Agepha Pharma

LODOCO

colchicine tablets 0.5 mg

Growth

ORAL · TABLET

12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of colchicine in the prevention of major cardiovascular events is not understood. However, it is known that colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation, and migration of neutrophils. Colchicine may also interfere with the intracellular assembly of the inflammasome complex in neutrophils and monocytes that mediates activation of interleukin-1β. These anti-inflammatory effects are consistent with clinical data demonstrating that colchicine reduces high sensitivity C- reactive protein (hs-CRP). 12.2 Pharmacodynamics The pharmacodynamics of colchicine in the intended indication is not completely understood. 12.3 Pharmacokinetics In healthy adults, colchicine exhibits linear pharmacokinetics within a dose range of 0.5 to 1.5 mg. Mean pharmacokinetic parameter values of LODOCO in healthy adults are shown in table 2. Table 2: Summary of LODOCO Pharmacokinetic Parameters in Healthy Adults under Fasting and Fed Conditions BE studies C max ng/ml T max * hours t ½ hours AUC 0-t ng·h/ml Single dose of 0.5 mg (fasting) 2.1± 1.0 1.0 (Range 0.5-2.3) 31.9 18.6± 7.0 Single dose of 0.5 mg (fed) 1.8± 0.4 1.7 (Range 0.7- 3.5) 31.0 16.4 ± 4.4 *Median and range are presented Absorption Oral colchicine intake undergoes an entero-hepatic recirculation. In healthy adults, LODOCO is absorbed when given orally, reaching a mean Cmax 2.1 ng/ml in approximately 1 hour after a single dose administered under fasting conditions. The mean absolute bioavailability of colchicine is reported to be approximately 45%. Effect of food When LODOCO was administered with or following a high-fat, high-calorie meal in a bioavailability study, the results showed a lack of a significant food effect, see Table 2, above. LODOCO may be administered with or without food. The mean peak plasma concentration of LODOCO under fed conditions was found to be 1.8 ng/ml in approximately 1.75 hour. Distribution The mean apparent volume of distribution in healthy volunteers is approximately 1300 L. Colchicine binding to serum protein is 39 ± 5%, primarily to albumin regardless of concentration. After reabsorption, is rapidly removed from the plasma and distributed to various tissues. Colchicine is found in high concentrations in leucocytes, kidneys, the liver, and spleen. Colchicine crosses the placenta. Colchicine also distributes into breast milk. Colchicine can also cross the blood-brain barrier and accumulate within the brain, which contains large amount of tubulin [see Use in Specific Populations (8.1, 8.2)] . Elimination Metabolism Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2- and 3-DMC, respectively) and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is

2023

$46K Part D

LOE: 2034

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