Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Abstract

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 + 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 + 75 liters/kg and 2,063 ± 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 + 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.The 4-amino quinoline amopyroquin was proposed for antimalarial therapy nearly 30 years ago. It has been effective in the treatment of acute Plasmodium falciparum and Plasmodium vivax malaria (10,11,17). Moreover, amopyroquin seems more active in vitro than the other 4-amino quinolines (chloroquine or monodesethyl amodiaquine) against resistant strains of P. falciparum (15).Amopyroquin is metabolized more extensively in rats than in rabbits to three metabolites, one of which is probably the primary amine derivative (15). In rats, amopyroquin is widely distributed in tissues and in plasma the drug concentrations are decreased, with a terminal half-life of 14 h (15,18). But during the 8 h after a single 60-or 120-mg/kg (body weight) dose of amopyroquin given intraperitoneally, this half-life has been estimated as 2 h (6). In rabbits, a similar bioavailability, about 70%, was observed after oral and intramuscular (i.m.) administration, and terminal elimination half-lives were 18, 24, and 26 h for intravenous (i.v.), i.m., and oral routes, respectively (15). No study has described the metabolism and the pharmacokinetic behavior of amopyroquin in humans.The aims of the present study were as follows: (i) to investigate the metabolism and the pharmacokinetic parameters of amopyroquin in healthy subjects after i.m. administration of amopyroquin base at 2 mg/kg (body weight) and (ii) to compare the following three i.m. therapeutic regimens in P. falciparum malaria patients on the basis of drug concentrations in the blood and in vivo efficacy: 3 mg/kg (body weight) (group 1), 6 mg/kg (group 2), and 6 mg/kg followed by 3 mg/kg 24 h later (group 3). * Corresponding...

The pharmacokinetics of chloroquine in healthy andPlasmodium chabaudi-infected mice: implications for chronotherapy

“…Terminal t1/2 were 14.5 hr, 22 hr and 5 days, respectively (Pussard et al, 1988;Verdier et al, 1989), indicating a correlation between the size of the animal and this parameter.…”

Efficacy of intramuscular amopyroquin for treatment of Plasmodium falciparum malaria in the Gabon Republic

“…The persistence or reappearance of parasites in blood was always associated with a lower hematocrit value, which mainly reflected the level of parasitemia, as confirmed by the difference in hematocrit values (on day 7) of the children who succeeded or failed therapy. Among the patients, who failed therapy, however, those who were parasitemic on day The levels of ApQ in blood obtained with the regimen described here 24 h after the second injection were lower than the theoretic value predicted by concentration-time curve models obtained from Caucasian, adult, and healthy volunteers (16). Ethnicity, age, and disease-related factors may contribute to these differences.…”

“…At the same time, multicenter studies in patients with acute malaria showed a poor efficacy when 3 mg/kg was used (16% in Gabon [n = 79]; 25% in Madagascar [n = 12]) and when 6 mg/kg was used (42% in Gabon [n = 25]) and only partial efficacy when 6 and 3 mg/kg were used at a 24-h interval (83% in Gabon [n = 23]; 80% in Cameroon [n = 78]) (10). From the results of those clinical trials and the results of a kinetic study in healthy subjects (16), we proposed the following regimen as being potentially therapeutic: two intramuscular injections of 6 mg/kg each at a 24-h interval.…”

“…After being abandoned in favor of chloroquine (Cq) and then Aq, interest in ApQ is now renewed following the extensive development of resistance to Cq and the appearance of severe side effects with Aq after prolonged prophylaxis (2,6). Since no pharmacokinetic studies of ApQ were available, we initially studied its metabolism and kinetics in the rat and rabbit (13) and then in healthy human volunteers (16), using the dosage of 3 mg/kg, which was initially effective. At the same time, multicenter studies in patients with acute malaria showed a poor efficacy when 3 mg/kg was used (16% in Gabon [n = 79]; 25% in Madagascar [n = 12]) and when 6 mg/kg was used (42% in Gabon [n = 25]) and only partial efficacy when 6 and 3 mg/kg were used at a 24-h interval (83% in Gabon [n = 23]; 80% in Cameroon [n = 78]) (10).…”

Optimized and convergent synthesis of potent anti-malarial aminoquinoline compounds: easy access to analogs

“…More excitingly, we developed a series of analogs where 4 ′ -hydroxy group was replaced by various amino substituents 4 (Paunescu et al , 2008 ). Furthermore, as AQ-analogs obtained by the replacement of the N -diethylamino function of the side chain, with a pyrrolidine cycle (amopyroquine, ApQ) or a Ntert -butyl group were proved to be as active and metabolically less labile (Hawley et al , 1996 ;Verdier et al , 1989 ), we completed our study with the development of parallel ApQ-analogs series. The substitution of 4 ′ -hydroxy by N -methylpiperazine (compound 5 ) or morpholine (compound 6 ) provided low nanomolar activity upon K1 chloroquino-resistant strain and low cytotoxicity (Paunescu et al , 2008 ).…”