malaria breakout

COMALAFIN the new antimalarial Dr. B. K. Iyer Better clarity, better outcomes

The place in therapy Is this cleared by the TFDA? Is there a need for this new antimalarial? How does this compare with Artemether + lumefantrine? Is the dosing justifiable ? Are there clinical trials on the efficacy and safety? Is there scientific rationale for this new antimalarial?

The Antimalarial basket Artesunate Artemether Mefloquine Quinine Chloroquine Primaquine Amodiaquine Pyronaridine Artemether-lumefantrine Pamaquine Mepacrine Proguanil Pyrimethamine Sulfa-Pyrimethamine Artemisinin Halofantrine Atovaquone-proguanil Chlorproguanil-dapsone

Combination Therapies: As Defined by WHO from “Use of Antimalarial Drugs” - Nov 2000 Free Combinations Fixed Dose Combinations Simultaneous use of 2 or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite To improve efficacy, To delay development of drug-resistance To prolong the useful therapeutic life of antimalarial drugs

Combination Therapies: As Perceived by WHO Antimalarial agents in combination therapy should
enhance the efficacy of medication [of agents which are not sufficienty effective on their own]
e.g. S/P in the case of first grade resistance to pyrimethamine, or
artesunate + mefloquine in the case of mefloquine resistance]
speed up clinical / therapeutic response, or Both

Combination Therapies: As Rejected by WHO from “Use of Antimalarial Drugs” - Nov 2000 WHAT IS NOT “ antimalarial combination therapy” Use of a blood schizonticidal with a gametocytocidal drug ( CQ plus primaquine )
Combinations in which neither components could be given alone, e.g.
S+P,
Atovaquone / proguanil &
LAP/DAP

Combination Therapies: Principles Dosages Contra- indications Ease of Use Principles

Combination Therapies: Fixed Dose Combinations
Fixed Dose Combinations
Artemisinin based Combinations under review Existing Coartem ? LapDap AS / AQ AS / MQ AS / LAPDAP AS / SP Short term AQ / SP DHA / Piperaquine WHO Technical Consultation on “ Antimalarial Combination Therapy” – April 2001 AS / Pyonaridine ACTS as recommended By WHO

Observations of International Studies
Data from Thailand suggest that for combination Therapy in malaria, Artemisinin derivatives are particularly effective combination partners as -
They are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle;
They reduce malaria transmissibility;
No resistance to these drugs has been reported yet .
Halts the progression of resistance
No adverse side effects from artesunate/artemether and safe for use in 2 nd /3 rd trimesters
Antimalarial drug resistance and combination chemotherapy, Philos Trans R Soc Lond B Biol Sci. 1999 Apr 29;354(1384):739-49, White N.

Adding artemisinins to monotherapy
Accelerates therapeutic response and so, deterioration of the patient's condition to severe malaria is extremely unusual
Superior cure rate / enhanced efficacy rate;
Greater parasite killing and more rapid parasite clearance;
Reduced gametocyte carriage and hence low recrudescence rates;
Shortened duration of therapy
No added overt toxicity

Parasite response with artemisinins

Why not Artemisinins as monotherapy?
If artemisinin or one of its derivatives is given alone, completion of a 7-day treatment course is needed because:
Cure rate of Artemisinin derivatives as monotherapy depends on:
Dosage used
Duration of treatment
Severity of patients

Artemisinins with reference to DHA
Use of dihydroartemisinin could be beneficial in 2 ways: [1] Easy to make and [2] Low cost
All Artemisinin derivatives act after being converted into dihydroartemisinin [DHA] which has intrinsically greater antimalarial activity than artes unate.
In terms of the current-in-vitro 50% inhibitory concentrations for P. falciparum in western Thailand, artesunate has approx. 70% of the potency of DHA.
Then, why is DHA still not popular over artemether or artesunate?

Artemisinins with reference to DHA
The time of dissolution of the relatively insoluble DHA tablet is higher providing:
A higher lag time and
Longer time to maximum antimalarial activity ( T max ).
Antimicrobial Agents and Chemotherapy, April 2002, p. 1125-1127, Vol. 46, No. 4

COMALAFIN Artesunate+ Sulfamethoxypyrazine-pyrimethamine

Artesunate + sulfamethoxaypyrazine and Pyrimethamine as therapy Choice of ACT As antimalarial Safety Costs Ease of use

Studies on Comalafin therapy
The efficacy of fixed co-formulated (f) artesunate-sulfamethoxypyrazine-pyrimethamine was studied & compared for 3 days for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan.:
Administered at a dose interval of 12 hrs
Administered at a dose interval of 24 hrs
Annals of Clinical Microbiology and Antimicrobials 2006, 5:18

Studies on Comalafin therapy Annals of Clinical Microbiology and Antimicrobials 2006, 5:18

Artemether-lumefantrine was given for treatment failures and the patients were followed. Classification was as follows:
Early Treatment Failures (ETF) in case of significant parasitaemia at day 2 / 3 or parasites and fever at day 3
Late Clinical Failures (LCF) for cases with parasites and fever during follow-up after day 3 and
Late Parasitological Failures (LPF) for parasite infections with/without fever during the follow-up period.

In this study, the cure rates at a dose interval of 12 hrs compared at a dose interval of 24 hrs was as follows:
92.3% and 97.1 (P > 0.05) for the 2 arms respectively.

There was no gametocytaemia during the follow-up period.
The ability of artesunate to reduce the post-treatment gametocytaemia is important, as it may reduce transmission.
Due to its simplicity the fixed dose one-day treatment regimen may improve compliance and therefore may be the preferred choice.

Packing and dosage of Comalafin
Indicated for adults:
Available as kit of 6 tablets –
3 orange tablets and 3 white tablets
Each orange tablet contains sulfamethoxypyrazine 500 mg. and pyrimethamine 25 mg.
Each white tablet contains artesunate 200 mg.
Dosage is as follows:
One white and one orange tablet once a day for 3 days

Benefits of Comalafin
High efficacy rates
Good tolerance
Shortened duration of therapy
Improved patient convenience
Low recrudescence.

Combination Therapies: costs Prices may come down as demand increases

Combination Therapies: costs ACT combination Therapy cost Artmether + lumefantrine T shilling 5500 - 7600 Artesunate + amodiaquine T shilling ??? DHA + Piperaquine T shilling 6000 COMALAFIN T shilling 2500 + retailer margin

Comparing Therapies Coartem Duo-Cotexin Comalafin

COMALAFIN

malaria breakout

by BALASUBRAMANIAM IYER

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