RECONSTITUTION OF ORAL ANTIMALARIAL SUSPENSIONS: AN UNRECOGNIZED FACTOR IN ANTIMALARIAL DRUG RESISTANCE

RECONSTITUTION OF ORAL ANTIMALARIAL SUSPENSIONS: AN UNRECOGNIZED FACTOR IN ANTIMALARIAL DRUG RESISTANCE

C. Y. Isimi ¹, O. J. Olayemi ^{* 1}, K. Ekere ¹, I. Ajeh ¹, J. E. Okoh ¹, D. Ugwu ¹ and M. O. Emeje ²

Department of Pharmaceutical Technology and Raw material Development ¹, Centre for Nanomedicine and Biophysical Drug Delivery ², National Institute for Pharmaceutical Research and Development (NIPRD), Abuja, Nigeria.

ABSTRACT: Malaria is a foremost universal public health problem, especially in the African region and development of resistance to the older and new generation malaria therapy, has become a persistent health threat requiring urgent solutions. This study intended to assess the ability of human subjects to accurately reconstitute antimalarial dry suspensions according to the manufacturer’s instructions. Two hundred (200) dry powders for suspension were procured and distributed to 200 human subjects, and the volumes reconstituted were noted. Results showed that only 24 subjects (12%) were able to reconstitute the suspensions as required by the manufacturer, while ninety-seven subjects (48.5%) made reconstitutions above the required volume and 79 subjects (39.5%) reconstituted below the required volume. Error in reconstitution was as high as 76%. This study emphasizes the need for health caregivers; especially nurses and pharmacists to make the required reconstitutions before dispensing the medication and also give adequate counsel to patients on the appropriate way to make reconstitutions to avoid untoward effects due to over or underdosing.

Malaria, Reconstitution, Suspension, Antimalarial

INTRODUCTION: Malaria is a serious and sometimes fatal disease caused by a parasite that is spread to humans through the bite of infected Anopheles mosquitoes, and the main strains that cause ill health and death are Plasmodium falciparum and Plasmodium vivax. In certain parts of Africa, P. falciparum is the prevalent strain while in other areas it is P. vivax. Although, malaria is a global health problem and contributes significantly to mortality, underdevelopment, and poverty in the endemic regions of the developing world, this problem is greatest in Africa, with reports of over 80 percent of malaria cases and consequent death ¹.

Malaria affects all ages and economic groups with a devastating impact on pregnant women and under-five children ². The total cost of malaria treatment in sub-Sahara Africa has been estimated to be the US $12 billion per year, with 40 percent of public health expenditures in high-burden countries going to malaria control and management. In 2015 alone, about 214 million cases were reported, although it was also postulated that there was a decrease in the reported clinical cases of malaria (37%) and mortality rate (60%) globally from 2000-2015. ³ It is no longer news that one of the biggest challenges in controlling malaria today is, how to combat drug resistance; however, the handicap is in the development of effective strategies in preventing and controlling such resistance. The most popular reason put forward for drug resistance is large circulation and continued use of fake and counterfeit drugs, unfortunately, even though appreciable efforts have been made in dealing with these, resistance to drugs has not declined.

We opine that there is the need to change strategy by expanding the net of root causes of drug resistance. Although there are various projections for the future to tackle the burden of malaria one of which is the Global Technical Strategy for Malaria 2016-2030, ³ it is only at best a “control” strategy. Furthermore, the World Health Organization (WHO) approved for implementation, the use of Artemisin in combination drugs as first-line treatment in malaria along with diagnostic tests as supportive tools. Pharmacological treatment of malaria with drugs such as Atovaquone-proguanil, Artemether-lumefantrine (ACTs), quinine, doxycycline, tetracycline, clindamycin, mefloquine, and artesunate, has been suggested to be combined with non-pharmacological measures for effective protection ⁴.

Plasmodium falciparium, responsible for malaria infection in Sub Sahara has reported resistance to such antimalarials like chloroquine, mefloquine, sulfadoxine-pyrimethamine, halofantrine and quinine ⁵. More recently, the subject of partial resistance or delayed response (P. falciparum) to Artemisinin Combination Therapies has also been described. This poses a great concern, therefore WHO recommends routine monitoring of the effectiveness of these antimalarials especially in the endemic regions. Investigations of antimalarial therapy in regions like Cambodia, Viet Nam and Thailand recorded treatment failure with ACTs and evidence of various mutations of P. falciparum ³.

