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

^a Quinine Sulfate dose was 648 mg (approximately 8.7 mg/kg) in healthy subjects; and 10 mg/kg in patients with malaria

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 AUC0-24h 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) 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 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 a₁-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).

Elimination: Quinine is eliminated primarily via hepatic biotransformation. Approximately 20% of quinine is excreted unchanged in urine. Because quinine is reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid when the urine is acidic than when it is alkaline. In various published studies, healthy subjects who received a single oral 600 mg dose of quinine sulfate exhibited a mean plasma clearance ranging from 0.08 to 0.47 L/h/kg (median value: 0.17 L/h/kg) with a mean plasma elimination half-life of 9.7 to 12.5 hours.

In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of quinine sulfate, the mean total clearance of quinine was slower (approximately 0.09 L/h/kg) during the acute phase of the infection, and faster (approximately 0.16 L/h/kg) during the recovery or convalescent phase.

Extracorporeal elimination:

Administration of multiple-dose activated charcoal (50 grams administered 4 hours after quinine dosing followed by 3 further doses over the next 12 hours) decreased the mean quinine elimination half-life from 8.2 to 4.6 hours, and increased the mean quinine clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult volunteers who received a single oral 600 mg dose of quinine sulfate. Likewise, in 5 symptomatic patients with acute quinine poisoning who received multiple-dose activated charcoal (50 grams every 4 hours),the mean quinine elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in patients who did not receive activated charcoal. (See OVERDOSAGE).

In 6 patients with quinine poisoning, forced acid diuresis did not change the half-life of quinine elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged quinine recovered in the urine, in comparison to 8 patients not treated in this manner (See OVERDOSAGE).

Special Populations:

Pediatrics: The pharmacokinetics of quinine in children (1.5 to 12 years old) with uncomplicated P. falciparum malaria appear to be similar to that seen in adults with uncomplicated malaria. Furthermore, as seen in adults, the mean total clearance and the volume of distribution of quinine were reduced in pediatric patients with malaria as compared to the healthy pediatric controls. Table 2 below provides a comparison of the mean ± SD pharmacokinetic parameters of quinine in pediatric patients vs. healthy pediatric controls.

TABLE 2

Quinine Pharmacokinetic Parameters Following the First 10 mg/kg Quinine Sulfate Oral Dose in Pediatric Patients (age 1.5 to 12 years) with Acute Uncomplicated P. falciparum Malaria versus Healthy Pediatric Controls

Geriatrics: Following a single oral dose of 600 mg quinine sulfate, the mean AUC was about 38% higher in 8 healthy elderly subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean T_maxand C_max were similar in elderly and younger subjects after a single oral dose of quinine sulfate 600 mg. The mean oral clearance of quinine was significantly decreased, and the mean elimination half-life was significantly increased in elderly subjects compared with younger subjects (0.06 vs. 0.08 L/h/kg, and 18.4 hours vs. 10.5 hours, respectively). Although there was no significant difference in the renal clearance of quinine between the two age groups, elderly subjects excreted a larger proportion of the dose in urine as unchanged drug than younger subjects (16.6% vs. 11.2%). Despite these pharmacokinetic changes, an alteration in the quinine dosage regimen in elderly patients is not needed.

Hepatic impairment: In otherwise healthy subjects with moderate hepatic impairment (Child-Pugh B; N=9) who received a single oral 600 mg dose of quinine sulfate, the mean AUC increased by 55% without a significant change in mean C_max, as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of quinine was prolonged, the elimination half-life was increased, the apparent volume of distribution was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate hepatic impairment, dosage adjustment is not needed, but patients should be monitored closely for adverse effects of quinine (See DOSAGE AND ADMINISTRATION). No pharmacokinetic data are available for patients with severe hepatic impairment (Child-Pugh C).

Renal impairment: Following a single oral 600 mg dose of quinine sulfate in otherwise healthy subjects with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine = 9.6 mg/dL), the median AUC was higher by 195% and the median C_max was higher by 79% than in subjects with normal renal function (mean serum creatinine = 1 mg/dL). The mean plasma half-life in subjects with severe chronic renal impairment was prolonged to 26 hours compared to 9.7 hours in the healthy controls. Computer assisted modeling and simulation indicates that in patients with malaria and severe chronic renal failure, a dosage regimen consisting of one loading dose of 648 mg quinine sulfate followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to quinine (See DOSAGE AND ADMINISTRATION). The effects of mild and moderate renal impairment on the pharmacokinetics and safety of quinine sulfate are not known. Negligible to minimal amounts of circulating quinine in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of quinine is removed in 1 hour. Plasma quinine concentrations do not change during or shortly after hemofiltration in subjects with CRF (See OVERDOSAGE).

Electrocardiogram:

QTc interval prolongation was evaluated in a crossover pharmacokinetic study in healthy volunteers (N=24) who received single oral doses of Qualaquin (324 mg and 648 mg). The mean ± SD maximum QTc change from baseline around the quinine T_max was 10 ± 19 msec and 12 ± 18 msec, respectively for the 324 mg and 648 mg doses. There were no subjects who had a QTc interval greater than 500 msec, or had a maximum QTc change from baseline of greater than 60 msec (See WARNINGS).

Microbiology

Mechanism of Action: Quinine inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes. However, the precise mechanism of the antimalarial activity of quinine sulfate is not completely understood.

Activity In Vitro and In Vivo: Quinine sulfate acts primarily on the blood schizont form of P. falciparum; it is not gametocidal and has little effect on the sporozoite or pre-erythrocytic forms.

Drug Resistance: Strains of P. falciparum with decreased susceptibility to quinine can be selected in vivo. P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh.