Role of ACT,s (Artemether + Lumefantrine) In The Treatment of Malaria

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WHO Guidelines for The Treatment of Malaria World Malaria Report 2008

Malaria Today

Global Malaria Action Plan

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WORLD MALARIA REPORT 2008

Persistent burden of malaria have become a familiar part of discussions in the global public health forum:

3 billion people at risk of infection in 109 malarious countries and territories and around 250 million cases annually, leading to approximately
1.Global burden of disease: 2004 update. Geneva, World Health Organization, 2008 (www.who.int/healthinfo/bodestimates/en/index.html).

1 million deaths. In 2004

Plasmodium falciparum was among the 4/28/12 leading causes of death worldwide from a

Population at risk
The 109 countries and territories classified as endemic The four groups describe the transition from control to elimination Malaria-free countries and malaria-endemic countries in phases of control, pre-elimination, elimination and prevention of reintroduction, end 2007

Source: World Malaria Report 2008. Geneva, World Health Organization,

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Burden of Malaria in Pakistan

Malaria has been a persistent problem

in Pakistan. There were an estimated 1.5 million malaria episodes in 2006

Most cases occur between July and November About 30% are due to P falciparum .

WORLD MALARIA REPORT 2008 4/28/12

EPIDEMIOLOGICAL PROFILE PAKISTAN

Population (000) %
v v v

2006
160 943 19 012 141 931 12

All age groups < 5 years > 5 years 88 Population by malaria endemicity (000)

%
v v

2006
7 149 521

High transmission 1/1000 Low transmission (01/1000) 93

11 422

WORLD MALARIA REPORT Malaria-free (0 cases) 4/28/12 2008 00

Policies, Strategies for Malaria Control

The government of every country affected by malaria has a national malaria control policy covering prevention and case-management.

Diagnosis and treatment of malaria, including preventive treatment

The objectives of an anti-malarial treatment policy are to:

Ensure rapid cure of the infection Reduce morbidity and mortality, including malaria-related anemia Prevent the progression of uncomplicated malaria into severe and 4/28/12

Malaria Prevention Through Mosquito Control

The main objective of malaria vector control is to reduce significantly the incidence and prevalence of both parasite infection and clinical malaria. There are two main approaches to malaria prevention by mosquito control:1.The use of insecticide-treated nets (ITNs)
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Antimalarial Drug Resistance

A key factor contributing to the increasing malaria mortality rate is the widespread resistance of P falciparum to conventional antimalarial drugs, . such as :

Chloroquine Sulphadoxine + Pyrimethamine (SP) Amodiaquine

Multi-drug resistant P .falciparum malaria is widely prevalent in 1- Wongsrichanalai,C. et al (2002). Epidemiology of drug-resistant malaria. The Lancet Southeast Asia and some Amazonian regions of South America.
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Infectious Diseases. 2(4) April, 209-18. Kidson,C. et al. (2000). The malaria cauldron of Southeast Asia: conflicting strategies of contiguous nation states. Parassitologia 42 (1-2) June 101-110

WHO Recommenda tions for Clinical Diagnosis

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WHO Recommendations for the

Clinical diagnosis
In settings where the risk of malaria is low, clinical
diagnosis of uncomplicated malaria should be based on:-

The degree of exposure to malaria History of fever in the previous 3 days with no features of other severe diseases. In settings where the risk of malaria is high, clinical diagnosis should be based on: History of fever in the previous 24 hours the presence of anemia, for which pallor of the palms WHO Expert Committee on Malaria. Twentieth report. Geneva, World Health Organization, 2000 inmost reliable sign in young appears to be the WHO Technical Report Series, No. 892. WHO Guidelines for the treatment of malaria 2nd edition 2010 page 23 children.

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WHO Recommendations for the Treatment of Malaria

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WHO Recommendations for the treatment of malaria

Recommendations unchanged from the first edition of the Guidelines (2006)

All uncomplicated P falciparum infections should be . treated with an ACT,s (Artemisinin - based combination therapy)

Five ACT,s are currently recommended for use:

1.

Artemether Lumefantrine
Artesunate - Amodiaquine Artesunate - WHO Guidelines for the treatment of malaria Mefloquine Artesunate 2nd edition 2010 Executive summary IX Sulfadoxine - pyrimethamine. 4/28/12

2. 3. 4.