In a study of the quality assessment of various antimalarials conducted in Gabon, one sample of the artemether-lumefantrine tablet was reported to have failed the TLC and HPLC content evaluation test, and the same artemether-lumefantrine antimalarial tablet did not meet the criteria set for disintegration test ⁶. Another study in Ghana examined the feature of various artemether-lumefantrine dosage forms (tablet, suspension, and injections) circulating the market and reported that all the formulations but one suspension met the required standards ⁷.

The quality of chloroquine tablets found in Senegal, Burkina Faso and Mali were found to be substandard when tablet dissolution and content uniformity were assessed ⁸. Pregnant women are more prone to malaria which most often leads to various complications, and this has led to the endorsement of the practice of Intermittent Preventive Therapy (sulfadoxine-pyrimethamine) in pregnant women by the World Health Organization. Research piloted in Tanzania reported after quality control testing that one of the failed samples was an antimalarial quinine sulfate 300 mg tablets which was confirmed to be falsified ⁹.

A similar study on the quality of sulfadoxine-pyrimethamine used in the routine care of pregnant women was also conducted in Ghana, and it was observed that the tablets did not meet the criteria set for in-vitro dissolution thus implying that the drug release and consequently bioavailability is compromised ¹⁰. A study conducted in Enugu, Nigeria showed that purchase of artemisinin combination therapy samples using convenience approach revealed the high prevalence of low-quality ACTs. In total, about 9.3 % of the samples were either substandard, degraded or falsified ¹¹.

The high costs of ACTs affect their accessibility; therefore various programmes have been initiated to subsidize their costs for private retailers. Consequently, it was observed that these programmes improved the use and availability of ACTs for children under five years of age ¹². In a similar but different study, done in Ethiopia, it was discovered that that the low affordability of artemether-lumefantrine influenced its availability and accessibility ¹³. Affordability of common antimalarials is a major issue as a study conducted in Malawi showed that cost for one course of treatment was greater than the daily income of a low paid government official ¹⁴.

Another study reported that antimalarials such as quinine, artemether, and sulfadoxine-pyrimethamine were available in the three health care facilities examined although in varying amounts ². Their finding is similar to that of ¹⁵ which showed that quinine and sulfadoxine-pyrimethamine were more frequently available in retail outlets compared to the new generation antimalarials (ACTs).

Artemisinin and Artemisinin combination drugs are formulated as a dry powder for reconstitution due to its poor solubility in water and instability. These formulations are marketed mostly for pediatrics and are essential because these groups of people have low immunity, therefore are vulnerable. Various studies have shown the therapeutic effectiveness of these ACTs in this special population ^{16, 17, 18}.

It is pertinent to ensure that these dry powders are reconstituted properly to minimize errors leading to over dosing or under dosing and consequent toxicity and treatment failure respectively.

The study to evaluate the effectiveness of preservatives in seven (7) samples of artemisinin combination therapy dry powder suspensions reported that only two (2) of the samples met the criteria as specified by the European Pharmacopoeia. In Africa, a study to assess the quality of various dosage forms of artemisinin derivatives showed that 71% of the reconstituted dry powders were of minimal quality. They also observed non-homogenous mixtures and powder aggregation after reconstitution which could result in inaccurate dosing ¹⁹.

Another investigation steered in Palestine on the reconstitution, administration, and storage of antibiotic suspensions showed that 86.8% of mothers included in the study were guided by the information leaflet for the reconstitution of antibiotic suspensions ¹. In France, a study focused on the errors made by caregivers in the reconstitution of Amoxicillin and Josamycin. The results postulated that about 46% and 56% of caregivers were not proficient in the reconstitution of amoxicillin and Josamycin respectively which led to a gross underdosing and overdosing respectively ²⁰.

Errors by parents or healthcare givers in administering liquid medications to pediatric patients are very common and are more significant in dosage forms that require reconstitution like antibiotics and antimalarials ²¹. Such errors could arise from the quantity of water used for reconstitution, but the training of these caregivers and enlightenment on the appropriate ways to carry these reconstitutions would go a long way in preventing errors.

The study by (Hu et al., ²² examined the consequence of various methods or forms of learning programs on caregiver’s knowledge of reconstitution and use of antibiotic. The patients were grouped to read the medicine information leaflet, receive step by step illustration or receive step by step illustration including face to face counseling from the pharmacist. They found out that the group that read the drug information leaflet alone had less knowledge of medication reconstitution and usage while those that received illustrations and pharmacist intervention had more knowledge. In developed countries such as USA and UK, pharmacists sometimes help patients with the reconstitution of medications thereby avoiding potential errors emanating from caregivers.

However, in developing or underdeveloped countries, this is not so due to the deficiency of human resources and the enormous number of patients to be attended to.

