summary of discussion and conclusions

TRbxacnoNsar ME RovaL SoClETVaiTRoPlUlMLDIClNEbND HVClENr (19%) 88, SUPPLEMENT I, 6f65

Summary of discussion and conclusions

S1163

Discussion What follows is a summary of the principle questions

which arose and the free discussion which took place at themeeting.

Clinrcal use (i) Would artemisinin or the derivatives reduce mor-

tality in Africa, where most of the world’s malaria deaths occur, and where quinine is still effective? After much crystal-ball gazing there was no agreement on this.

(ii) How much artemisinin has already been used in China? On the basis of sales, 1 563 000 persons have been treated with artesunate tablets, 56 000 with parenteral artesunate. and 132 000 with narenteral artemether. China no lot& uses quinine, piefaring tn use these derivatives for the treatment of malaria.

(iii) What is the cause of pyrogenic reactions to the drugs? This was not known.

(iv) Was there evidence of resistance, and what could be done to prevent it? There was no clear evidence of resistance either in vitro or in viw; the recrudescent infections observed could all be explained by inadequate primary treatment. But this was not cause for complacency; the artemisinin drugs were already readily available in countries such as Via Nam, Cambodia and China and uncontrolled use could well lead tn resistance.

(v) Which of the available artemisinin preparations should be used? There was not a clear answer. The following points emerged. Artesunate appeared to be the most rapidly acting of the available drugs, but it was less stable than artemether, and for parenteral use needed to be made up in 5% sodium bicarbonate before injection. The parenteral drug was not manufactured to good manufacturing pracnces (GMI’) standard at the present time. As a consequence most of the research investment was going towards artemether and arteether and these were likely to gain international registration in the near future, despite the possibility that artesunate was a ge- nuinely better drug. Oral artesunate was probably a pro- drug for the metabolite dihydroartemisinin (which itself was now being produced-in China). There was not enough information on oral artemether. l’arenteral artemether was manufactured m GMP, was stable for >4 years, and was the subject of several large mortality studies. However, it could not be given intravenously, required use of a 1 mL syringe for accurate dispensing in children as volumes were so small, and was slightly slower acting than artesunate. Artemisinin suppositories were clearly effective and could well represent a major advance, especially in rural areas where injections could not be gtven. But they were not generally available and in some areas there could be cultural difficulties with their acceptance (although this was not thought a major problem).

(vi) How important were the observations of neurotoxicity of artemether and arteether in animal studies? The clinicians working with the drugs did not consider these observations a limiting factor. From a drug regulatory standpoint they would be taken very seriously. There was general cnncern that more animal studies (also including artesunate) and detailed clinical and neuropathological investigations were needed tn resolve this important question.

Pharmacologv There was concern about the possible acid lability of

derivatives given orally. The ensuing discussion con- cluded that all of the artemisinin derivatives could be pro-drugs acting as a delivery system for the biologically active metabolite dihydroartemisinin.

(i)What progress was there in the development of the trioxanes and tetraoxanes? A number of lead compounds have been synthesized. Although these compounds have good antimalarial activity they will need improvement in

terms of their hysicochemical characteristics. None has yet been test&i humans.

(ii) Is there any evidence that the artemisinin derivatives cause lipid peroxidation and is there a selective difference between the interaction seen with parasitized versus non-parasitized erythrocytes? At the drug cnncen- trations used, there was no evidence for lipid per&da- tion. Selective antimalarial activity is achieved by the apparent requirement for haemin which limits drug effects tu the parasitized cell. Additional parasite-induced changes in the host red cell may be implicated in the selective toxicity tn the parasite.

(iii) Could the albumin adducts formed in vitro act as haptens and thereby induce an autoimmune response m moo, and why did mteraction with other haem moieties within the host not result in mnre generalized host tnx- icity? Artemisinin-albumin adducts could theoretically act as haptens although there is certainly no evidence for this vet. The reason that eeneralized toxicitv is not ob- se&d is because the inter&ion with iron appears tn be relativelv smcific to haemin.

(iv) Could the anttmalar~al effects of the artemisinin derivatives be separated from the neuropathological effects? For example, do the inactive dewy-metabolites produce any neurological effects? This question was being addressed currently. As artemisinin and its derivatives are available and are in clinical use in some countries, immediate and detailed investigation of the toxicity issue is needed. Also there is an urgent need for a robust clinical method which can be used tn assess any neurotoxicity in viva in the field. With the excemion of ar- teethe; and artemether, no other derivative has been assessed for neurotoxicity (including the trioxanes). The studies were time-consuming and required the services of an expert neuroanatomistipathologisf. A suitable non- human primate model is also being sought.

(v) What are the best methods of sample storage and processing for drug assays? This was not yet known for certain. Plasma appeared to be the mat appropriate biol- ogical medium for analysis. Plasma should be separated and frozen as quickly as possible at -70°C.

