Pathway Amodiaquine Pathway, Pharmacokinetics

Description

Amodiaquine is a Mannich base 4-aminoquinoline with a mode of action similar to that of chloroquine [Article:18855526]. Amodiaquine was first introduced as an alternative to chloroquine since it appeared to have activity against chloroquine resistant Plasmodium falciparum (P. falciparum) parasites. The drug was actively used for malaria prophylaxis but consequently removed from the Essential Drugs List due to rare but serious adverse effects of hepatitis and agranulocytosis associated with its long-term use [Articles:18193915, 2868340]. The drug is being re-introduced as a component of the artesunate-amodiaquine combination therapy for the treatment of uncomplicated malaria, particularly in Africa. Artesunate is a short-acting artemisinin derivative (see Artimesinins Pathway). Combination therapy of artemesinins with one or two long-acting antimalarial drugs (amodiaquine, mefloquine, sulfadoxine/pyrimethamine or lumefantrine) is favored to retard the development and progression of drug resistance in P. falciparum [Article:19926036]. In a multicentre phase III trial in Gabon, Kenya, and Senegal, the artesunate-amodiaquine drug combination showed a better overall efficacy than amodiaquine alone in African children [Article:11978332]. However, a small number of patients in both groups developed neutropenia, a finding that warrants further investigation. More amodiaquine safety data will also need to be collected systematically on the use of repeat amodiaquine treatments. [Article:11978332]. A multicentre, randomized, controlled, investigator-blinded, parallel-group study conducted in five African centers (Cameroon, Madagascar, Mali and Senegal) concluded that the once-a-day intake of a fixed-dose combination of artesunate-amodiaquine appears to be an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria [Article:19505304]. In this trial, comprised of African children and adults, seven cases of severe transient and asymptomatic neutropenia occurred [Article:19505304]. Several others trials have also investigated the efficacy and tolerability of artesunate-amodiaquine combinations in African malaria patients with similar results [Articles:20214761, 20170477, 20166428]. One patient developed CTC grade 4 hepatitis in another trial in young African children treated with artesunate-amodiaquine [Article:19691851]. Vomiting, skin rashes, and pruritus were other reported adverse effects of artesunate-amodiaquine treatment [Articles:11978332, 19505304, 19691851]. A recent case study reported the adverse effects acute dystonic reaction and persistent asymptomatic bradycardia in two African children after treatment amodiaquine for uncomplicated malaria [Article:20126327].

After oral administration, amodiaqine is rapidly absorbed from the gastrointestinal tract. In the liver it undergoes rapid and extensive metabolism to N-desethyl-amodiaquine (DEAQ) which concentrates in blood cells [Article:3814460]. Amodiaquine is three-times more potent than DEAQ but the concentration of amodiaquine in blood is quite low [Article:3965841]. Therefore, DEAQ is responsible for most of the observed antimalarial activity [Article:3965841] (see below for of mechanisms of action). In vitro, amodiaquine showed synergistic activity and enhanced the efficacy of DEAQ against P. falciparum [Article:15504826]. Amodiaquine and DEAQ are over 90% bound to plasma proteins, which is a potential site for drug interaction [Article:11432537]. An in vitro study using human liver microsomes and two sets of recombinant human cytochrome P450 isoforms (from lymphoblastoids and yeast) established that the oxidation step from amodiaquine to DEAQ in the liver is mainly performed by CYP2C8 [Article:11805197]. These experiments also showed that there is an unidentified metabolite (M2), which is a product of amodiaquine metabolism by the extrahepatic CYP1A1 and CYP1B1 enzymes [Articles:11805197, 18855526]. Several studies isolated N-bis-desethyl-amodiaquine and 2-hydroxydesethylamodiaquine as minor metabolites compared to DEAQ in human urine and blood, but the pharmacological importance of these metabolites remains unclear [Articles:3965841, 3519640, 3549750]. Further metabolism of DEAQ to N-bis-desethyl-amodiaquine has been suggested although the plasma and urine concentrations of this metabolite were low in healthy volunteers [Article:8329010]. The above mentioned in vitro study, which identified CYP2C8 as main metabolizing enzyme, did not observe the bis-desethyl-amodiaquine and 2-hydroxydesethylamodiaquine metabolites.

