ARTEMETHER-LUMEFANTRINE; UNDERSTANDING THE CLOCK

Written by Timothy Okooboh
                         

The Artemether-lumefantrine clock

Recently, there have been widespread reports regarding the ineffectiveness of Artemether-lumefantrine for the treatment of malaria infection. This treatment failure is mostly due to a poor understanding of the correct dosage interval of Artemether-lumefantrine, that is, the various times of the day the drug should be taken during the three day therapy.

Below are two common case scenarios of a health care provider and patient interaction that take place in health care facilities across the world especially Sub-Saharan Africa where malaria is most prevalent.

Scenario one

Health care provider : Good morning madam. This is Artemether-lumefantrine 80/480 mg. It is a medicine that will take care of your malaria infection. Take one tablet when you get home and one tablet 8 hrs later. Then from tomorrow, take one tablet morning and night.

Scenario two

Health care provider : Good morning madam. This is Artemether-lumefantrine 80/480 mg. It is a medicine that will take care of your malaria infection. When are you likely to take the first dose?

Patient : Hmm immediately I get home by 11 AM.

Health care provider : That's alright. When you take the first tablet by 11 AM, take the second tablet 8hrs later. Then from tomorrow you can take one tablet morning and night, say 8 AM and 8PM.

Now which of the two scenarios above does the health care provider accurately informed the patient on the proper dosage interval of Artemether-lumefantrine? (a) Case 1 (b) Case 2  (c) None of the above.

Wondering what the right answer is? Well by the end of this article you will find out.

WHO recommends Artemisinin-based Combination therapy (ACTs) as the first line of drugs for the treatment of uncomplicated P. falciparum malaria. Commonly available ACTs include Artemether-lumefantrine, Artesunate-Amodiaquine, Artesunate-Mefloquine, Artesunate plus Sulfadoxine-pyrimethamine, and Dihyroartemisin and Piperaquine. However, Artemether-lumefantrine popularly known as Coartem is the most popular and commonly recommended ACT for the treatment of malaria. Despite its popularity and daily usage in the treatment of malaria, many health care providers and patients still make error regarding the correct dosage interval of Artemether-lumefantrine.

Artemether-lumefantrine Dosage Interval

Artemether-lumefantrine 20/120 mg or 80/480 mg is taken for three days with a total of six doses within the three days given at 8, 24, 36, 48 and 60hrs after the first dose. This implies that there is an 8hr interval between the 1st and 2nd dose, while there is a 12hr interval between the 3rd and 4th dose and also between the 5th and 6th dose. The error is usually made with the timing of the 3rd dose. The 3rd dose is administered exactly 24hrs after taking the first dose of Artemether-lumefantrine. This dosage interval is clearly written on the leaflets of most Artemether-lumefantrine brand.

For instance, in the case scenario above where the adult patient was given Artemether-lumefantrine 80/480 mg to be started by 11 AM, she is supposed to take one tablet by 11 AM then one tablet by 7 PM on day one. Thereafter on the second and third day, she is to take one tablet by 11 AM ( 24 hr from the first dose ) and one tablet by 11 PM respectively. It's so simple isn't it? So the answer to the question above is option C ( none of the above ).

Why must the timing of the dosage interval be followed strictly?

Due to the pharmacokinetic profile of Artemether-lumefantrine ( how it is absorbed, distributed, metabolized and excreted ), the time to reach and maintain steady state concentration effective to kill the susceptible plasmodium species is only attained when the dosage interval is 0hr, 8hr, 24hr, 36hr, 48hr and 60hr. 0hr is the exact time the patient took the first dose of the drug. If the drug is not taken at the right times, it can lead to treatment failure, resistance of plasmodium to Artemether-lumefantrine and increased cost of care due to treatment failure and drug resistance, as the patient will have to spend more money treating malaria over and over again.

Let's take a few examples. If a patient takes the first dose by 10 AM, then the dosage interval will be: 10 AM, 6 PM, 10 AM, 10 PM, 10 AM and 10 PM.

