KRINTAFEL Film‑coated tablet Ref.[10201] Active ingredients: Tafenoquine

Cardiac Electrophysiology

The effect of tafenoquine on the QTc interval was evaluated in a Phase 1 randomized, single-blind, placebo- and positive-controlled, parallel-group thorough QTc study in 260 healthy adult subjects. At a cumulative dose of 1,200 mg (400 mg/day for 3 days; 4 times the maximum recommended dose), tafenoquine did not prolong the QTc interval to any clinically relevant extent.

Exposure-Response Relationships

A saturable relationship between tafenoquine exposure (AUC) and clinical response (recurrence-free rate at 6 months) was identified. Tafenoquine exposures achieved with doses of 300 mg and higher are on the plateau of the exposure-response curve. Use of KRINTAFEL at doses or regimens other than a 300-mg single dose is not approved by the FDA.

Absorption

Maximum plasma concentrations were generally observed 12 to 15 hours following oral administration.

Food Effect

Plasma tafenoquine AUC increased by 41% and C_max increased by 31% when administered as an investigational capsule formulation with a high-calorie, high-fat meal (approximately 1,000 calories with 15% protein, 25% carbohydrate, and 60% fat) compared with the fasted state.

Distribution

Protein binding of tafenoquine is >99.5%. The apparent oral volume of distribution is ~1,600 L. Following single- and multiple-oral-dose administration, tafenoquine whole blood concentrations were on average 67% higher than corresponding plasma values.

Elimination

The apparent oral clearance of tafenoquine is approximately 3 L/h. The average terminal half-life is approximately 15 days.

Metabolism

Tafenoquine undergoes slow metabolism. Unchanged tafenoquine represented the only notable drug-related component in human plasma after a single oral dose of tafenoquine.

Excretion

The full excretion profile of tafenoquine in humans is unknown. Over a 6-day collection period, renal elimination of unchanged tafenoquine was low.

Specific Populations

Pharmacokinetics of tafenoquine were not significantly impacted by age, sex, ethnicity, and body weight. The effect of renal or hepatic impairment on tafenoquine pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

No clinically significant effects on tafenoquine pharmacokinetics were observed following coadministration with chloroquine, dihydroartemisinin-piperaquine, or artemether-lumefantrine in healthy subjects.

No clinically significant effects on the pharmacokinetics of dihydroartemisinin, piperaquine, artemether, lumefantrine, or substrates of cytochrome P450 isoenzymes (CYP)1A2 (caffeine), CYP2D6 (desipramine), CYP2C8 (chloroquine), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam, chloroquine) were observed following coadministration of tafenoquine in healthy subjects.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Tafenoquine inhibited metformin transport via human OCT2, MATE-1, and MATE2-K transporters. Clinical drug interaction studies with tafenoquine and OCT2 and MATE substrates have not been conducted [see Drug Interactions (7)].

The effect of tafenoquine on substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides 1B1/1B3 (OATP1B1/OATP1B3) is unknown.

Mechanism of Action

Tafenoquine, an 8-aminoquinoline antimalarial, is active against the liver stages including the hypnozoite (dormant stage) of P. vivax. In addition to its effect on the parasite, tafenoquine causes red blood cell shrinkage in vitro. The molecular target of tafenoquine is not known.

Antimicrobial Activity

Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of P. vivax. The activity of tafenoquine against the pre-erythrocytic liver stages of the parasite prevents the development of the erythrocytic forms of the parasite, which are responsible for relapses in P. vivax malaria [see Clinical Studies (14)].

Resistance

A potential for development of resistance of Plasmodium species to tafenoquine was not evaluated.

Carcinogenesis

Two-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses of 1 mg/kg/day and above (3 times the clinical exposure based on AUC comparisons). Tafenoquine was not carcinogenic in mice. Given the single-dose administration of KRINTAFEL, these findings may not represent a carcinogenicity risk to humans.

Mutagenesis

Tafenoquine did not cause mutations or chromosomal damage in 2 definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.

Impairment of Fertility

In a rat fertility study, tafenoquine was given orally at 1.5, 5, and 15 mg/kg/day (up to about 0.5 times the human dose based on body surface area comparisons) to males for at least 67 days, including 29 days prior to mating, and to females from 15 days prior to mating through early pregnancy. Tafenoquine resulted in reduced number of viable fetuses, implantation sites, and corpora lutea at 15 mg/kg in the presence of maternal toxicity (mortality, piloerection, rough coat, and reduced body weight).

Trial 1 (NCT01376167) was a double-blind, controlled clinical trial of 522 adults positive for P. vivax across 3 regions (Asia, Africa, and Latin America). All patients received chloroquine phosphate (600-mg free base on Days 1 and 2 with 300-mg free base on Day 3) to treat the acute infection in addition to either a one-time dose of KRINTAFEL (two 150-mg tablets) on Day 1 or Day 2 (n=260), an active control (n=129), or placebo (n=133) in a 2:1:1 fashion. Patients included in the trial had a mean age of 35 (range: 16 to 79 years), were 75% male and from the following regions: 70% Latin America (Brazil and Peru), 19% SE Asia (Thailand, Cambodia, and the Philippines), and 11% Africa (Ethiopia).

Patients were considered recurrence-free at 6 months if they demonstrated initial parasite clearance, took no antimalarial medications, and were confirmed parasite-free at the 6-month final assessment (i.e., absence of relapse or new infection).

Due to the risk of hemolytic anemia, patients were excluded from the trial if they had a G6PD enzyme activity level <70% of the site median value for G6PD normals (8.2 IU/gHb). In this trial, the minimum G6PD enzyme level of any subject was 5.4 IU/gHb. Patients with severe malaria were excluded from the trial.

The recurrence-free efficacy rates at 6 months among the groups receiving KRINTAFEL and placebo are presented in Table 2. The risk of recurrence for KRINTAFEL plus chloroquine was reduced by 76% compared with placebo plus chloroquine.

Table 2. Recurrence-Free Efficacy Rates of KRINTAFEL in Patients with P. Vivax at 6 Months – Trial 1^a:

^a All randomized patients were treated and had a positive parasite smear for P. vivax at baseline.
^b Odds ratio of the risk of recurrence of KRINTAFEL plus chloroquine versus placebo plus chloroquine using logistic regression model with treatment and region as covariates. Subjects who did not demonstrate initial clearance, took a concomitant medication with antimalarial activity, or who had a missing Day 180 assessment were considered ‘missing/indeterminate’ and were counted as recurrences in the analysis.

In Trial 2 (NCT01376167), a dose-ranging trial with a study design similar to Trial 1, 57 and 54 subjects were randomized to KRINTAFEL 300-mg single dose plus chloroquine (same dose as in Trial 1) and placebo plus chloroquine groups, respectively. KRINTAFEL plus chloroquine demonstrated a statistically significantly higher rate of recurrence-free efficacy at 6 months compared with the placebo plus chloroquine control group (84% versus 39%, with a difference of 45% and 95% CI [29%, 61%]).