Atorvastatin (and Evolocumab)

Pharmacokinetics

High Resolution Pharmacokinetics

• Atorvastatin (Oral Route): Rapid intestinal absorption. Absolute bioavailability around 14% due to an extensive hepatic first pass effect. Maximum plasma concentration reached 1-2 hours post-administration. Extreme binding to circulating plasma proteins (>98%). Massive phase I hepatic metabolism mediated exclusively by the CYP3A4 isoenzyme. It generates two main active metabolites: ortho-hydroxylated acid and para-hydroxylated acid, which are responsible for 70% of the global inhibitory effect of HMG-CoA reductase. Mainly biliary and fecal elimination, less than 2% recovered unchanged in urine. Elimination half-life of 14 hours, but the persistence of actual enzyme inhibition is 20 to 30 hours due to circulating active metabolites.
• Evolocumab (Subcutaneous Route): SC administration by autoinjectors every 2 or 4 weeks. Bioavailability of 72%. Maximum plasma concentration (C_max) reached 3-4 days after SC injection. It does not bind to plasma proteins. Purification by nonspecific proteolytic degradation in the mononuclear phagocytic system. Terminal elimination half-life of 11 to 17 days, allowing stable monthly dosing regimens.

Indicators and dose

Clinical Indications and Off-Label Uses

• Primary Hypercholesterolemia and Mixed Dyslipidemia: Net reduction in elevated serum levels of total cholesterol, LDL cholesterol, apolipoprotein B (ApoB) and triglycerides.
• Primary and Secondary Prevention of Cardiovascular Events: Drastic reduction in the risk of myocardial infarction, ischemic stroke, coronary revascularization and cardiovascular death in high or extreme risk patients according to consensus guidelines.
• Homozygous and Heterozygous Familial Hypercholesterolemia (FH): The joint use of high-dose atorvastatin with evolocumab is especially indicated to normalize refractory LDL.

Dosage and Clinical Adjustment

Atorvastatin (Standard Therapy):

• Initial Dose (Moderate intensity): 10 mg to 20 mg orally once a day. Due to its long half-life, atorvastatin can be administered at any time of day, with or without food (unlike statins with a short half-life such as simvastatin, which require nighttime administration).
• High Intensity Dose (Recommended in Secondary Prevention of CV Events or after myocardial infarction): Administer 40 mg to 80 mg once a day continuously.

Evolocumab (Combination therapy or intolerance):

• Dose of 140 mg administered subcutaneously once every 2 weeks via self-disposable autoinjector pen; or alternative dose of 420 mg once a month SC.

Adjustment in Renal Failure: No specific dose adjustment is required for atorvastatin or evolocumab in the presence of chronic kidney disease of any grade. Statins do not increase the risk of kidney damage and evolocumab is not glomerularly filtered.

Security

Absolute and Relative Contraindications

Contraindications of Atorvastatin

• Known hypersensitivity to statins.
• Active liver disease or decompensated cirrhosis Child-Pugh C: (Increased risk of severe hepatotoxicity and organ dysfunction).
• Persistent elevation of hepatic transaminases of unknown origin greater than 3 times the upper limit of normal.
• Confirmed pregnancy and ongoing breastfeeding.

Contraindications of Evolocumab

• Hypersensitivity to the monoclonal antibody evolocumab or to components of the formulation (such as allergy to the latex of the protective autoinjector needle).

Adverse Effects (ADR) and Specific Toxicity

• Atorvastatin (Common 1%-10%): Symmetric bilateral myalgias (dull muscle pain in thighs or calves without initial elevation of creatine kinase), arthralgia, headache, nasopharyngitis, dyspepsia, constipation, transient increase in hepatic transaminases, increased risk of developing de novo diabetes mellitus (slight increase in predisposed patients due to subtle insulin resistance effect).
• Atorvastatin (Rare <0.1%): Severe statin myopathy (severe myalgias accompanied by marked elevation of serum creatine kinase > 10 times the upper limit of normal), fulminant rhabdomyolysis, autoimmune necrotizing myopathy (associated with antibodies anti-HMGCR).
• Evolocumab (Common 1%-10%): Mild painful local reactions at the injection site (erythema, pruritus), common cold symptoms (nasopharyngitis, influenza), nonspecific dorsal myalgias, transient skin rashes.

Critical Toxicity: Statin-Induced Rhabdomyolysis

Rhabdomyolysis is a rare but extremely serious complication characterized by massive necrosis of skeletal muscle and massive release of myoglobin into the capillary circulation. The patient presents with severe generalized intense myalgias, prostrate muscle weakness, and urine emission of dark/brownish appearance ("cola-soda urine color") due to background destructive myoglobinuria.

Extreme elevation of CK (> 10,000 IU/L) Precipitation of Myoglobin in renal tubules Acute Tubular Necrosis

If there is clinical suspicion of rhabdomyolysis or elevation of creatine kinase (CK) > 10 times the upper limit of normal, atorvastatin should be discontinued immediately and intensive intravenous saline hydration therapy with sodium bicarbonate should be instituted to alkalinize the urine and prevent the development of irreversible obstructive acute renal failure.

Drug Interactions of Clinical Relevance

• Strong CYP3A4 inhibitors (Clarithromycin, Erythromycin, Itraconazole, Ketoconazole, Ciclosporin, Ritonavir, high intake grapefruit juice): They block the first-pass hepatic clearance of atorvastatin, exponentially raising the circulating plasma AUC by up to 5-10 times, severely increasing the risk of toxic myopathy and rhabdomyolysis. It is recommended to avoid coadministration or limit the dose of atorvastatin to a maximum of 10-20 mg per day under close CK monitoring.
• Bile acid sequestrants (Cholestyramine, Colestipol): They moderately reduce the intestinal absorption of atorvastatin if they are co-administered simultaneously. Physically separate feedings by at least 4 hours.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Absolutely contraindicated (FDA Category X). Cholesterol is a fundamental and mandatory substrate essential for the synthesis of cell membranes and steroid hormones during embryonic and early fetal development. Suppression of the mevalonate pathway is epidemiologically associated with major congenital skeletal malformations. Stop at least 1 month before trying to get pregnant.
• Breastfeeding: Absolutely contraindicated. Due to the potential to seriously interfere with lipid metabolism and normal functional development of the infant.