Study to Investigate the Safety, Tolerability and Pharmacokinetics of AD 452 [(+)-Mefloquine] Compared With Racemic Mefloquine

A Phase I Randomised, Double-Blind Study to Investigate the Safety, Tolerability and Pharmacokinetics of AD 452 [(+)-Mefloquine] Compared With Racemic Mefloquine

Mefloquine is a quinolinemethanol antimalarial that is effective as therapy and prophylaxis for all species of malaria infecting humans, including multi-drug resistant Plasmodium falciparum. The marketed anti-malaria drug consists of two enantiomers of mefloquine.

Mefloquine's clinical utility has been impaired by its association with neuropsychiatric side effects. The pharmacological basis of mefloquine's side effects is not known but two of the most reported hypotheses relate to its action on (i) the adenosine receptor and (ii) its effect on the cholinesterase enzyme. For both of these mechanisms, there is a significant stereoselective activity of the two enantiomers. In vitro studies show that the (-) isomer is 50-100 fold more potent towards adenosine receptors compared with the (+) isomer. In addition, (-)-mefloquine has considerably more anti-cholinesterase activity. It has therefore been hypothesised that (+)-mefloquine may have a better central nervous system (CNS) safety profile compared with either the racemate or (-)-mefloquine.

This study is a randomized, ascending dose, double-blind, active and placebo-controlled, parallel group study in healthy male and female volunteers designed to investigate this hypothesis and to describe the comparative pharmacokinetics of the racemate and the single enantiomer.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: AD 452 (+) mefloquine; Drug: Racemic Mefloquine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB23 2TN
      • LCG Bioscience

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A BMI of between 19 and 28
• Negative urine drugs of abuse and breath alcohol test
• Willing to use double barrier contraception for 13 weeks after administration of study drug

Exclusion Criteria:

• Pregnant or lactating females
• Existence of any surgical or medical condition which, in the judgement of the Principal Investigator, might interfere with the absorption and disposition of the drug or with the aim of the study including clinically significant lactose intolerance
• Receipt of prescription medication within 21 days of the first study day or over the counter medication (with the exception of multi-vitamins or paracetamol) within 1 week before the planned dosing date without prior approval
• Definite or suspected personal or family history of adverse drug reaction or hypersensitivity to drugs with a chemical structure similar to AD 452
• Participation in a clinical study within the previous 12 weeks
• A history of sensitivity to antimalarial or related compounds
• Definite or suspected personal or family history of adverse drug reaction or hypersensitivity to drugs with a chemical structure similar to AD 452
• Active depression or a recent history of depression or generalised anxiety disorder
• Any personal history of psychosis or schizophrenia or other major psychiatric disorders or convulsions
• Previous exposure to racemic mefloquine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Over-encapsulated placebo to maintain blinding
Experimental: AD 452 (+) mefloquine	Drug: AD 452 (+) mefloquine; Single dose delivered as over-encapsulated tablet at ascending doses
Active Comparator: Racemic mefloquine	Drug: Racemic Mefloquine; Single dose delivered as over-encapsulated tablet at ascending dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The dose-concentration-effect relationship of AD 452 [(+)-mefloquine] for safety and toleration in comparison with that of racemic mefloquine across a range of potentially therapeutic doses and concentrations.	Following single dose

Secondary Outcome Measures

Outcome Measure	Time Frame
The comparative pharmacokinetics of AD 452 [(+)mefloquine] and racemic mefloquine	Single dose

Collaborators and Investigators

• Sponsor: Treague Ltd
• Collaborators: Medicines for Malaria Venture
• Investigators: Study Director: Robert Tansley, MBBS, Treague Ltd

Publications and helpful links

Helpful Links

• Medicines for Malaria Venture website

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): November 1, 2009
• Study Completion (Actual): November 1, 2009

Study Registration Dates

• First Submitted: June 29, 2009
• First Submitted That Met QC Criteria: June 30, 2009
• First Posted (Estimate): July 2, 2009

Study Record Updates

• Last Update Posted (Estimate): August 3, 2010
• Last Update Submitted That Met QC Criteria: July 30, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Keywords: Malaria; Pharmacokinetics; Mefloquine; (+) Mefloquine
• Additional Relevant MeSH Terms: Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Mefloquine
• Other Study ID Numbers: P-AD452-023