This study, therefore, was conducted to assess the inconsistency or otherwise of different subjects in reconstituting Artemether-lumefantrine oral powder for suspension.

MATERIALS AND METHODS: Artemether-lumefantrine 180 mg / 1080 mg powder for suspension, (Ultimar plus®), water, measuring cylinders (100 mL),

Product Details: Manufacturing date: 05/14, Expiry Date: 05/17, Batch No: 140512, NAFDAC No: A4-6956, Manufactured by Shanxi Federal Pharmaceuticals Co, Ltd.

The pictorial in Fig. 1 shows a representation of the antimalarial product used for the study. Two hundred (200) units of artemether-lumefantrine antimalarial oral powder for suspension were procured from a wholesale pharmacy and coded (A1 - A200) for identification purposes. The coded samples were then distributed within AMAC, Abuja, Nigeria to various subjects who were instructed to reconstitute the suspensions with water according to the manufacturer’s (leaflet) instructions.

After reconstitution, the samples were retrieved and taken to the laboratory for analysis. In the laboratory, the suspensions were shaken to achieve a homogenous mix, and each sample suspension was poured into a measuring cylinder to measure its actual volume (mL).

FIG. 1: PICTORIAL REPRESENTATION OF ANTI-MALARIAL ORAL POWDER FOR SUSPENSION IN PRODUCT PACKAGE

RESULTS AND DISCUSSION: Drugs in liquid dosage forms are more readily available for pediatrics, geriatrics and those with such conditions that limit swallowing of solid dosage forms and same prescribed due to the convenience of administration. Also, dosing of these liquid formulations can be tailored to individual needs. Consequently, more of these liquid dosage forms; especially antibiotics and antimalarials, are being manufactured as a powder for reconstitution due to stability concerns ^{22, 23}. Incidences of error in medication with these dry powders have been reported to be as high as 63% with those due to reconstitution having a significant percentage.

Also, other issues relating to storage and dosing which could lead to treatment failure and possible development of resistance have been implicated in medication errors ⁹. In HIV infections, for example, no suitable liquid combination or individual formulations for children exists more so, they cannot be administered the solid combination formulations given to adults. Therefore there is a need for pediatric formulations of ART for easy administration to these special group ²⁴. Where these liquid formulations are available, as in the treatment of malaria in children, and adults who enjoy the benefits of taking these liquid malaria formulations are reported ²⁵, it is very important that its reconstitution is done properly.

Malaria burden is greatest in African regions with about 90% deaths being recorded from the 80% reported cases. Deaths due to malaria infection is estimated to be about 445,000 and those attributed to children being about 285,000 alone in the year 2016 ²⁶. Those children less than five (5) years are the major focus of antimalarial therapy in those endemic areas because they are more at risk. The strategies to control this disease include the use of insecticide-treated nets (ITN), insecticide sprays and chemotherapeutic agents. The antimalarial therapy recommended for use by the WHO is the Artemisinin-based combination therapies (ACTs) in uncomplicated malaria infection, but the tablets are not recommended for children who weigh less than 5 kg, this makes it imperative that the quality of ACTs formulated as liquid products be assured. Artemether-lumefantrine suspensions are administered only once daily for 3 days instead of twice daily for 3 days recommended when taking the tablets; this improves patient compliance. However, the comparative study of artemether-lumefantrine suspensions and tablets by ²⁷ showed that both formulations were well tolerated and effective in the treatment of malaria infection due to P. falciparum. There has been a case report on dosing error with antimalarials which led to detrimental effect ^{28, 29}. It becomes very important then to ensure that methods/processes that would guarantee quality and efficiency be adhered to; as in the appropriate reconstitution of the powders for suspensions and dosing of the required volume.

Fig. 2 below is a pictorial showing the singular analysis (volume estimation) carried out on the received samples while Table 1 shows the volumes of individual reconstituted suspensions which were used in further analysis of the results.

FIG. 2: PICTORIAL REPRESENTATION OF ALREADY RECONSTITUTED SUSPENSIONS ANALYZED IN THE LABORATORY

The distribution of subjects and the corresponding volumes of reconstituted suspensions are presented in Fig. 3. It was observed that a large number of subjects (97) representing 48.5% of the total subjects reconstituted the suspensions to volumes above the required 60 mL.

TABLE 1: LABELLED ANTIMALARIAL SUSPENSIONS AND THEIR RESPECTIVE RECONSTITUTED VOLUMES (mL)

Key: SC - Sample code, V RS - Volume of reconstituted samples

Also, a high proportion of subjects (39.5%) were observed to have reconstituted the volumes to less than the required volume while only 24 subjects (12%) reconstituted accurately according to the manufacturer’s stated volume (60 mL).

