Moxidectin (Page 3 of 5)

8.6 Renal Impairment

No dose adjustment of Moxidectin Tablets is necessary for patients with mild (creatinine clearance (CrCL) 60 to 89 mL/min) to moderate (CrCL 30 to 59 mL/min) renal impairment. The safety of Moxidectin Tablets in patients with severe renal impairment (CrCL 15 to 29 mL/min) or end stage renal disease, is unknown [ see Clinical Pharmacology ( 12.3) ].

10 OVERDOSAGE

No specific antidote is available for overdose with Moxidectin Tablets. If overdose occurs, the patient should be monitored for evidence of toxicity. Treatment of overdose with Moxidectin Tablets consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Supportive therapy, if indicated, should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present.

11 DESCRIPTION

Moxidectin Tablets contain moxidectin, an anthelmintic drug and a macrocyclic lactone of the milbemycin class derived from the actinomycete Streptomyces cyanogriseus.

The chemical name of moxidectin is (2aE,4E,5’R,6R,6’S,8E,11R,13S,15S,17aR,20R,20aR,20bS)-6′-[(E)-1,3-dimethyl-1-butenyl]-5′,6,6′,7,10,11,14,15,17a,20,20a,20b-dodecahydro-20,20b-dihydroxy-5′,6,8,19-tetramethylspiro[11,15-methano-2H,13H,17H-furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2′-[2H]pyran]-4′,17(3’H)-dione 4′-(E)-(O-methyloxime). The structural formula is:

Figure 1: Moxidectin Structure

Figure 1 : Moxidectin Structure

Moxidectin is a white or pale-yellow, amorphous powder. The empirical formula is C 37 H 53 NO 8 and the molecular weight is 639.82 Dalton. Moxidectin is readily soluble in organic solvents such as methylene chloride, diethyl ether, ethanol, acetonitrile, and ethyl acetate. It is only slightly soluble in water (0.51 mg/L) and the melting point range for moxidectin powder is 145°C to 154°C.

Moxidectin Tablets are for oral administration. Each tablet contains 2 mg of moxidectin. The tablets are uncoated and include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose anhydrous, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Moxidectin, a macrocyclic lactone, is an anthelmintic drug [see Microbiology ( 12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

At a dose 4.5 times the approved recommended dose, moxidectin does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetic parameters of moxidectin following a single 8 mg oral dose of Moxidectin Tablets to healthy subjects and patients with onchocerciasis under fasted conditions are shown in Table 4. Mean moxidectin C max and AUC increased approximately proportionally to dose over a dose range of 2 to 36 mg (0.25 to 4.5 times the approved recommended dose) in healthy subjects under fasted conditions.

Table 4: Mean (± SD) Pharmacokinetic Parameters of Moxidectin Following a Single 8 mg Oral Dose of Moxidectin Tablets to Healthy Subjects and Patients with Onchocerciasis Under Fasted Conditions
PK Parameter Healthy Subjects (N = 27 ) Patients with Onchocerciasis (N = 3 1 )
C max (ng/mL) 58.9 ± 12.5 63.1 ± 20.0
T max * (hours) 4 (2, 8) 4 (1, 4)
AUC inf (ng•h/mL) 3387 ± 1328 2738 ± 1606
Half-life (hours) 784 ± 347 559 ± 525

C max = maximum plasma concentration; T max = time to reach C max ; AUC inf = area under the plasma concentration-time curve from time 0 to infinity; * Median (range)

Absorption

Effect of Food

Moxidectin mean C max and AUC increased on average by 34% and 39%, respectively, when administered with a standard high fat meal (900 calories, with a nutritional distribution of approximately 55% fat, 31% carbohydrates and 14% protein), compared to fasted conditions [see Dosage and Administration ( 2.1)].

Distribution

The apparent mean ± SD volume of distribution of moxidectin is 2421 ± 1658 L in patients with onchocerciasis. The plasma protein binding in humans is unknown.

Elimination

The mean terminal half-life of moxidectin in patients with onchocerciasis is 23.3 days (559 hours) following a single 8 mg dose of Moxidectin Tablets.

The apparent mean ± SD total clearance of moxidectin is approximately 3.50 ± 1.23 L/hour in patients with onchocerciasis.

Metabolism

The hepatic metabolism of moxidectin is minimal.

Excretion

Following administration of a single 8 mg oral dose of Moxidectin Tablets to healthy subjects, 2% of the dose is eliminated unchanged in the feces within the first 72 hours. Renal elimination of intact drug is negligible.

Specific Populations

In clinical studies, no clinically significant differences in the pharmacokinetics of moxidectin were observed based on age (18 to 60 years), sex, weight (42.7 to 107.2 kg), or renal impairment (creatinine clearance (CrCL) 47 to 89 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of moxidectin in patients with CrCL less than 47 mL/min is unknown. The pharmacokinetics of moxidectin in patients with hepatic impairment is unknown.

Patients with Renal Impairment

Based on a population pharmacokinetic analysis and the fact that renal elimination of intact drug is negligible, mild (creatinine clearance (CrCL), estimated by Cockcroft-Gault of 60 to 89 mL/min) and moderate (CrCL 30 to 59 mL/min) renal impairment is not likely to have an impact on the exposure of moxidectin. The effect of severe renal impairment (CrCL 15 to 29 mL/min) or of end-stage renal disease on the pharmacokinetics of moxidectin is unknown.

Drug Interaction Studie s

Clinical Study with Midazolam (CYP3A4 substrate )

Co-administration of a single 8 mg dose of Moxidectin Tablets with a single oral 7.5 mg dose of midazolam (a sensitive CYP3A substrate) to healthy subjects (n = 37) did not affect the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy midazolam.

In Vitro Studies

CYP Enzymes: Moxidectin is not a substrate or inhibitor of CYP enzymes.

Uridine 5′-diphospho-glucuronosyltransferases (UGTs): Moxidectin is not a UGT substrate.

Transporter Systems: Moxidectin is not a substrate of P-glycoprotein (P-gp) nor breast cancer resistance protein 1 (BCRP1).

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