Amether (i) Pharmacokinetics. Are the a

relationship between the dose o P parent lack of a linear arteether and the area

under the curve, and the apparent lengthening of the half-time with higher doses, indicative of zero-order kinetics? No, they probably reflect a de

E” t of drug in the

muscle after intramuscular injection. urthermore, the tail of the plasma concentration-time curve was near the limit of assay detection, and was therefore subject to cnn- siderable error.

(ii) From a regulatory and practical clinical standpoint is arteether the same as, or a different drug from, we- mether? If it is different were the studies on mortality now under way with artemether to be repeated with arteether? Yes, art&her had tn be considered a different drug from artemether with potential for important dif- ferences in efficacy, disposition and toxicity but no, the mortality studies were not going to be repeated with arteether. The development of arteether sponsored by the World Health Organization (WHO) Tropical Disease Research Programme would proceed because it was essential to produce a drug that was manufactured to the standards required by, and therefore would obtain the full approval of, the regulatory authorities of western countries, and which was cheap and widely available. The production of any drug which was ‘incompletely’ registered could be threatened by changes in pharmaceu- tical company policies or mergers.

use (i) Should the artemisinin drugs be licensed in Africa,

S1164

and how should they be controlled? There was not a role yet for these drugs, as quinine was still effective in Africa ior the treatmeniof faldparum malaria and there was not yet convincing evidence that artemisinin or its derivatives would reduce mortality in Africa. If they were released, it would be very difficult to control their use. Education, advertising, and tough government controls would be necessary to support their distribution. However, for most African countries,, the available artemisinin derivatives were too expenwe to be used widely at current prices.

How were prices to be determined? The prices of the artemisinin compounds should be as low as possible. For parenteral treatment quinine was the usual comparator. An international price should be agreed. This was going to happen for artemether (RhBn*Poulenc Row) and arteether (ACF Chemifarnu).

Regisnation and regulatory issues RhBne-Poulenc Rarer are committed to artemether,

and are seeking international registration of the compound. This will be manufactured under GMl’ and dis- tributed at a standard international price (which will be comparable to that of parenteral quinine treatment).

It was revealed that several African countries have now either registered artemether, or are about to do so. Many participants expressed concern over the potential for uncontrolled drug use. The Tropical Disease Research Pro- gr-e of the WHO remained firmly committed to the development of arteether, and will seek to obtain international regisuation of this compound. It was acknow- ledged that there was probably no significant difference between artemether and arteether, although from a regulatory standpoint they had to be considered differently.

How were promising artemisinin derivatives to be se- lected for further development? This was a problem area, not just for the artemisinin derivatives, but for the whole field of natural products and their derivatives. The inter- face between identification and development needed investment of more scientific and financial resources.

Conclusions l’karmocology

A major concern was the inability to optimize dosage regimens in a rational way due to a current lack of ac- ceptable pharmacokinetic information. Without this information it is not possible to determine if drug and metabolite concentrations correlate in any way to the clinical response. As conventional chemical methods of drug assay (thin-layer chromatography, high performance liquid chromatography, gas chromatography and mass spectometry) had proved difficult to develop, the use of a bioassay to infer the concentration of pharmacologically active drug and metabolites (in terms of artemisinin equi- valents) has been advocated. This was considered a use- ful adjunct to physicochemical methods of anal measured total antimalarial activity (ix., that o Y

sis as it the par-

ent compound plus active metabolites). For the bioassay, analytical rigour similar to that required for chemical assay methods in terms of accuracy, precision and comparability berween laboratories would be essential. Al- though it is unlikely that the data obtained could be used in the drug regulatory process, bioassay would provide information of value in developing optimum treatment reeinlens.

A number of analytical techniques based on high performance liquid chromatography are now available, but as yet there are no reliable data on the pharmacokinetxs of artemisinin and its derivatives in atients infected with malaria. The important issues wh~c ,Yl need immediate at- tention are the inter-laboratory comparability of these assays and the most appropriate sample matrix, collection, storage and treatment procedures. All the analytical laboratories have agreed to undertake a series of cross-laboratory validation experiments in order to provide answers to these questions. The findings of these experiments will be circulated to clinical investigators involved

in pharmacokinetic studies. These experiments will be carried out in parallel with the pharmacodynamic evalu- ations.

A complete understanding of the metabolism of the artemisinin derivatives is essential. The antimalarial properties and potential toxicities of identified metabolites need to be addressed. Many hydroxylated and de- alkylated metabolites of artemether and arteether have been isolated and chemically characterized at the Univer- sity of Mississippi, USA. These metabolites are to be made available in limited amounts to the scientific corn- munity. The relative contribution of each metabolic pathway to the metabolism of these drugs in humans is unknown. Drug metabolism studies in human tissue are urgently needed.

In terms of antimalarial pharmacodynamics, the arte- m&in derivatives give a greater log kill per cycle than other classes of compound. They also have the broadest stage-specificity of drug action although, in terms of therapeutic outcome in severe infections, it is not yet clear whether the predominant parasite stage at the time of starting artemisinin treatment matters or not. Studies are continuing in this important area.

