG will be recorded at a standard paper speed of 25 mm/s and gain of 10 mm/mV. Print-outs for each ECG will include: date, time, initials of the Investigator or its deputy. The ECGs will be performed in 6 × 2 leads during this study. The corresponding source data will consist of the ECG recorder paper print-outs. The ECGs will be read and analysed by the Investigator.
Time frame: Up to Day 22
To evaluate the laboratory safety, Hemoglobin, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, hemoglobin, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, Red blood cell count, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, Red blood cell count, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, hematocrit, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, hematocrit, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, white blood cells count, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, white blood cells count, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, mean corpuscular volume, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, mean corpuscular volume, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, mean corpuscular hemoglobin, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, mean corpuscular hemoglobin, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, red cell distribution width, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, red cell distribution width, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, neutrophils, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, neutrophils, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, lymphocytes, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, lymphocytes, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, monocytes, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, monocytes, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, eosinophils, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, eosinophils, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, basophils, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, basophils, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, platelet count, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, platelet count, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, ALP, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, ALP, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, ALT, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, ALT, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, AST, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, AST, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, GGT, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, GGT, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, CPK, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, CPK, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, total bilirubin, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, total bilirubin, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, direct bilirubin, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, direct bilirubin, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, indirect bilirubin, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, indirect bilirubin, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, total protein, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, total protein, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, albumin, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, albumin, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, creatinine, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, creatinine, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, eGFR, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, eGFR, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, fasting glucose, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, fasting glucose, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, urea, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, urea, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, calcium, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, calcium, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, Na+, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, Na+, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, K+, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, K+, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, Cl-, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, Cl-, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the laboratory safety, bicarbonates, of acoziborole co-administered with midazolam and dextromethorphan as compared to administration of midazolam and dextromethorphan alone.
Laboratory safety assessments, bicarbonates, from baseline to EoS visit.
Time frame: Up to Day 22
To evaluate the Tmax of midazolam when co-administered with acoziborole.
Time to maximum observed plasma concentration (tmax) for midazolam
Time frame: Up to Day 22
To evaluate the Tmax of dextromethorphan when co-administered with acoziborole.
Time to maximum observed plasma concentration (tmax) for dextromethorphan.
Time frame: Up to Day 22
To evaluate the apparent terminal elimination half-life of midazolam when co-administered with acoziborole.
Apparent terminal elimination half-life (t½) for midazolam
Time frame: Up to Day 22
To evaluate the apparent terminal elimination half-life of dextromethorphan, when co-administered with acoziborole.
Apparent terminal elimination half-life (t½) for dextromethorphan.
Time frame: Up to Day 22
To evaluate the AUC0-∞ of midazolam when co-administered with acoziborole.
AUC0-∞ for midazolam
Time frame: Up to Day 22
To evaluate the AUC0-∞ of dextromethorphan when co-administered with acoziborole.
AUC0-∞ for dextromethorphan.
Time frame: Up to Day 22
To evaluate the Acoziborole plasma concentrations when co-administered with midazolam and dextromethorpharm
Acoziborole plasma concentrations
Time frame: Up to Day 22
To evaluate the Cmax of midazolam's metabolite, 1'hydroxy-midazolam, when co-administered with acoziborole.
1'-hydroxy-midazolam: Cmax for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the Tmax of midazolam's metabolite, 1'hydroxy-midazolam, when co-administered with acoziborole.
1'-hydroxy-midazolam: tmax for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the AUC0-24 of midazolam's metabolite, 1'hydroxy-midazolam, when co-administered with acoziborole.
1'-hydroxy-midazolam:AUC0-24 for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the AUC0-t of midazolam's metabolite, 1'hydroxy-midazolam, when co-administered with acoziborole.
1'-hydroxy-midazolam: AUC0-t for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the t½ of midazolam's metabolite, 1'hydroxy-midazolam, when co-administered with acoziborole.
1'-hydroxy-midazolam: t½ for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the AUC0-∞ of midazolam's metabolite, 1'hydroxy-midazolam, when co-administered with acoziborole.
1'-hydroxy-midazolam: AUC0-∞ for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the Cmax of dextromethorphan's metabolite, dextrorphan (DXO), when co-administered with acoziborole.
DXO: Cmax for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the Tmax of dextromethorphan's metabolite, dextrorphan (DXO), when co-administered with acoziborole.
DXO: tmax for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the AUC0-24 of dextromethorphan's metabolite, dextrorphan (DXO), when co-administered with acoziborole.
DXO: AUC0-24 for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the AUC0-t of dextromethorphan's metabolite, dextrorphan (DXO), when co-administered with acoziborole.
DXO: AUC0-t for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the t½ of dextromethorphan's metabolite, dextrorphan (DXO), when co-administered with acoziborole.
DXO: t½ for Period 1 and Period 2.
Time frame: Up to Day 22
To evaluate the AUC0-∞ of dextromethorphan's metabolite, dextrorphan (DXO), when co-administered with acoziborole.
DXO: AUC0-∞ for Period 1 and Period 2.
Time frame: Up to Day 22
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Drugs for Neglected Diseases