Atovaquone and Proguanil Hydrochloride

ATOVAQUONE AND PROGUANIL HYDROCHLORIDE- atovaquone and proguanil hydrochloride tablet, film coated
Aidarex Pharmaceuticals LLC

Rx only

DESCRIPTION

Atovaquone and proguanil hydrochloride is a fixed-dose combination of the antimalarial agents atovaquone and proguanil hydrochloride. 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 C22 H19 ClO3 . The compound has the following structural formula:

Structural Formula for Atovaquone

The chemical name of proguanil hydrochloride USP is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride USP is a white crystalline solid that is sparingly soluble in water. It has a molecular weight of 290.22 and the molecular formula C11 H16 ClN5 •HCl. The compound has the following structural formula:

Structural Formula for Proguanil HCl

Atovaquone and proguanil hydrochloride tablets are for oral administration. Each atovaquone and proguanil hydrochloride tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride USP. The inactive ingredients in the tablet are colloidal silicon dioxide, ferric oxide red, hypromellose 2910, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, polyethylene glycol 400, polyethylene glycol 8000, sodium starch glycolate, titanium dioxide.

CLINICAL PHARMACOLOGY

Microbiology:

Mechanism of Action:

The constituents of atovaquone and proguanil hydrochloride 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 hydrochloride 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 hydrochloride alone was demonstrated in clinical studies in both immune and non-immune patients (see CLINICAL 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 hydrochloride 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 to 3 times and Cmax 5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. Atovaquone and proguanil hydrochloride tablets should be taken with food or a milky drink.

Proguanil hydrochloride is extensively absorbed regardless of food intake.

Distribution:

Atovaquone is highly protein bound (>99%) over the concentration range of 1 to 90 mcg/mL. A population pharmacokinetic analysis demonstrated that the apparent volume of distribution of atovaquone (V/F) in adult and pediatric patients after oral administration is approximately 8.8 L/kg.

Proguanil is 75% protein bound. A population pharmacokinetic analysis demonstrated that the apparent V/F of proguanil in adult and pediatric patients >15 years of age with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients’ ≤15 years of age with body weights from 11 to 56 kg, the V/F of proguanil ranged from 462 to 966 L.

In human plasma, the binding of atovaquone and proguanil was unaffected by the presence of the other.

Metabolism:

In a study where 14 C-labeled 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% to 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 to 3 days in adult patients.The elimination half-life of proguanil is 12 to 21 hours in both adult patients and pediatric patients, but may be longer in individuals who are slow metabolizers.

A population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil are related to the body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight ≥11 kg are shown in Table 1.

Table 1. Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight
*
SD = standard deviation.

Body Weight

Atovaquone

Proguanil

N

CL/F (L/hr) Mean ± SD* (range)

N

CL/F (L/hr) Mean ± SD * (range)

11-20 Kg

159

1.34 ± 0.63 (0.52-4.26)

146

29.5 ± 6.5 (10.3-48.3)

21-30 Kg

117

1.87 ± 0.81 (0.52-5.38)

113

40.0 ± 7.5 (15.9-62.7)

31-40 Kg

95

2.76 ± 2.07 (0.97-12.5)

91

49.5 ± 8.30 (25.8-71.5)

> 40 Kg

368

6.61 ± 3.92 (1.32-20.3)

282

67.9 ± 19.9 (14.0 — 145)

The pharmacokinetics of atovaquone and proguanil in patients with body weight below 11 kg have not been adequately characterized.

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