Qualaquin (Quinine Sulfate) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

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 T_max was longer, and mean AUC and C_max 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 ¹ of Oral Quinine Sulfate Capsules

PHARMACOKINETIC PARAMETER	Healthy Subjects (N = 23) Mean ± SD	Uncomplicated P.falciparum Malaria Patients (N = 15) Mean ± SD
Dose (mg/kg)	8.7	10
Tmax (h)	2.8 ± 0.8	5.9 ± 4.7
Cmax (mcg/mL)	3.2 ± 0.7	8.4
AUC0-12(mcg*h/mL)	28.0	73.0

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 T_max of quinine was prolonged to about 4.0 hours, but the mean C_max 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 inα₁-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. In vitro studies using human liver microsomes and recombinant P450 enzymes have shown CYP3A4 is the major enzyme responsible for quinine metabolism and to a lesser extent CYP1A2. Other enzymes, including CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 have some role in the metabolism of quinine but the rank order differs depending on methodology used in the in vitro studies. Therefore, co-administration of drugs that inhibit these enzymes may result in an increase in plasma quinine concentrations, whereas co-administration of drugs that induce these enzymes 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

PHARMACOKINETIC PARAMETER	P. falciparum malaria pediatric patients (n = 15) Mean ± SD	Healthy pediatric controls (n = 5) Mean ± SD
Tmax (h)	4.0	2.0
Cmax (mcg/mL)	7.5 ± 1.1	3.4 ± 1.18
Half-life (h)	12.1 ± 1.4	3.2 ± 0.3
Total CL (L/h/kg)	0.06 ± 0.01	0.30 ± 0.04
Vd (L/kg)	0.87 ± 0.12	1.43 ± 0.18

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_max and 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 Qualaquin dosage regimen in elderly patients is not needed.

Cigarette Smoking

Smoking increases the clearance of quinine due to induction of CYP1A2. Quinine AUC following a single 600-mg dose is 44% lower in smokers than in non-smokers and the elimination half-life is 4.5 hours shorter (7.5 hours versus 12 hours in smokers and non-smokers, respectively). Similarly, plasma levels of quinine and 3-hydroxyquinine have been found to be lower in patients with P. falciparum who smoke as compared to those who do not. This factor should be considered in the event that an anticipated response to treatment is not seen.

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 Qualaquin 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).

Drug-Drug Interactions (see also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS/Drug Interactions)

Quinine directly inhibits the activity of CYP2C8 enzymes with an IC50 value of 47.4 µM. Quinine also inhibits CYP2D6 enzyme with an IC50 value of 20.1 μM. Quinine may increase plasma concentrations of drugs that are substrates of CYP2C8 or CYP2D6. Quinine does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4.

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.

CLINICAL STUDIES

Quinine has been used worldwide for hundreds of years in the treatment of malaria. Thorough searches of the published literature identified over 1300 references to the treatment of malaria with quinine, and from these, 21 randomized, active-controlled studies were identified which evaluated oral quinine monotherapy or combination therapy for treatment of uncomplicated P. falciparum malaria. Over 2900 patients from malaria-endemic areas were enrolled in these studies, and more than 1400 patients received oral quinine. The following conclusions were drawn from review of these studies:

In areas where multi-drug resistance of P. falciparum is increasing, such as Southeast Asia, cure rates with 7 days of oral quinine monotherapy were at least 80%; while cure rates for 7-days of oral quinine combined with an antimicrobial agent (tetracycline or clindamycin) were greater than 90%. In areas where multi-drug resistance of the parasite was not as widespread, cure rates with 7 days of quinine monotherapy ranged from 86 to 100%. Cure was defined as initial clearing of parasitemia within 7 days without recrudescence by day 28 after treatment initiation. P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh, and quinine may not be as effective in those areas.

Completion of a 7 day oral quinine treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of quinine combination therapy have been used. However, the published data from randomized, controlled clinical trials for shorter regimens of oral quinine in conjunction with tetracycline, doxycycline, or clindamycin for treatment of uncomplicated P. falciparum malaria is limited, and these shorter course combination regimens may not be as effective as the longer regimens.