Clinical trial NCT00931697: Study to Investigate the Safety, Tolerability and Pharmacokinetics of AD 452 [(+)-Mefloquine] Compared With Racemic Mefloquine
Official title: A Phase I Randomised, Double-Blind Study to Investigate the Safety, Tolerability and Pharmacokinetics of AD 452 [(+)-Mefloquine] Compared With Racemic Mefloquine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: Mefloquine
Malaria
(+) Mefloquine
Pharmacokinetics
Lead sponsor: Treague Ltd
Sponsor class: INDUSTRY
Collaborators: name: Medicines for Malaria Venture
First posted: 2009-07-02
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: Following single dose
Secondary outcomes:
measure: The comparative pharmacokinetics of AD 452 [(+)mefloquine] and racemic mefloquine
timeFrame: Single dose
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: LCG Bioscience
state: Cambridgeshire
Study officials:
affiliation: Treague Ltd
name: Robert Tansley, MBBS
role: STUDY_DIRECTOR
References: