Artenimol is able to reach high concentrations within the parasitized erythrocytes. Its endoperoxide bridge is thought to be essential for its antimalarial activity, causing free-radical damage to parasite membrane systems including:
The exact mechanism of action of piperaquine is unknown, but it likely mirrors that of chloroquine, a close structural analogue. Chloroquine binds to toxic haeme (derived from the patient’s haemoglobin) within the malaria parasite, preventing its detoxification via a polymerisation step.
Piperaquine is a bisquinoline, and this class has shown good antimalarial activity against chloroquineresistant Plasmodium strains in vitro. The bulky bisquinolone structure may be important for activity against chloroquine-resistant strains, and may act through the following mechanisms:
Resistance to piperaquine (when used as monotherapy) has been reported.
Pharmacokinetic profiles of artenimol and piperaquine have been investigated in animal models and in different human populations (healthy volunteers, adult patients and paediatric patients).
Artenimol is very rapidly absorbed, Tmax being approximately 1-2 hrs after single and multiple dosing. In patients, mean Cmax (CV%) and AUCINF of artenimol (observed after the first dose of artenimol/piperaquine) were 752 (47%) ng/ml and 2,002 (45%) ng/ml*h, respectively.
Artenimol bioavailability appears to be higher in malaria patients than in healthy volunteers, possibly because malaria per se has an effect on artenimol disposition. This may reflect malaria-associated impairment of hepatic function, causing an increase in artenimol bioavailability (reduction of first hepatic effect) without affecting its apparent elimination half-life, which is absorption rate limited. In healthy male volunteers under fasting conditions, mean Cmax and AUCINF of artenimol ranged between 180-252 ng/ml and 516-684 ng/ml*h, respectively.
The systemic exposure to artenimol was slightly lower following the last dose of artenimol/piperaquine combination (lower than after the first dose by up to 15%). Artenimol pharmacokinetic parameters were found to be similar in healthy volunteers of Asian and Caucasian origin. artenimol systemic exposure on the last day of treatment was higher in females than in males, the difference being within 30%.
In healthy volunteers, artenimol exposure was increased by 43% when administered with a high fat/high calorie meal.
Piperaquine, a highly lipophilic compound, is slowly absorbed. In humans, piperaquine has a Tmax of approximately 5 hours following a single and repeated dose. In patients mean (CV%) Cmax and AUC0-24 (observed after the first dose of artenimol/piperaquine) were 179 (62%) ng/ml and 1,679 (47%) ng/ml*h, respectively. Due to its slow elimination, piperaquine accumulates in plasma after multiple doses with an accumulation factor of approximately 3. Piperaquine pharmacokinetic parameters were found to be similar in healthy volunteers of Asian and Caucasian origin. On the other hand, on the last day of Eurtartesim treatment, the piperaquine maximum plasma concentration was higher in female than in male healthy volunteers, the difference being in the order of 30 to 50%.
In healthy volunteers, piperaquine exposure is increased approximately 3-fold when administered with a high fat/high calorie meal. This pharmacokinetic effect is accompanied by an increased effect on prolongation of the QT interval. Accordingly, artenimol/piperaquine combination should be administered with water no less than 3 hours after the last food intake, and no food should be taken within 3 hours after each dose.
Both piperaquine and artenimol are highly bound to human plasma proteins: the protein binding observed in in vitro studies was 44-93% for artenimol and >99% for piperaquine. Moreover, from in vitro and in vivo data in animals, piperaquine and artenimol tend to accumulate in RBC.
Artenimol was observed to have a small volume of distribution in humans (0.8 l/kg; CV 35.5%). Pharmacokinetic parameters observed for piperaquine in humans indicate that this active substance has a large volume of distribution (730 l/kg; CV 37.5%).
Artenimol is principally converted to α-artenimol-β-glucuronide (α-artenimol-G). Studies in human liver microsomes showed that artenimol was metabolised by the UDP-glucuronosyltransferase (UGT1A9 and UGT2B7) to α-artenimol-G with no cytochrome P450-mediated metabolism.
In vitro drug-drug interaction studies revealed that artenimol is an inhibitor of CYP1A2; therefore, there is the potential for artenimol to increase plasma concentrations of CYP1A2 substrates.
In vitro metabolism studies demonstrated that piperaquine is metabolised by human hepatocytes (approximately 85% of piperaquine remained after 2 hours incubation at 37°C). Piperaquine was mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Piperaquine was found to be an inhibitor of CYP3A4 (also in a time-dependent way) and to a lesser extent of CYP2C19, while it stimulated the activity of CYP2E1.
