Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antimalarials, ATC Code: P01B B51

Mode of Action
The constituents of Malarone, atovaquone and proguanil hydrochloride, interfere with two different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. The mechanism of action of atovaquone against P. falciparum is via inhibition of mitochondrial electron transport, at the level of the cytochrome bc1 complex, and collapse of mitochondrial membrane potential.
One mechanism of action of proguanil, via its metabolite cycloguanil, is inhibition of dihydrofolate reductase, which disrupts deoxythymidylate synthesis. Proguanil also has antimalarial activity independent of its metabolism to cycloguanil, and proguanil, but not cycloguanil, is able to potentiate the ability of atovaquone to collapse mitochondrial membrane potential in malaria parasites. This latter mechanism may explain the synergy seen when atovaquone and proguanil are used in combination.

Microbiology

Atovaquone has potent activity against Plasmodium spp (in vitro IC50 against P. falciparum 0.23-1.43 ng/mL).

Atovaquone is not cross-resistant with any other antimalarial drugs in current use. Among more than 30 P. falciparum isolates, in vitro resistance was detected against chloroquine (41% of isolates), quinine (32% of isolates), mefloquine (29% of isolates), and halofantrine (48% of isolates) but not atovaquone (0% of isolates).

The antimalarial activity of proguanil is exerted via the primary metabolite cycloguanil (in vitro IC50 against various P. falciparum strains of 4-20 ng/mL; some activity of proguanil and another metabolite, 4-chlorophenylbiguanide, is seen in vitro at 600-3000 ng/mL).

In in vitro studies of P. falciparum the combination of atovaquone and proguanil was shown to be synergistic. This enhanced efficacy was also demonstrated in clinical studies in both immune and non- immune patients.

Clinical Efficacy- Malarone paediatric tablets

Prophylaxis
The efficacy in non-immune paediatric travellers has not been directly established, but may be assumed through extrapolation by the results on safety and efficacy in studies of up to 12 weeks in paediatric residents (semi-immune) of endemic areas, and from results of safety and efficacy in both semi-immune and non-immune adults.

Data in the paediatric population are available from two trials that primarily evaluated the safety of Malarone paediatric tablets in (non-immune) travellers to endemic areas. In these trials, a total of 93 travellers weighing <40 kg were given Malarone and 93 received another prophylactic antimalarial regimen (81 chloroquine/proguanil and 12 mefloquine). The majority of travellers went to Africa and the mean duration of stay was between 2-3 weeks. There were no cases of malaria recorded in any subjects who took part in these studies.

Treatment

An open-label, randomised, parallel-group trial was undertaken in Gabon in 200 children weighing ≥5 kg and <11 kg with confirmed, uncomplicated P. falciparum malaria. Treatment was with Malarone paediatric tablets or amodiaquine suspension. In the intent-to-treat population, the 28-day cure rate was 87% in the Malarone group (87/100 subjects). In the per-protocol population, the 28-day cure rate was 95% in the Malarone group (87/92 subjects). The parasitological cure rates for the Malarone group were 88% and 95% for the ITT and PP populations, respectively.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.
In clinical trials, where children have received Malarone dosed by bodyweight, trough levels of atovaquone, proguanil and cycloguanil in children are generally within the range observed in adults.

In prophylaxis clinical trials where children have received Malarone dosed by bodyweight, trough levels of atovaquone, proguanil and cycloguanil in children are generally within the range observed in adults (see following table).

Trough Plasma Concentrations [Mean ± SD, (range)] of Atovaquone, Proguanil and Cycloguanil during Prophylaxis with Malarone in Children* and Adults