Second-line antimalarial treatment

Alternative ACT known to be effective in the region;

Artesunate plus tetracycline or doxycycline or clindamycin; any of these combinations to be given for7 days;

WHO Guidelines for the treatment of malaria 2nd edition 2010 Quinine plus tetracycline or doxycycline or clindamycin; any of Executive summary IX

these

Combinations should be given for 7days

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TREATMENT OF SEVERE MALARIA

Severe malaria is a medical emergency. After rapid clinical assessment and confirmation of the diagnosis, full doses of Parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available.

For adults, artesunate IV or IM:

Quinine is an acceptable alternative if parenteral artesunate is not available

WHO Artesunate IV or IM Guidelines for the treatment of malaria 2nd edition 2010 Executive summary X

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Treating Malaria & The Role of Drugs

The aim of treatment is to fight an established parasite infection and includes:

Elimination of the parasites supportive measures to overcome morbidity associated with infection monitoring - to ensure early diagnosis and treatment of complications that can lead to death within hours.

The choice of an antimalarial depends on a variety of factors including:

Parasite type
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Level of drug resistance Patients general health and medical history

Artemisinin Derivatives (ACTs)

Over the past decade, a new group of antimalarial the Artemisinin Compounds, especially Artesunate, artemether and dihydroartemisinin have been deployed on an increasingly large scale. These produce a rapid therapeutic response, are active against multi-drug resistant P falciparum malaria, are well tolerated by patients and . reduce gametocyte carriage. To date, no parasite resistance to these compounds has been detected. Studies in Southeast Asia have shown that combinations of 4/28/12 artemisinin

Artemisinin Derivatives (ACTs) Cont

Artemisinin is a sesquiterpene lactone containing a bridged endoperoxide. It has:

Two main lipophilic derivatives, artemether and arteether A lesser, hydrophilic derivative, artesunate A major active metabolite in vivo, dihydroartemisinin.

The artemisinin derivatives (artesunate, dihydroartemisinin, artemether or arteether) are fast acting and potent antimalarial that offer an 4/28/12 important

Artemether + Lumefantrine A highly effective fixed combination

Artemether (20 mg), a derivative of artemisinin, and lumefantrine (120 mg) a highly lipophilic aryl amino alcohol.

Lumefantrine has a much longer elimination half-life (several days) than artemether With a low recrudescence rate the complementary properties of artemether with its fast onset of action and Lumefantrine with its long duration of action and high cure rate result in a highly effective combination.

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Artemether + Lumefantrine Product Characteristics

overview of

Highly effective against acute, uncomplicated malaria caused by P falciparum in areas of multi-drug resistance . Eliminates parasites and symptoms significantly faster than most current antimalarials1,2 Is rapidly gametocytocidal, helping to reduce transmission Achieves high cure rates

Well tolerated, particularly when compared to most established antimalarials3 1. van Agtmael M, Bouchaud O, Malvy D, et al. The comparative efficacy and tolerability of CGP
56697 (artemether +lumefantrine) versus halofantrine in the treatment of uncomplicated An easy-to-use fixed-dose combination treatment: falciparum malaria in travellers returning from the tropics to The Netherlands and France. Int J Antimicrob Agents 1999; 12: 159-169 simplifies compliance 2. Kshirsagar NA, Gogtay NJ, Moorthy NS, et al. A randomized, double-blind, parallel-group, comparative safety, and efficacy trial of oral co-artemether versus oral chloroquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in India. Am J Trop Med Hyg 2000;62: 402-408 Ref: 4/28/12 3. van Vugt M, Looareesuwan S, Wilairatana P, et al. Artemether-lumefantrine for the treatment

Indications
Artemether + lumefentrine is indicated for the Treatment of uncomplicated infections due to P. falciparum or mixed Artemether + lumefentrine is Not Indicated infections including P. Falciparum in adults and for prophylaxis, or for treating severe malaria, children including cerebral malaria, pulmonary edema, or renal failure, because treatment of severe malaria requires Injectable medication
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Efficacy of

Artemether + Lumefantrine

28-day cure rates in a multi-drug resistant area with 6-dose Artemether + Lumefentrine

