Sitagliptin

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: Absolute bioavailability of 87%. Concomitant intake of high-fat foods does not alter its overall pharmacokinetic profile.
• Distribution: Apparent volume of distribution of approximately 198 L. Low binding to circulating plasma proteins (38%).
• Metabolism: Marginal hepatic metabolism (only 16% of the administered dose is transformed). It is mediated in a minority way by the cytochrome isoenzymes CYP3A4 and CYP2C8 to inactive metabolites.
• Excretion: Elimination mainly via the kidneys unchanged at 79% through glomerular filtration and active tubular secretion mediated by renal organic cation transporters (hOAT3) and P-glycoprotein (P-gp).
• Half-life (t_1/2): Terminal elimination half-life of approximately 12.4 hours.

Indicators and dose

Clinical Indications and Off-Label Uses

• Type 2 Diabetes Mellitus: As adjuvant therapy to diet and exercise, in monotherapy or combined with metformin, sulfonylureas or insulins. Highly tolerated drug, neutral in body weight, ideal for frail patients or older adults.

Dosage and Clinical Adjustment

Adults with Preserved Kidney Function: 100 mg once a day orally, with or without food.

Mandatory Adjustment for Kidney Failure:

• eGFR 45 to < 90 mL/min/1.73 m²: No dose adjustment required (100 mg/day).
• eGFR 30 to 44 mL/min/1.73 m² (Moderate Renal Failure): Reduce the dose by 50% (administer 50 mg once a day).
• eGFR < 30 mL/min/1.73 m² (Severe or Terminal Renal Failure): Reduce the dose to 25% (administer 25 mg once a day). It can be dosed even on hemodialysis days.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to the drug or components (documented risk of anaphylaxis, angioedema or Stevens-Johnson syndrome).
• Diabetes Mellitus Type 1 or diabetic ketoacidosis.

Relative Contraindications

• Personal history of chronic pancreatitis or idiopathic acute pancreatitis.
• Advanced or terminal renal failure (not contraindicated, but requires rigorous dose reduction).

Adverse Effects (ADR) and Specific Toxicity

• Common (1%-10%): Headache, nasopharyngitis, upper respiratory tract infection, mild hypoglycemia (only when associated with insulin secretagogues or insulin).
• Uncommon (0.1%-1%): Constipation, dizziness, severe and disabling arthralgias (class ADRs in DPP-4 inhibitors, of presumed autoimmune origin, reversible after discontinuation of the drug).
• Rare (0.01%-0.1%): Severe hypersensitivity reactions (anaphylaxis, Stevens-Johnson syndrome, bullous pemphigoid), acute pancreatitis.

Class Differentiation: Gliptins and Heart Failure

Unlike saxagliptin (which significantly increased the rate of hospitalizations for heart failure in the SAVOR-TIMI 53 safety trial), sitagliptin demonstrated absolute cardiovascular neutrality and clinical safety in the TECOS study, emerging as a highly safe option for patients with pre-existing cardiac pathology.

Drug Interactions of Clinical Relevance

• Digoxin: A slight increase in the area under the curve and maximum concentration of digoxin has been observed when administered together with sitagliptin, mediated by competition at the level of the P-gp transporter. It is recommended to monitor plasma digoxin levels.
• Potent CYP3A4 inhibitors (Ketoconazole, Itraconazole, Ritonavir): There are no clinically significant changes in the pharmacokinetics of sitagliptin.

Safety in Pregnancy and Breastfeeding

• Pregnancy: FDA Category B. Limited data in humans do not indicate embryonic damage, but robust prospective studies are lacking. Prefer insulin.
• Breastfeeding: Not recommended. Passes into breast milk in preclinical models. There are no safety data available in infants.