Atovaquone:Proguanil        62.5 mg:25 mg     125 mg:50 mg     187.5 mg:75 mg      250mg:100 mg HCl Daily Dose
[Weight Category]           [11-20 kg]        [21-30 kg]       [31-40 kg]          Adult ( >40 kg) Atovaquone (µg/mL)          2.2 + 1.1         3.2 + 1.8        4.1 + 1.8           2.1 + 1.2 (0.2-5.8)         (0.2-10.9)       (0.7-8.8)           (0.1-5.7)
No. Subjects                n=87              n=88             n=76                n=100 
Proguanil (ng/mL)           12.3 + 14.4       18.8 + 11.2      26.8 + 17.1         26.8 + 14.0 (<5.0-14.3)       (<5.0-87.0)      (5.1-55.9)          (5.2-73.2)
No. Subjects                n=72              n=83             n=75                n=95 
Cycloguanil (ng/mL)         7.7 + 7.2         8.1 + 6.3        8.7 + 7.3           10.9 + 5.6 (<5.0-43.5)       (<5.0-44.1)      (6.4-17.0)          (5.0-37.8)
No. Subjects                n=58              n=69             n=66                n=95 
* Pooled data from two studies

Absorption
Atovaquone is a highly lipophilic compound with low aqueous solubility. In HIV-infected patients, the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 23% with an inter-subject variability of about 45%.

Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3 times and Cmax 5 times over fasting. Patients are recommended to take Malarone tablets with food or a milky drink (see section 4.2).

Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.

Distribution
Apparent volume of distribution of atovaquone and proguanil is a function of bodyweight.

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.

Following oral administration, the volume of distribution of atovaquone in adults and children is approximately 8.8 L/kg.

Proguanil is 75% protein bound. Following oral administration, the volume of distribution of proguanil in adults and children ranged from 20 to 42 L/kg.

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

Biotransformation
There is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone in urine with the parent drug being predominantly (>90%) eliminated unchanged in faeces.

Proguanil hydrochloride is partially metabolised, primarily by the polymorphic cytochrome P450 isoenzyme 2C19, with less than 40% being excreted unchanged in the urine. Its metabolites, cycloguanil and 4-chlorophenylbiguanide, are also excreted in the urine.

During administration of Malarone at recommended doses proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.

Elimination

The elimination half life of atovaquone is about 2-3 days in adults and 1-2 days in children.
The elimination half lives of proguanil and cycloguanil are about 12-15 hours in both adults and children.

Malarone Paediatric Tablets
Oral clearance for atovaquone and proguanil increases with increased body weight and is about 70% higher in a 40 kg subject relative to a 20 kg subject. The mean oral clearance in paediatric and adult patients weighing 5 to 40 kg ranged from 0.5 to 6.3 L/h for atovaquone and from 8.7 to 64 L/h for proguanil.

Malarone Tablets for Adults
Oral clearance for atovaquone and proguanil increases with increased bodyweight and is about 70% higher in an 80 kg subject relative to a 40 kg subject. The mean oral clearance in paediatric and adult patients weighing 10 to 80 kg ranged from 0.8 to 10.8 L/h for atovaquone and from 15 to 106 L/h for proguanil.

Pharmacokinetics in the elderly

There is no clinically significant change in the average rate or extent of absorption of atovaquone or proguanil between elderly and young patients. Systemic availability of cycloguanil is higher in the elderly compared to the young patients (AUC is increased by 140% and Cmax is increased by 80%), but there is no clinically significant change in its elimination half life (see section 4.2).

Pharmacokinetics in renal impairment

There are no studies in children with renal impairment.
In adult patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone, proguanil and cycloguanil are within the range of values observed in patients with normal renal function.
Atovaquone Cmax and AUC are reduced by 64% and 54%, respectively, in adult patients with severe renal impairment (<30 mL/min/1.73 m2).
In adult patients with severe renal impairment, the elimination half lives for proguanil (t½ 39 h) and cycloguanil (t½ 37 h) are prolonged, resulting in the potential for drug accumulation with repeated dosing (see sections 4.2 and 4.4).

Pharmacokinetics in hepatic impairment

There are no studies in children with hepatic impairment.

In adult patients with mild to moderate hepatic impairment there is no clinically significant change in exposure to atovaquone when compared to healthy patients.
In adult patients with mild to moderate hepatic impairment there is an 85% increase in proguanil AUC with no change in elimination half life and there is a 65-68% decrease in Cmax and AUC for cycloguanil.

No data are available in adult patients with severe hepatic impairment (see section 4.2).