Pharmacokinetics

Absorption: The oral bioavailability of quinine is 76 to 88% in healthy adults. Quinine exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of quinine sulfate, the mean quinine Tmax was longer, and mean AUC and Cmax were higher in patients with uncomplicated P. falciparum malaria than in healthy subjects, as shown in Table 1 below.

TABLE 1 Pharmacokinetic Parameters of Quinine in Healthy Volunteers and Patients with Uncomplicated P. falciparum Malaria after a Single Dose^a of Oral Quinine Sulfate Capsules

Qualaquin capsules may be administered without regard to meals. When a single oral 324 mg capsule of Qualaquin was administered to healthy volunteers (N=26) with a standardized high-fat breakfast, the mean Tmax of quinine was prolonged to about 4.0 hours, but the mean Cmax and AUC_0-24h were similar to those achieved when Qualaquin capsule was given under fasted conditions (See DOSAGE AND ADMINISTRATION).

Distribution: In patients with malaria, the volume of distribution (Vd/f) decreases in proportion to the severity of the infection. In published studies with healthy subjects who received a single oral 600 mg dose of quinine sulfate, the mean Vd/f ranged from 2.5 to 7.1 L/kg.

Quinine is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of quinine is increased to 78 to 95%, corresponding to the increase in α₁-acid glycoprotein that occurs with malaria infection.

Intra-erythrocytic levels of quinine are approximately 30 to 50% of the plasma concentration. Quinine penetrates relatively poorly into the cerebrospinal fluid (CSF) in patients with cerebral malaria, with CSF concentration approximately 2 to 7% of plasma concentration.

In one study, quinine concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of quinine concentrations in maternal plasma. The estimated total dose of quinine secreted into breast milk was less than 2 to 3 mg per day (See Pregnancy and Nursing Mothers).

Metabolism: Quinine is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine 2´-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug. The CYP isoenzyme pathways involved in quinine metabolism are not completely elucidated, but it is known that the formation of 3-hydroxyquinine is mediated mainly by CYP3A4 and to a minor extent, by CYP2C19. Therefore, co-administration of drugs that inhibit CYP3A4 may result in an increase in plasma quinine concentrations, whereas co-administration of drugs that induce CYP3A4 may decrease plasma quinine concentrations (See WARNINGS, PRECAUTIONS: DRUG INTERACTIONS ).

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