Atoguanil BA Study

NCT04866602 | Completed Phase 1

• 1 other identifier: MMV_SMC_19_02
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This trial aims to characterise the pharmacokinetic (PK) profile and estimate drug exposure from Atoguanil in comparison to Malarone®.

Conditions

Bioavailability

Keywords

Pharmacokinetics; Bioavailability; Malaria prevention; Malaria

Outcome Measures

Primary Outcomes (5)

• Ratio of maximum observed plasma concentration (Cmax) of ATV, PG and CG from Atoguanil in comparison to Malarone.

  Blood samples are collected at indicated time points to measure the maximum observed plasma concentration (Cmax) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods.

  ATV evaluation: Measured pre-dose -1 hours, then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168, 336, 504 hours post-dose. PG/CG evaluation: At pre-dose -1 then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

• Ratio of the area under the plasma concentration-time curve from time zero to last detectable plasma concentration (AUC0-t) of ATV, PG and CG for Atoguanil compared to Malarone

  Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero to last detectable plasma concentration (AUC0-t) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods

  ATV evaluation: Measured pre-dose -1 hours, then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168, 336, 504 hours post-dose. PG/CG evaluation: At pre-dose -1 then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

• Ratio of area under the plasma concentration-time curve from time zero to 72 hours (AUC0-72h), of ATV, PG and CG for Atoguanil compared to Malarone.

  Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero to 72 hours (AUC0-72h) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods

  Measured from 0 to 72 hours ATV/PG/CG evaluation: At pre-dose -1 and then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

• Ratio of the area under the plasma concentration-time curve from time zero to 168 hours (AUC0-168h) [ATV only] for Atoguanil compared to Malarone

  Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero to 168 hours (AUC0-168h) for pharmacokinetic analysis of ATV. Pharmacokinetic parameters are determined using standard non-compartmental methods.

  Measured from 0 to 168 hours (ATV) ATV evaluation: At pre-dose -1, and then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168 hours post-dose

• Ratio of the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf), of ATV, PG and CG for Atoguanil compared to Malarone

  Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods.

  ATV evaluation: Measured pre-dose -1 hours, then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168, 336, 504 hours post-dose. PG/CG evaluation: At pre-dose -1 then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

Study Arms (2)

Atoguanil

EXPERIMENTAL

Atovaquone 500 mg + Proguanil 348 mg

Drug: Atoguanil

Malarone®

ACTIVE COMPARATOR

Atovaquone 1000 mg + Proguanil HCl 400 mg

Drug: Malarone

Interventions

Atoguanil DRUG

Atovaquone + Proguanil free base:125 mg: 87 mg, 4 tablets

Also known as: Atovaquone + Proguanil

Atoguanil

Malarone DRUG

Atovaquone + Proguanil HCl: 250 mg: 100 mg, 4 tablets

Also known as: Atovaquone + Proguanil

Malarone®

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male or female (of childbearing and non-childbearing potential) aged 18 to 55 years, inclusive. Efforts will be made to ensure a reasonable gender balance.
• Satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by medical history, physical examination, vital signs and clinical laboratory evaluation (haematology, biochemistry, coagulation, and urinalysis) that is reasonably likely to interfere with the participant's participation in or ability to complete the trial as assessed by the Investigator.
• Participant has a body weight of 50 to 80 kg and a body mass index (BMI) of 18.0-25.0 kg/m2, inclusive at screening.
• All participants must comply with the contraception criteria in Section 5.5.
• Participants must agree not to donate sperm or ova from the time of the first administration of trial medication until three months after the end of the systemic exposure of the trial drug (for this trial, this is until Day 22 of Period 2).
• Participants are non-smokers (fewer than 100 lifetime cigarettes and zero cigarettes in the past 6 months).
• Participants who are able to provide written, personally signed, and dated informed consent to participate in the trial, in accordance with the ICH Good Clinical Practice (GCP) Guideline E6 (R2) (2016) and applicable regulations, before completing any trial-related procedures.
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, restrictions, and other trial procedures. Participants must be willing to complete all meals, which may contain meat (in particular, the high fat, high calorie breakfast on dosing days).
• Participants who are willing to comply with the latest site guidelines regarding COVID-19 safety precautions, measures and testing