Fig. 4 shows that 97 subjects reconstituted to volumes less than 60 mL accounting for 36.5% error in reconstitution while 79 subjects reconstituted to volumes greater than 60 mL accounting for 27.5% error and only 12% of the subjects reconstituted to exact volume. This translates to 176 subjects (88%) making mistakes which amount to about 76% error. This is a high percentage of error with devastating consequences in possible under and overdosing of this antimalarial formulation.

Inappropriate reconstitution signifies that the right dose would not be administered; optimum dosing restricts the spread of antimalarial resistance and alterations in drug pharmacokinetics ¹⁶. Dosing children with tablets and fractions of it rather than the appropriate liquid formulations makes them susceptible to suboptimal plasma concentrations and reduced metabolism of drug ³⁰. Dosing inadequacies could be as a result of the method/process of reconstitution of dry powder formulations; incorporation of excess water, for example, dilutes the product and reduces the potency of the active ingredient which could result in under dosing and reduced efficacy ^{31, 32}. On the other hand, the addition of too little water makes the active ingredient concentrated which can lead to overdosing and untoward effects. Accurate dosing is essential in the administration of all formulations; however, caution is required in pediatric formulations due to the vulnerability of these age groups. To prevent the development and extent of resistance to ACTs as being experienced globally, it is necessary to ensure that patients receive the correct dose of the antimalarial. Furthermore, optimum dosing of antimalarial results in completely eradicates the P. falciparum parasite and consequent recurrent infection ^{33, 34}.

A different but related study by Ryu and Lee ¹² focused on the accuracy of the actual dose of liquid medication administered using a variety of measuring devices. Their results which showed that only about 10% of subjects administered a dose above 10% of the required dose (5 mL) is in contrast with ours where 48.5% of subjects reconstituted to volumes above the required. This tells us that if these large numbers of subjects are actual caregivers, they will endanger the lives of their patients.

In our study, the product bottle had been calibrated and fitted with a dosing cup which could be used to measure the water to reconstitution. The varied discrepancies observed could be attributed to inappropriate method or process of reconstitution by the patients, it also suggests that the patients did not use the tools (leaflet, dosing cups) provided by the manufacturer for this product. Similar findings have also been reported ²⁰ where it was revealed that reconstitution errors occurred in 46% and 56% of two antibiotics studied due to the reluctance of patients to read the medicine leaflet instructions, for such reasons as was not comprehensible. This present study also shows that some subjects were reluctant to read the leaflets, while others failed to read the leaflet claiming to have administered the drug before and relied on such knowledge/experience. This could be the reason why only a minority of subjects was able to reconstitute appropriately to the required volume.

Correct practices in dispensing medications are essential to reduce the risk of medication errors and treatment failure; such as giving correct counsel, providing the appropriate tools like syringes and water for dilution. The study by Al-Ramahi et al., ¹ showed that about 86% of the caregivers understood and followed the manufacturer’s instructions while 44% sought pharmacist’s intervention the interpretation of such instructions.

Another report ³⁵ showed how a caregiver erroneously administered 9 mL of amoxicillin powder to a boy instead of 9 mL of the required suspension. The report also revealed another scenario where a mother noticed her son’s medication looked more viscous than usual and was only half full, suggesting that the suspension was not reconstituted with the appropriate amount of diluent. These show the extreme importance of appropriate dispensing by trained personnel and discourage dispensing of un-reconstituted medications in order to avoid fatal consequences.

CONCLUSION: It is recommended that pharmacists ensure that these oral dry powders are reconstituted before handing them over to patients. In the event that this is not possible, pharmacists should ensure that adequate information and proper counselling is given to caregivers/patients on the appropriate manner of reconstitution. This study lends credence to the database of information which could be used in constituting appropriate platforms for establishing enlightenment in both hospital and community practices.

ACKNOWLEDGEMENT: The authors wish to thank the management of the National Institute for Pharmaceutical Research and Development for the provision of the facility to carry out this work. Also, the authors acknowledge Professor Martins Emeje for the conceptualization and design of the work.

CONFLICT OF INTEREST: The authors declare no conflict of interest

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    How to cite this article:

    Isimi CY, Olayemi OJ, Ekere K, Ajeh I, Okoh JE, Ugwu D and Emeje MO: Reconstitution of oral antimalarial suspensions: an unrecognized factor in antimalarial drug resistance. Int J Pharm Sci & Res 2019; 10(5): 2257-64. doi: 10.13040/IJPSR.0975-8232.10(5). 2257-64.

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