Monograph: |
Atovaquone; Proguanil Hydrochloride
Indications: Malaria; Malaria, prevention
DESCRIPTION:
Malarone (atovaquone and proguanil HCl) is a fixed-dose combination of the antimalarial agents atovaquone and proguanil HCl. The chemical name of atovaquone is trans -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19CIO3.
The chemical name of proguanil HCl is 1-(4-chlorophenyl)-5-isopropyl-biguanide HCl. Proguanil HCl is a white crystalline solid that is sparingly soluble in water. It has a molecular weight of 290.22 and the molecular formula C11H16CIN5Β·HCl.
Atovaquone; proguanil HCl tablets and atovaquone; proguanil HCl pediatric tablets are for oral administration. Each atovaquone; proguanil HCl tablet contains 250 mg of atovaquone and 100 mg of proguanil HCl and each atovaquone; proguanil HCl pediatric tablet contains 62.5 mg of atovaquone and 25 mg of proguanil HCl. The inactive ingredients in both tablets are low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, and sodium starch glycolate. The tablet coating contains red iron oxide, polyethylene glycol 400, hydroxypropyl methylcellulose, polyethylene glycol 8000, and titanium dioxide.
CLINICAL PHARMACOLOGY:
Microbiology
Mechanism of Action
The constituents of atovaquone; proguanil HCl, interfere with 2 different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Atovaquone is a selective inhibitor of parasite mitochondrial electron transport. Proguanil HCl primarily exerts its effect by means of the metabolite cycloguanil, a dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the malaria parasite disrupts deoxythymidylate synthesis.
Activity In Vitro and In Vivo
Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodium spp. Enhanced efficacy of the combination compared to either atovaquone or proguanil HCl alone was demonstrated in clinical studies in both immune and nonimmune patients (seeCLINICAL STUDIES).
Drug Resistance
Strains of P. falciparum with decreased susceptibility to atovaquone or proguanil/cycloguanil alone can be selected in vitro or in vivo . The combination of atovaquone and proguanil HCl may not be effective for treatment of recrudescent malaria that develops after prior therapy with the combination.
Pharmacokinetics
Absorption
Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter-individual variability.
Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3 times and Cmax 5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. Atovaquone; proguanil HCl tablets should be taken with food or a milky drink.
Proguanil HCl is extensively absorbed regardless of food intake.
Distribution
Atovaquone is highly protein bound (>99%) over the concentration range of 1-90 mug/ml. The apparent volume of distribution of atovaquone after oral administration is approximately 3.5 L/kg.
Proguanil is 75% protein bound. The apparent volume of distribution is approximately 42 L/kg.
In human plasma, the binding of atovaquone and proguanil was unaffected by the presence of the other.
Metabolism
In a study where 14C-labelled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified. Between 40-60% of proguanil is excreted by the kidneys. Proguanil is metabolized to cycloguanil (primarily via CYP2C19) and 4-chlorophenylbiguanide. The main routes of elimination are hepatic biotransformation and renal excretion.
Elimination
The elimination half-life of atovaquone is about 2-3 days in adult patients.
The mean oral clearance of atovaquone is approximately 0.04 L/hr per kg.
The mean oral clearance of proguanil is 3.22 L/hr per kg. The elimination half-life of proguanil is 12-21 hours in both adult patients and pediatric patients, but may be longer in individuals who are slow metabolizers.
Special Populations
Pediatrics
The pharmacokinetics of proguanil and cycloguanil are similar in adult patients and pediatric patients. However, the elimination half-life of atovaquone is shorter in pediatric patients (1-2 days) than in adult patients (2-3 days).
Geriatrics
No studies have been carried out in geriatric patients to assess the pharmacokinetics in this patient population. Since geriatric patients may have reduced renal function, caution should be taken when treating geriatric patients with atovaquone; proguanil HCl (see Special Populations, Renal Impairment and PRECAUTIONS).
Hepatic Impairment
The pharmacokinetics of atovaquone; proguanil HCl have not been studied in patients with hepatic impairment. The effect of hepatic dysfunction on the conversion of proguanil to cycloguanil is unknown.
Renal Impairment
The pharmacokinetics of atovaquone; proguanil HCl have not been studied in patients with renal impairment. Since proguanil and cycloguanil are eliminated primarily via the renal route, the clinical implication of treating patients with severe renal dysfunction with atovaquone; proguanil HCl is unknown (see PRECAUTIONS,General).
Drug Interactions
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.
Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.
Concomitant treatment with metoclopramide has also been associated with decreased bioavailability of atovaquone.
Concomitant administration of rifampin is known to reduce atovaquone levels by approximately 50% (see DRUG INTERACTIONS). The mechanism of this interaction is unknown.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely (see DRUG INTERACTIONS). Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions with other substrates or inhibitors of this pathway are unknown.
CLINICAL STUDIES:
Treatment of Acute Malarial Infections
In 3 phase II clinical trials, atovaquone alone, proguanil HCl alone, and the combination of atovaquone and proguanil HCl were evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum . Among 156 evaluable patients, the parasitological cure rate was 59/89 (66%) with atovaquone alone, 1/17 (6%) with proguanil HCl alone, and 50/50 (100%) with the combination of atovaquone and proguanil HCl.
Atovaquone; proguanil HCl was evaluated for treatment of acute, uncomplicated malaria caused by P. falciparum in 8 phase III controlled clinical trials. Among 471 evaluable patients treated with the equivalent of 4 atovaquone; proguanil HCl tablets once daily for 3 days, 464 had a sensitive response (elimination of parasitemia with no recurrent parasitemia during follow up for 28 days) (see TABLE 1). Seven patients had a response of R1 resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28 days after starting treatment). In these trials, the response to treatment with atovaquone; proguanil HCl was similar to treatment with the comparator drug in 4 trials, and better than the response to treatment with the comparator drug in the other 4 trials.
The overall efficacy in 521 evaluable patients was 98.7%
Eighteen of 521 (3.5%) evaluable patients with acute falciparum malaria presented with a pretreatment serum creatinine greater than 2.0 mg/dl (range 2.1-4.3 mg/dl). All were successfully treated with atovaquone; proguanil HCl and 17 of 18 (94.4%) had normal serum creatinine levels by day 7.
Data from a phase II trial of atovaquone conducted in Zambia suggested that approximately 40% of the study population in this country were HIV-infected patients. The enrollment criteria were similar for the phase III trial of atovaquone; proguanil HCl conducted in Zambia and the results are presented in TABLE 1. Efficacy rates for atovaquone; proguanil HCl in this study population were high and comparable to other populations studied.
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