Determination of the Optimal Single Dose Treatment for Acoziborole, a Novel Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Study

2.1 Participants and Procedures

This study was conducted in accordance with the Declaration of Helsinki, French Huriet law (No. 2004-806), and Good Clinical Practice guidelines [16]. The protocol and amendments were approved by the Committee of Protection of Persons (Paris, France) and by the national competent authority (Agence Nationale de Sécurité du Médicament). Written informed consent was obtained from all participants. Details of study design and analytical methods employed are provided in Online Resource 1. Healthy male volunteers of sub-Saharan origin aged 18–45 years with a body mass index of 18–28 kg/m2 living in France were eligible for inclusion. Exclusion criteria included history of gastrointestinal (GI) disturbances, or a positive drug screening test.

2.2 Study Drugs

The interventional product acoziborole was administered in either 20 mg or 80 mg capsules with matching placebo (Penn Pharma, Tredegar, UK) or in 40 mg or 160 mg tablets (Patheon Pharmaceutical Development, Swindon, UK). Activated charcoal (Toxicarb®) was used in oral suspension (20 g/100 mL). The 20-mg starting dose in the initial SAD study was based on the 15 mg/kg/day no observed adverse effect level determined in 4-week toxicity studies in rat and dog.

2.3 Design of Studies

The study was initially designed in three parts: safety and tolerability of oral single ascending doses of acoziborole (I), food effect (II), and safety and tolerability of oral multiple ascending doses (III). However, after the lowest dose of acoziborole (20 mg), it was found that the half-life in human (t1/2 > 400 h) was longer than predicted from preclinical data. Part I was suspended while additional preclinical pharmacokinetic studies in dogs, including charcoal-block methodology to evaluate the adsorption on charcoal and bile-duct cannulation, were conducted that highlighted mild enterohepatic recirculation of acoziborole. The protocol was amended as presented in Table 1 and a Safety Review Committee (SRC) constituted to oversee ascending-dose studies.

Table 1 Design of the study2.4 Study Protocol

Part I was a randomised, double-blind, within-cohort placebo-controlled SAD study of oral doses of acoziborole ranging from 20 to 1200 mg in capsule or tablet form, to determine the safety and tolerability of the drug. All cohorts, except 1 and 9, also received once-daily activated charcoal (60 g) in oral suspension (300 mL) for 7 days starting from Day 5. For Cohort 1, blood samples were taken up to 168 h post-dose; for Cohorts 2–14, blood samples were collected up to 240 h and then at every ambulatory visit. Cerebrospinal fluid (CSF) was collected on Day 5 in cohorts 7 and 8. Participants were monitored for adverse events (AEs), physical signs, vital signs, electrocardiogram (ECG) findings, and changes in clinical laboratory tests (haematology, biochemistry, and urinalysis). Quintuplicate ECGs were averaged from 24-h continuous ECG Holter recordings taken for cohorts 7–14 on up to 3 separate days. Triplicate ECGs were recorded in cohorts 9 and 12–14 on three separate days and five follow-up visits. Safety and plasma pharmacokinetic (PK) data from Day 15 post-dose were reviewed in a blinded fashion by the SRC prior to administration of the next dose. Blood samples for plasma PK analysis were collected over a follow-up period of 6 months after the end-of-study, or until the plasma concentration of acoziborole was below the level of quantification (BLQ).

Parts II (food effect) and III (multiple dose escalation) were cancelled following the first dose in part one due to the long half-life of acoziborole in healthy volunteers.

Part IV was an intermediate open-label pharmacokinetic study to assess the effect of activated charcoal on the plasma concentration of acoziborole, following the results of the bile-duct cannulation in dogs. Two cohorts of three participants received charcoal 24 h after administration of a single oral dose of 20 mg acoziborole in capsule form. Cohort 1 received 60 g activated charcoal 10 minutes before breakfast for seven days. Cohort 2 received 20 g activated charcoal three times daily 10 minutes before each meal for 7 days. Blood samples were collected up to 192 h post-dose for PK analysis. Participants were monitored as in part I. Data were reviewed by the SRC to determine an adapted treatment schedule of acoziborole with charcoal to allow resumption of part I.