No effect on the metabolite profile of piperaquine in human hepatocytes was observed when piperaquine was co-incubated with artenimol. The piperaquine major metabolites were a carboxyl acid cleavage product, and a mono-N-oxidated product. In human studies, piperaquine was found to be a mild inhibitor of CYP3A4 enzyme while potent inhibitors of CYP3A4 activity caused mild inhibition of piperaquine metabolism.
The elimination half-life of artenimol is approximately 1 hour. The mean oral clearance for adult patients with malaria was 1.34 l/h/kg. The mean oral clearance was slightly higher for paediatric patients, however the differences were minor in magnitude (<20%). artenimol is eliminated by metabolism (mainly glucuroconjugation). Its clearance was found to be slightly lower in female than in male healthy volunteers. Data regarding artenimol excretion in humans are scarce. However, it is reported in the literature that the excretion of unchanged active substance in human urine and faeces is negligible for artemisinin derivatives.
The elimination half-life of piperaquine is around 22 days for adult patients and around 20 days for paediatric patients. The mean oral clearance for adult patients with malaria was 2.09 l/h/kg, while in paediatric patients was 2.43 l/h/kg. Due to its long elimination half-life, piperaquine accumulates after multiple dosing.
Animal studies showed that radiolabelled piperaquine is excreted by the biliary route, while urinary excretion is negligible.
No specific pharmacokinetic studies have been performed in patients with hepatic or renal insufficiency, or in elderly people.
In a paediatric pharmacokinetic study, and based on very limited sampling, minor differences were observed for artenimol pharmacokinetics between the paediatric and adult populations. The mean clearance (1.45 l/h/kg) was slightly faster in the paediatric patients than in the adult patients (1.34 l/h/kg), while the mean volume of distribution in the paediatric patients (0.705 l/kg) was lower than in the adults (0.801 l/kg).
The same comparison showed that piperaquine absorption rate constant and terminal half-life in children were predominantly similar to those seen in adults. However, the apparent clearance was faster (1.30 versus 1.14 l/h/kg) and the apparent total volume of distribution was lower in the paediatric population (623 versus 730 l/kg).
Literature data concerning chronic toxicity of piperaquine in dogs and monkeys indicate some hepatotoxicity and mild reversible depression of total white cell and neutrophil counts.
The most important nonclinical safety findings after repeated dosing were the infiltration of macrophages with intracytoplasmic basophilic granular material consistent with phospholipidosis and degenerative lesions in numerous organs and tissues. These adverse reactions were seen in animals at exposure levels similar to clinical exposure levels, and with possible relevance to clinical use. It is not known whether these toxic effects are reversible.
Artenimol and piperaquine were not genotoxic/clastogenic based on in vitro and in vivo testing.
No carcinogenicity studies have been performed.
Artenimol causes embryolethality and teratogenicity in rats and rabbits.
Piperaquine did not induce malformation in rats and rabbits. In a perinatal and postnatal development study (segment III) in female rats treated with 80 mg/kg, some animals had a delay of delivery inducing mortality of the neonates. In females delivering normally the development, behaviour and growth of the surviving progeny was normal following exposure in utero or via milk.
No reproduction toxicity studies have been performed with the combination of artenimol and piperaquine.
There is potential for neurotoxicity of artemisinin derivatives in man and animals, which is strongly related to the dose, route and formulations of the different artenimol pro-drugs. In humans, the potential neurotoxicity of orally administered artenimol can be considered highly unlikely, given the rapid clearance ofartenimol, and its short exposure (3 days of treatment for malaria patients). There was no evidence of artenimol-induced lesions in the specific nuclei in rats or dogs, even at lethal dose.
Effects on blood pressure and on PR and QRS duration were observed at high piperaquine doses. The most important potential cardiac effect was related to cardiac conduction.
In the hERG test, the IC50 was 0.15 µmol for piperaquine and 7.7 µmol forartenimol. The association of artenimol and piperaquine does not produce hERG inhibition greater than that of the single compounds.
There are no phototoxicity concerns withartenimol, as it does not absorb in the range of 290-700 nm. Piperaquine has an absorption maximum at 352 nm. Since piperaquine is present in the skin (about 9% in the non-pigmented rat and only 3% in the pigmented rat), slight phototoxic reactions (swelling and erythema) were observed 24 hours after oral treatment in mice exposed to UV radiation.
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