Mechanism of action
In vitro studies suggest that amodiaquine inhibits the digestion of hemoglobin as the antimalarial mode of action [Article:11853690]. The drug also inhibits the glutathione-dependent destruction of ferriprotoporphyrin IX in the malaria parasite, resulting in the accumulation of this peptide, which is toxic for the parasite [Article:18193915].

Toxicity
The mechanisms involved in agranulocytosis and hepatotoxicity have not been fully defined. Direct dose-dependent toxicity has been suggested as a possible mechanism [Articles:2328196, 3082409], also a number of studies have indicated the involvement of the immune response [Articles:2917131, 3668269, 3997496]. The toxic agent has been proposed to be an amodiaquine reactive quinoneimine metabolite [Articles:3342086, 7618347]. The quinoneimine metabolite is believed to exert its toxicity through covalent binding to cell components, leading to direct disruption of its functions and/or triggering an anti-amodiaquine IgG antibody-based immunological response [Articles:2917131, 2210868, 7575670, 18855526].

Pharmacogenetics
Pharmacokinetic studies on amodiaquine and DEAQ showed that there is great interindividual variability in kinetic parameters [Article:11805197]. This variation could have implications in the therapeutic and toxicological response to the drug. Polymorphisms in the CYP2C8 gene have been shown to impact function: Recombinant CYP2C8*2 and CYP2C8*3 decreased the metabolism of the anticancer agent paclitaxel in vitro, and CYP2C8*3 had also reduced activity towards the endogenous substrate arachidonic acid [Article:11668219]. Contrary to in vitro data, most in vivo studies did not find an association between the CYP2C8*3 allele and paclitaxel pharmacokinetics [Article:19761371]. CYP2C8*2 (rs11572103) was only found in populations of African descent [Articles:11668219, 19381162]. CYP2C8*3 (rs10509681; rs11572080) was most prevalent among Caucasians [Article:11668219] and much less common in African populations [Articles:11668219, 15785959, 17361129]. In vitro experiments showed that CYP2C8*2 had a threefold higher Km and six fold lower intrinsic clearance for amodiaquine compared with the wildtype enzyme and the CYP2C8*3 variant had an even more profound decreased activity [Article:17361129]. As part of the same study, the association of the CYP2C8 genotype with treatment outcome and adverse events was investigated in 275 African malaria patients treated with amodiaquine monotherapy [Article:17361129]. Interestingly, no difference in antimalarial efficacy was noted in individuals who were homozygous or heterozygous for CYP2C8*2 alleles [Article:17361129]. CYP2C8*2 carriers had a higher frequency of treatment-associated mild side effects (abdominal pain) but no other associations were seen between CYP2C8*2 genotype and specific adverse events, including nausea, vomiting, fatigue, and jaundice [Article:17361129]. No differences between CYP2C8 genotypes with regard to amodiaquine efficacy or safety were evident in 103 Ghanaian children with uncomplicated malaria treated with either amodiaquine or with artesunate-amodiaquine [Article:18779360].

Drug-Drug interaction
A study in twelve healthy Swedish volunteers showed that a single dose of amodiaquine decreased CYP2D6 and CYP2C9 activities significantly compared to baseline values using debrisoquine and losartan as probe drugs [Article:16783563]. The antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations [Article:17361129]. A study in two healthy volunteers compared the metabolism of artesunate-amodiaquine and the combination of artesunate-amodiaquine with efavirenz. The addition of efavirenz to the artesunate-amodiaquine treatment increased amodiaquine exposure and decreased DEAQ exposure in both subjects [Article:17304470]. Both volunteers developed asymptomatic hepatotoxicity several weeks after study completion [Article:17304470]. This finding suggests that liver function monitoring may be especially necessary in HIV-positive patients receiving efavirenz together with amodiaquine.

Authors: Katrin Sangkuhl.
Citation:
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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History:
Therapeutic Categories:
  • Anti-infective agents

Entities in the Pathway

Genes (3)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
amodiaquine 2-hydroxy-desethyl- amodiaquine 3519640, 3549750, 3965841
amodiaquine M2 CYP1A1, CYP1B1 11805197, 18855526
amodiaquine N-bis-desethyl- amodiaquine 3519640, 3549750, 3965841
amodiaquine N-desethyl- amodiaquine (DEAQ) CYPs, CYP2C8 11805197, 3814460
N-desethyl- amodiaquine (DEAQ) N-bis-desethyl- amodiaquine 8329010

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