Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: CIPLA MEDPRO (PTY) LTD., Building 9, Parc du Cap, Mispel Street, Bellville, 7530, RSA Company Contact Details: Phone: +27 21 943 4200 Customer Care: 080 222 6662
A 21.2 Oral hypoglycaemics
Dapagliflozin is a reversible inhibitor of sodium glucose co-transporter 2 (SGLT2). SGLT2 is selectively expressed in the kidney and is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycaemia in type 2 diabetes mellitus, reabsorption of filtered glucose continues. Dapagliflozin reduces both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and glomerular filtration rate (GFR). Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Over time, improvement in beta cell function (HOMA-2) may be observed with dapagliflozin.
Urinary glucose excretion (glycosuria) induced by dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated with mild diuresis and transient natriuresis. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 3 000 times more selective for SGLT2 vs. SGLT1, the major transporter in the gut responsible for glucose absorption.
The urinary glucose excretion with dapagliflozin results in osmotic diuresis and increases in urinary volume. The increase in urinary volume may be associated with a transient increase in urinary sodium excretion that which may not be associated with changes in serum sodium concentrations.
Dapagliflozin may cause a decrease in systolic blood pressure and diastolic blood pressure.
Urinary uric acid excretion was also increased and accompanied by a reduction in serum uric concentration. At 24 weeks, changes in serum uric concentrations from baseline ranged from – 0,0183 mmol/L to -0,0483 mmol/L.
Dapagliflozin is absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (Cmax) is attained within 2 hours after administration in the fasted state. The Cmax and AUC values increases proportionally to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food had relatively modest effects on the pharmacokinetics of dapagliflozin. Administration with a high-fat meal may decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1 hour but may not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin is 118 L.
Dapagliflozin is a C-linked glucoside, meaning the aglycone component is attached to glucose by a carbon-carbon bond, thereby conferring stability against glucosidase enzymes. The mean plasma terminal half-life (t1/2) for dapagliflozin is 12,9 hours following a single oral dose of dapagliflozin 10 mg. Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and was the predominant medicine-related component in human plasma, accounting for 42% [based on AUC(0-12 h)] of total plasma radioactivity, similar to the 39% contribution by parent compound. No other metabolite accounted for >5% of the total plasma radioactivity at any time point measured. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP mediated metabolism was a minor clearance pathway in humans.
Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin. After administration of 50 mg [14C]-dapagliflozin dose, 96% may be recovered, 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose may be excreted as parent compound.
Dapagliflozin exposure increases proportional to the increment in dapagliflozin dose over the range of 0,1 to 500 mg and its pharmacokinetics does not change with time upon repeated daily dosing.
At steady-state (20 mg once daily dapagliflozin for 7 days), patients with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin that are 32%, 60% and 87% higher, respectively, than those of patients with type 2 diabetes mellitus and normal renal function. At dapagliflozin 20 mg once daily, higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment may not result in a correspondingly higher renal glucose clearance or 24-hour glucose excretion. The renal glucose clearance and 24-hour glucose excretion was lower in patients with moderate or severe renal impairment as compared to patients with normal and mild renal, impairment. The steady-state 24-hour urinary glucose excretion, was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day may be excreted by patients with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. There is no difference in the protein binding of dapagliflozin between renal impairment groups compared to healthy subjects. The impact of haemodialysis on dapagliflozin exposure is not known. Dapagliflozin is contraindicated in patients whose GFR is less than 60 mL/min (see section 4.3).
There is no difference in the protein binding of dapagliflozin between hepatic impairment groups compared to healthy subjects. In patients with mild or moderate hepatic impairment mean Cmax and AUC of dapagliflozin may be up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences are not considered to be clinically meaningful and no dose adjustment from the proposed usual dose of 10 mg once daily for dapagliflozin is proposed for these populations. In patients with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin may be up to 40% and 67% higher than matched healthy controls, respectively. Dapagliflozin is not recommended for use in severe hepatic impairment (see section 4.4).
No dosage adjustment for dapagliflozin from the dose of 10 mg once daily is recommended on the basis of age.
Pharmacokinetics in the paediatric and adolescent population have not been studied.
No dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with high body weight (≥120 kg) is recommended. No dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with low body weight (<50 kg) is recommended.
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