Lariam Pharmacology, Pharmacokinetics, Studies, Metabolism - Mefloquine

Lariam Pharmacology, Pharmacokinetics, Studies, Metabolism - Mefloquine

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption

The absolute oral bioavailability of Mefloquineuine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of Lariam. In a similar group of volunteers, maximum plasma concentrations in mg/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 mg/L).

In healthy volunteers, a dose of 250 mg once weekly, produces maximum steady-state plasma concentrations of 1000 to 2000 mg/L, which are reached after 7 to 10 weeks.

Distribution

In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes, was found to be reversible. Protein binding is about 98%.

Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see PRECAUTIONS: Nursing Mothers ).

Metabolism

Two metabolites have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations, which were about 50% higher than those of Mefloquineuine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and Mefloquineuine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.

Elimination

In several studies in healthy adults, the mean elimination half-life of Mefloquineuine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that Mefloquineuine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged Mefloquineuine and its main metabolite under steady-state condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other metabolites could not be measured in the urine.

Pharmacokinetics in Special Clinical Situations

Children and the Elderly

No relevant age-related changes have been observed in the pharmacokinetics of Mefloquineuine. Therefore, the dosage for children has been extrapolated from the recommended adult dose.

No pharmacokinetic studies have been performed in patients with renal insufficiency since only a small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy persons.

Although clearance of Mefloquineuine may increase in late pregnancy, in general, pregnancy has no clinically relevant effect on the pharmacokinetics of Mefloquineuine.

The pharmacokinetics of Mefloquineuine may be altered in acute malaria.

Pharmacokinetic differences have been observed between various ethnic populations. In practice, however, these are of minor importance compared with host immune status and sensitivity of the parasite.

During long-term prophylaxis (>2 years), the trough concentrations and the elimination half-life of Mefloquineuine were similar to those obtained in the same population after 6 months of drug use, which is when they reached steady state.

In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase deficiency (see ANIMAL TOXICOLOGY).

Microbiology

Mechanism of Action

Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action is not known.

Activity In Vitro and In Vivo

Mefloquine is active against the erythrocytic stages of Plasmodium species (see INDICATIONS AND USAGE). However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective against malaria parasites resistant to chloroquine (see INDICATIONS AND USAGE).

Drug Resistance

Strains of P. falciparum with decreased susceptibility to Mefloquineuine can be selected in vitro or in vivo. Resistance of P. falciparum to Mefloquineuine has been reported in areas of multi-drug resistance in South East Asia. Increased incidences of resistance have also been reported in other parts of the world.

Cross Resistance

Cross-resistance between Mefloquineuine and halofantrine and cross-resistance between Mefloquineuine and quinine have been observed in some regions.