What if the patient takes the first dose by 2 PM, what will be the correct dosage interval? The dosage interval will be: 2 PM, 10 PM, 2 PM, 2 AM, 2 PM and 2AM. But do you really think the patient can take the drug by 2 AM? The patient should be asleep by then so the possibility of taking the drug at the right times it should be taken may not be possible. Now this brings us to what I call the Artemether-lumefantrine clock which you can see above or below and which I will discuss shortly.

So there you have it! In order to ensure treatment success with Artemether-lumefantrine, the drug should be taken at the correct dosage interval. The health care provider should accurately calculate the timing of the dosage interval for the patient and inform the patient or care giver on the importance of taking the medicine at the right times. However, it is important to note that other factors contribute to treatment outcome with Artemether-lumefantrine. These factors include correct dosage and drug-drug interaction. The dosage of Artemether-lumefantrine is based on the weight of the patient for instance, patients above 35kg should be given 4 tablets of Artemether-lumefantrine 20/120mg following the correct dosage interval.

The Artemether-lumefantrine Clock Explained

The Artemether-lumefantrine clock reveals the hours of the day that starting to take the drug may either lead to high adherence or low adherence by the patient to take the drug at the right times during the three day therapy. Here, adherence is determined by the possibility of the patient to be AWAKE to take the drugs. 

• In the clock above, the figures marked red are periods of the day that Artemether-lumefantrine should not be started at either the AM or PM of those times. For instance, if a patient walks into the health facility and is given Artemether-lumefantrine to be started by 1 PM, the second dose will be by 9 PM but subsequently the patient will have to take the drug by 1 PM and 1 AM. 1 AM is not so feasible to take the drug as the patient is most likely to be asleep by then. The same goes for starting the medication by 2 PM, 3 PM, 4 PM and 5 PM. Even if the patient starts the drug at the AM of those times, the possibility of taking the drug at the subsequent doses that will fall on the AM of those times is still low as the patient may be asleep by then.

• The figures marked blue are periods of the day that Artemether-lumefantrine should be started only at the AM of those times but not at the PM. For instance, if a patient starts Artemether-lumefantrine by 8 AM, subsequent doses will be by 4 PM, 8 AM, 8 PM, 8 AM and 8 PM. These times are very feasible as the patient is most likely to be awake to take the medicine. But let's say the patient starts the drug by 8 PM, the next dose will be by 4 AM. Can the patient be awake to take the drug by 4 AM? Well the possibility is quite low. The same goes for figures 9, 7 and 6. You can do the calculation yourself and see. Artemether-lumefantrine is best taken at the AM of those figures.

• The figures 10 and 11 are unmarked. This is because adherence is high when Artemether-lumefantrine is started at either the AM or PM of those times. For instance, if the drug is started by 10 AM, subsequent doses will be by 6 PM, 10 AM, 10 PM, 10 AM and 10 PM. If it is started by 10 PM, subsequent doses will be by 6 AM, 10 PM, 10 AM, 10 PM and 10 AM. The patient is most likely to be awake by 10 PM and 6 AM to take the drug so adherence is high.

• Figure 12 is marked green as the level of adherence is intermediate. Taking the drug by 12 PM, subsequent doses will be by 8 PM, 12 PM, 12 AM, 12 PM and 12 AM. Can the patient be awake to take the drug by 12 midnight? Well the possibility is intermediate.. not too high or not too low.

Summary of Key learnings and recommendations

1. Inappropriate dosage interval of Artemether-lumefantrine is one of the causes of treatment failure and drug resistance.

2. Based on the pharmacokinetic profile of Artemether-lumefantrine, the correct dosage interval is 8, 24, 36, 48 and 60hrs after the first dose. When taken at these times, the possibility of treatment failure is minimal in the absence of resistance and poor quality Artemether-lumefantrine drug.

3. The Artemether-lumefantrine clock shows the times of the day that starting to take the drug can lead to high or low adherence with respect to a patient being awake to take the drug.

4. There is no need to memorize the clock. But before recommending or dispensing Artemether-lumefantrine, the patient should be engaged and the dosage interval calculated based on when the patient is likely to start the medication. If the times fall at an hour when the patient may be asleep, then other ACTs with 24hr dosage interval should be given instead such as P-Alaxin, Synriam, Artequick etc., except if the patient agrees to adhere to therapy.

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