Part VI was a complementary open-label study in two cohorts of six participants to evaluate the bioavailability of acoziborole in tablet compared with capsule form (part I). Each cohort received a single dose of either 40 or 160 mg acoziborole in tablet form. To explore the impact of high-dose activated charcoal on acoziborole pharmacokinetics, both cohorts received 50 g activated charcoal starting on Day 5 in the morning, and every 4 h for 3 days, and one single dose of charcoal on follow-up visits. The same monitoring was applied as in part I.

Levels of acoziborole and its metabolite SCYX-3109 were determined in plasma and cerebrospinal fluid (CSF). Details of treatment duration, dosage regimen, criteria for evaluation, and sample (blood, urine, CSF) collection are given on page 4 of online resource 1.

2.5 Pharmacokinetic Analysis

Levels of SCYX-7158 and its metabolite SCYX-3109 were determined in plasma and analysed on a Kinetex C18, 2.6 µm, 50 × 3.0 mm I.D. column using a validated liquid chromatography–tandem mass spectrometry (LCMS/MS) method. In lithium heparinised plasma, the quantification limit of SCYX-7158 and SCYX-3109 was 0.25 ng/mL and 10 ng/mL, respectively.

Pharmacokinetic parameters for acoziborole and its metabolite SCYX-3109 were estimated using non-compartmental methods (Phoenix WinNonlin® software, version 6.3, Pharsight Corporation, Mountain View, CA, USA). The plasma pharmacokinetic parameters studied were: maximum plasma concentration (Cmax); time to reach Cmax (tmax); time to the start of absorption (tlag); elimination rate constant (ke), determined by log-linear regression using at least three time points on the terminal phase including the last time point and excluding Cmax; terminal elimination half-life (t1/2), determined by linear regression using at least three time points; area under the plasma concentration–time curve (AUC) from time zero to 96 h post-dose (AUC0–96) before the administration of activated charcoal, AUC from time zero to the last measurable concentration (AUC0–t), and AUC and from time zero to infinity (AUC0–∞), all determined by a linear trapezoidal method. Free fraction of the drug in plasma was calculated using the ratio of the free plasma concentration to the total plasma concentration, multiplied by 100. The fraction of the drug in CSF was calculated using the ratio of the CSF concentration to the total plasma concentration, multiplied by 100.

2.6 Statistical Analysis

All plasma concentrations were summarised by dose level or treatment. The derived PK parameters were listed by participant and summarised by dose level or treatment and day where appropriate. Similar descriptive statistics were presented for acoziborole plasma free fraction concentrations by dose level. Moreover, ratios of each free fraction concentration to the matching plasma concentration were calculated and similar descriptive concentrations were presented by dose level.

In part I, AUC0–96 and Cmax values were analysed for dose proportionality using analysis of variance techniques, and acoziborole concentrations in CSF were summarised by dose level. Descriptive statistics were performed in part IV. In part VI, the relative bioavailability between the capsule and the tablet formulation was assessed by comparing the participants receiving the new tablet formulation at doses of 40 and 160 mg, to participants receiving the same doses using the capsule formulation in part I. The comparison was performed on Cmax and AUC0–96, which were dose-normalised, log-transformed, and evaluated using a one-way analysis of variance, including a factor for formulation. The difference between formulations (tablet and capsule) was calculated with its 90% CI.

Populations used for the analyses are summarised in Table 2, and include:

Table 2 Participants included and analysed

Safety Analysis Set all randomised participants, who received a dose of the study drug and have a post-randomisation safety evaluation. Participants were analysed according to the treatment schedule they actually received.

Pharmacokinetic Analysis Set all participants who completed the study and did not have any protocol deviation or events implying a bias for the PK evaluation.

Replicate ECG analysis set (part I) all participants from the safety population with reliable replicate ECG data.

All statistical analyses were performed using SAS® software, version 9.2 (SAS Institute Inc., Cary, NC, USA).

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