Drug toxicity, based on neuropathological changes seen in the rat and dog, is a cause of great concern. The relevance of these observations in animals to the use of the drug in humans is uncertain but requires urgent at- tention. Detailed studies of the neuropathological effects of this class of drugs as a whole are under way. These investigations should also reveal whether the perceived neurotoxic effects of artemisiti and its derivatives are linked to their antimalarial activity. Obviously, if the 2 can be dissociated safer compounds could be synthesized. In the continuing clinical studies brain tissue from patients with fatal malaria treated with artemisinin derivatives will be obtained at autopsy for histological investigations to see if there is any evidence of similar le- sions to those induced in animals. There will also be detailed follow-up of patients given oral preparations for malaria treatment, with specific evaluation of neurological toxicity.

Despite these concerns, the evident benefits of these compounds in drug-resistant malaria clearly outweigh the undefined potential for neurotoxicity. The use of the parenteral compounds for the treatment of severe malaria m areas with quinine resistance is justified and appropriate. It was also accepted that there is currently no alternative to the oral artemisinin derivatives in some parts of south-east Asia. Obviously, parenteral drugs should not be used for non-severe malaria.

Severe malaria. In south-east Asia, where multiple drug resistance of Plasmodium falctpamm is already a major problem, use of the artemisinin derivatives will in- crease. Monitored use of the drugs and continued clinical study should determine whether there are adverse neurological effects or not. If there are neurological adverse effects, they have not been apparent in the thousands of patients included thus far in clinical trials and in over a million people who have been treated with these drugs. The results of current mortality studies should be available in 2 years. There is a general consensus that artesunate is the most rapidly acting of the available compounds, but the chnical importance of this has not been assessed. A comparison of parenreral artesunate and arte- merher in severe falciparum malaria is the next priority. Artemisinin suppositories may represent an important advance in the rural management of severe malaria, but their stability, efficacy and cultural acceptability need further study. Further develo rica will depend on the

merit of these drugs in Af- resu ts of the current mortality P

studies (which should be of sufficient size and statistical oowerl.

Uncwnplicared malana. The artemisinin compounds are already in widespread use in much of south-east Asia.

Sl165

multi-dru used for t It

resistant strains of P. falciparum and can be e treatment of severe infections or for uncom-

plicated falciparum malaria in areas where l’. falcipamm is known to be multi-drug resistant. There is no evtdence of artemisinin resistance. The drugs are rapidly effective, and there is no evidence yet of significant toxicity in man. There is suggestive (but not conclusive) evidence that the derivatives of artemisinin may reduce mortalitv in areas of studies ~111 .%

uinine resistance. The r&Its of continuing e awlable SOOT and will clarifv the role of

the drugs (i.e., whether they will be&e drugs of choice, or alternatives for the treatment of severe malaria).

The following schedules have been used. (i) Severe infections. (a) Intramuscular artemether: 3.2

mgikg on the first day, followed by 1.6 mgikg per day until the patient can take effective oral therapy of another antimalarial. The daily dose of artemether can be given as one daily injection or 2 injections 12 h apart. (b) In- travenous or intramuscular artesunate: 2 @kg on the first day followed by 1 mgikg per day until oral therapy is possible. In hyperparasitaemic cases the following regimen has been used: 2 mgikg followed by 1 mgikg &6 h later and then 1 mgikgid until oral therapy.

(ii) Uncomplicated malaria. Use of the artemisinin derivatives should be regulated. The drugs should not be available ‘over the counter’. They should be prescribed only after microscopical coniirmation of the diagnosis of falciparum malaria, and not as prophylaxis because of the (unquantified) potential for toxicit If used, the artemisinin derivatives should be given or a minimum of 3 d P and in combination with an effective dose of mefloquine or any other long-acting, effective drug in order to achieve 290% cure rate, and to minimize the potential for development of resistance.

When given alone for at least 5 d cure rates are generally statisfactory, but compliance with longer course regimens is usually poor (even if the drugs are well tolerated). Poor compliance is associated wnb inadequate treatment, and provides selective pressure for the devel- omnent of resistance.

‘The best drug regimen for non-severe malaria is not established, but S5 d of artesunate (total dose 10 mgikg) plus mefloquine (15-25 mglkg depending on mefloquine sensitivity) seems very promising and should be studied further.

The following consensus recommendations will be modified by the results of trials in progress and should be updated regularly. Regional policies should be reviewed frequently in view of the rapid spread of drug resistant I’. falciparum. In pregnancy the artemisinin derivatives should probably not be used as primary treatment for uncomplicated malaria (unless there is no alternative), but they can be used for severe infections in areas of quinine resistance. Otherwise, the drugs are equally well tolerated and effective in adults and children. They should be reserved for the treatment of malaria, and not used for prophylaxis.

Africa. The consensus was for a neutral statement. Until the results of continuing trials are available there is no need to change the current policies ot recommendations for the treatment of severe malaria, as there is no evidence yet of an advantage from the use of the artemisinin derivatives in Africa. Artemisinin derivatives should not be introduced for the treatment of uncomplicated malaria in Africa at the present time.

Asia. The artemisinin derivatives are active against Nicholas J. White

summary of discussion and conclusions

Documents