Co-Artemether 4 doses Co-Artemether 6 doses/ 60 hours Co-Artemether 6 doses/ these (van Vugt One of 95 hours et al. 1999) was a Mefloquine + doseoptimisation study Artesunate for coartemether in multidrug resistant areas.1 The 4-dose regimen was compared with two 6-dose regimens 1.van Vugt M, Wilairatana P, Gemperli B, et al. Efficacy of six doses of artemether-lumefantrine 4/28/12 (given (benflumetol) in multidrugresistant Plasmodium falciparum malaria. Am J Trop Med Hyg1999;

Overview of Cure Rates in adults and Adolescents

28-day parasitological cure rates by treatment, pooled studies, evaluable population, PCR-corrected

The following graphic provides an overview of 28-day cure rates for coartemether and other antimalarials, based on pooled results from evaluable patients >12 years of age.

Comparator

Patient number to

small in the Evaluation population

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Fast Parasite Elimination in P falciparum . Malaria

Comparator
Median percentage parasite reduction at 24 hours was significantly better (p<0.001) for patients receiving co-artemether than for tested comparators. 4/28/12

Parasite Clearance in Infants and Children

study on infants and small children in sub-Saharan Africa (Kenya, Nigeria and Tanzania) with the 6-dose regimen of co-artemether demonstrated that, overall,170/305 (55.7%) of patients achieved clearance within 24 hours, and 302/307 (98.4%) within 48 hours

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Prompt Reduction in Fever clearance

in infants & children
In African children, fever clearance (and hence, symptomatic improvement) occurred significantly faster with co-artemether than with sulphadoxine+ pyrimethamine (SP) African children with fever Co-Artemether >37.5C (n=144) Sulphadoxine + pyrimethamine (n=143)

von Seidlein L, Bojang K, Jones P, et al. A randomized controlled trial of artemether / benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of 4/28/12 uncomplicated falciparum malaria in African children. Am J Trop Med Hyg 1998; 58(5): 638-644

Fever Clearance in Adults and Adolescents

Fever clearance times, pooled studies
Comparato r

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Gametocyte Clearance in Infants and Children Rapid gametocyte

clearance, 6-dose regimen

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0-3 days Day 7 Day 14

Proportion of patients with gametocytes by Day 28, pooled studies Comparato r

Gametocyte Clearance in Adults and Adolescents

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Safety & Tolerability

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DISCUSSION DOSAGE
Click to edit Master ArtemethersubtitleLumefantrine + style Suspension

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WHO dosage guidelines for ArtemetherLumefantrine

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WHO guidelines for the treatment of malaria

The recommended dose for Artemether/ Lumefantrine tablets (Coartem) when used for children between 5 and 14 kg is 1 tablet at time 0h and 1 tablet at time 8h followed by two tablets a day for two days (24, 36, 48 and 60h). Calculated as mg artemether per kg body weight (bw), this means that for a child of 5 kg a dose of 8 mg artemether/kg per day spread over two doses is given. Evidence that this high dose of more than 4 mg/kg bw of artemether is needed for small babies ( 5kg) is scanty or non existent. Moreover, this overdosing situation is in contrast with the adult dose of 8 pills a day divided over two intakes. 4/28/12 This means that an adult of 50 kg takes a dose of 3.2 mg/kg of

WHO guidelines (WHO, 2006, pages 24, 25) it is clearly stated for Artesunate that the total recommended dose given per day for three days is 4 mg/kg bw. The pharmacokinetics of Artesunate and Artemether are quite similar (Newton et al., 2000 and Silamut et al., 2003).

Artesunate

and

Artemether

can be

considered as prodrugs for dihydroartemisinin.Biotransformation into the active metabolite dihydroartemisinin occurs rapidly, almost immediately for Artesunate and somewhat later for artemether.

The reported elimination halflife of Artesunate is less than 1 hour (Newton et al., 2000) and for between 2hours

Artemether

(Silamut et al., 2003).