You may not qualify if:

• Female detected to be pregnant, breast feeding or who is likely to become pregnant during the trial.
• Male participants with a female partner(s) who is (are) pregnant or lactating from the time of the administration of trial medication.
• Evidence or history of clinically significant haematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug or food allergies, anaphylaxis or other severe allergic reactions but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
• Current or relevant history of physical or psychiatric illness (in particular, anxiety disorders) that may require treatment or make the participant unlikely to fully comply with the requirements or complete the trial, or any condition that presents undue risk from the investigational product or trial procedures.
• Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease, etc.), distribution, metabolism or excretion or any food intolerance.
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of the participation in the trial may influence the result of the trial, or the participant's ability to participate in the trial.
• History of photosensitivity.
• History or clinical evidence of substance and/or alcohol abuse within the 12 months before screening. Alcohol abuse is defined as regular weekly intake of more than 14 units for males and females (using alcohol tracker http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx).
• Treatment with an investigational drug within 90 days or 5 half-lives preceding the first dose of trial medication (or as determined by the local requirement, whichever is the longer).
• Donation of blood or blood products (excluding plasma) within 90 days prior to trial medication administration.
• Has used any medication listed on the Flockhart table (http://medicine.iupui.edu/clinpharm/ddis/main-table/) that is either a moderate or strong inhibitor or inducer of CYP450 within 30 days or 5 half-lives (whichever is longer) prior to the planned first day of dosing.
• Additionally, participants must not have consumed other substances known to be potent inhibitors or inducers of CYP P450s . This includes food or drink products containing cranberry, pomegranate, star fruit, grapefruit, pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from these fruits) in the two weeks before the planned first trial drug administration.
• Has used any other prescription medication (excluding hormonal contraception, hormone replacement therapy) within 14 days or 10 half-lives (whichever is longer) prior to Day 1 of the dosing period that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating.
• Has used any over-the-counter medication (including multivitamin, herbal, or homeopathic preparations; excluding paracetamol - up to 4g paracetamol per day permitted) during the 7 days or 10 half-lives of the drug (whichever is longer) prior to Day 1 of the dosing period, that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating.
• Use of herbal supplements at least 30 days prior to the first dose of trial medication.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Richmond Pharmacology Limited: collaborator

Study Sites (1)

Richmond Pharmacology Limited

London, SE1 1YR, United Kingdom

Location

Related Publications (1)

• Kuemmerle A, Gossen D, Marx MW, Lorch U, Szramowska M, Kumar A, Singh D, Singh S, Ramachandruni H, Thankachen B, Kore S, Gaaloul ME, Borghini-Fuhrer I, Chalon S. A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil) versus atovaquone-proguanil hydrochloride (Malarone(R)) in healthy adult participants. Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec;397(12):9823-9832. doi: 10.1007/s00210-024-03245-x. Epub 2024 Jun 25.

  PMID: 38918235 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

atovaquone, proguanil drug combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Officials

• Ulrike Lorch, MD FRCA FFPM

  Richmond Pharmacology Limited

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: In Period 1, 16 participants will be enrolled and randomised to one of two treatments in a ratio of 1:1, and to the alternative treatment in Period 2, as described below: * Treatment 1: Single dose of Atoguanil . (Atovaquone 500 mg + Proguanil 348 mg administered as 4 tablets of 125 mg: 87 mg). * Treatment 2: Single dose of Malarone® . (Atovaquone 1000 mg + Proguanil HCl 400 mg administered as 4 tablets of 250 mg: 100 mg), Both doses are administered in the fed state and with 240mL of drinking water.

Study Record Dates

• First Submitted: April 20, 2021
• First Posted: April 30, 2021
• Study Start: November 17, 2021
• Primary Completion: March 18, 2022
• Study Completion: March 18, 2022
• Last Updated: May 5, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Data will be available within 6 months after study completion.
• Access Criteria: Requestors will be required to sign a Data Access Agreement.

Locations

GB (1)