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of Artemether necessary to obtain antimalarial

Calculate for every kg bw how many mg artemether is given at the recommended dose of Coartem and compare those values with those obtained with Co - Artesiane we see the following picture:

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Dafra Pharma developed a paediatric Artemether-Lumefantrine suspension that allows correct dosing for that target group. The suspension enables an adequate daily dosing of artemether over the whole body weight range (5 to 30 kg). The syrup therefore allows dosing around the baseline of 4mg/kg artemether, considered by WHO as the necessary dose. Excessive overdosing for very small children and potential under dosing in some weight groups are avoidable. For example:

Co-Artesiane: 5 kg child receives a dose of 4.2 mg/kg artemether per day (correct dose) Coartem: 5 kg child receives a dose of 8 mg/kg per day (overdosing) Co-Artesiane: 14 kg child receives a dose of 4.3 mg/kg artemether per day (correctdose) Coartem: 14 kg child receives a dose of 2.86 mg/kg per day (underdosing)
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Our results did clearly demonstrate that we achieved

One Dose Versus Two Doses a Day

the same efficacy with single dosing per day of the Co- Artesian syrup then obtained with the twice daily dosing of the Coartem tablets.

This could be due to two facts: Either there were strain

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differences of the parasite between

The following graphs were calculated based on a bioequivalence study. It is clearly shown that the peak plasma concentrations of artemether and dihydroartemisinin are higher with 3 intakes of Co- Artesiane suspension than with the 6 intakes of Coartem.

Coartem dosing leads to a low and constant baseline plasma concentration which could facilitate the induction of tolerance. 4/28/12

Peak plasma concentrations of Artemether

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Peak plasma concentrations of Dihydroartemisinin

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References
Ashley EA, Stepniewska K, Lindegardh N, McGready R, Annerberg A, Hutagalung R, Singtoroj T, Hla G, Brockman A, Proux S, Wilahphaingern J, Singhasivanon P, White NJ, Nosten F (2007) Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria.Trop Med Int Health, 12(2):201-8. qChanda P, Hawela M, Kango M, Sipilanyambe N (2006) Assessment of the therapeutic efficacy of a paediatric formulation of artemether-lumefantrine (Coartesiane) for the treatment of uncomplicated Plasmodium falciparum in children in Zambia. Malar J, 5:75 qNewton P, Suputtamongkol Y, Teja-Isavadharm P, Pukrittayakamee S, Navaratnam V, Bates I, White N (2000) Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrob Agents Chemother, 44(4):972-7 qSilamut K, Newton PN, Teja-Isavadharm P, Suputtamongkol Y, Siriyanonda D, Rasameesoraj M, Pukrittayakamee S, White NJ (2003) Artemether bioavailability after oral or intramuscular administration in uncomplicated falciparum malaria.Antimicrob Agents Chemother, 47(12):3795-8) 4/28/12 qWorld Health Organisation (2006) Guidelines for the treatment of malaria.
q

Complying with need of time and recommendations of WHO proudly presents

Tabros Pharma

Co - Misomal is a new, safe

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and effective fixed dose combination Antimalarial therapy that provides an important addition to the armory against

DOSAGE CONVENIENCE & COMPLIANCE IN CHILDREN

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Complying with need of time and recommendations of WHO proudly presents

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CO-MISOMAL DS SUSPENSION SCHEDULE

Product strength
COMISOMAL DS 15 ml

DOSAGE

Body Weight

CO-MISOMAL CO-MISOMAL DS Artemethe SUSP SUSP. r / mg/kg

Artemether 15mg+Lumefantrine 90mg Artemether 30mg+Lumefantrine 180mg

bw

Daily Dose (ml)

Daily Dose (ml)

5kg 6kg 7kg - 8kg 9kg -10kg

7 ml 8 ml 10 ml 13 ml 15 ml 18 ml 22 ml 25 ml 29 ml 33 ml 37 ml

3.5ml 4 ml 5 ml 6.5 ml 7.5 ml 9 ml 11 ml 12.5 ml 14.5 ml 16.5 ml 18.5 ml

4.2 4,3 ( 4,3 - 3,8 ) ( 4,3 - 3,9) ( 4,1 - 3,8 ) ( 4,1 - 3,9) ( 4,4 - 3,9 ) ( 4,1 - 3,8 ) ( 4,1 - 3,8 ) ( 4,1 - 3,8 ) ( 4,1 - 3,8 )

COMISOMAL DS 30 ml

11kg -12kg 13kg -14kg 15kg - 17kg 18kg - 20kg

COMISOMAL DS 60 ml 4/28/12

21kg - 23kg 24kg - 26kg 27kg - 29kg

Complying with need of time and recommendations of WHO proudly presents

Tabros Pharma

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THANKS
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