Toxicology Litigation Support

Baycol

Baycol (cerivastatin) is a cholesterol lowering drug that operates in the liver by preventing HMG-CoA from being metabolized to mevalonate and subsequently to cholesterol. It does this by blocking the enzyme that metabolizes HMG-CoA (the HMG-CoA reductase enzyme). Baycol (cerivastatin) and some of the statins have chemical structures similar to HMG-CoA and the enzyme system can’t tell the difference so it gets poisoned and cannot function. This results in a decreased cholesterol synthesis in the liver and a decreased concentration in circulating blood. This is a simplistic picture but it may help for you to be able to conceptualize the process.

Baycol (cerivastatin) is one of a class of drugs called statins and the whole class of drugs is known to produce myotoxicity (muscle toxicity) but the risk and prevalence of this condition is much higher with cerivastatin than with the other drugs in the class. As a matter of fact. an extreme form of this myotoxicity is called rhabdomyolysis and is said to be ten times more common with use of cerivastatin than the other drugs in the statin class.

Baycol (cerivastatin) is metabolized in the liver by two cytochrome P450 isoenzyme systems, P4502C8 and P4503A4. This metabolism is part of the natural dynamics of the drug therapy but, if you mix the drug with other drugs that block this metabolism such as cyclosporin, erythromycin, itraconazole, ketoconazole and clarithromycin, then you end up building-up higher concentrations of cervastatin in the blood and you end up with muscle toxicity. If you start with higher doses of the drug, you can also produce toxicity in the liver and elsewhere. This toxicity is expressed by elevated serum liver snzymes (AST, ALT) reflecting liver damage and elevated serum creatine phosphokinase (CPK) which is released from muscle tissue and may, in high concentrations (> 10 times upper limit of normal), indicate a condition called rhabdomyolysis. Thus, observation of elevated liver enzymes and CPK in clinical trials becomes an important marker for possible future problems.

• Values for Upper Limit of Normal (ULN)
• Liver enzymes: ALT (SGPT) = 25 u/L (range 8-20);
• AST (SGOT) = 22 u/L (range 8-20);
• Creatine Phosphokinase (CPK) = 120 u/L (range 12-80 for males, 10-55 for females);

During rhabdomyolysis, myoglobin is released into the bloodstream. Myoglobin is a heme protein that stores oxygen in muscle tissue and contributes oxygen to muscle when muscle is deprived of bloodborn oxygen. Normally, myoglobin levels in serum range from 3 to 80 ug/L. Myoglobin levels greater than 2000 ug/L are associated with renal complications. At lower urine pHs, myoglobin dissociates into ferrihemate and globulin and the ferrihemate causes a deterioration of renal function and subsequent renal failure and possible death.

Symptoms of rhabdomyolysis include muscle pain, weakness, tenderness, malaise, fever, dark urine, nausea and vomiting. As of August of last year, there were 1,100 cases of rhabdomyolysis associated with Baycol (cerivastatin) reported and as of January of this year, 100 fatalities have occurred worldwide. Risk factors for rhabdomyolysis include increased age, diabetes, excess alcohol intake, trauma, female gender, hypothyroidism, heavy exercise, renal or liver disease, debilitated status and surgery while pre-disposing factors include dehydration, hypokalemia, hypophosphatemia, malnutrition, psychiatric disease, agitation, confusion, delerium, endocrinopathies (hypothyroidism, diabetic ketoacidosis), shock, hypotension, hypoxia and rhabdomyolysis and subsequent kidney damage.

In formulating a differential diagnosis for a case of rhabdomyolysis, the following conditions and situations should be considered:

Drug-Induced:

• Toxic-induced; secondary to muscle ischemia in drug overdose; malignant hyperthermia, neuroleptic malignant syndrome; central anticholinergic syndrome, drug-induced polymyositis dermatomyositis

Muscle Ischemia:

• Crush, compartment syndrome, tourniquet shock; sickle-cell trait, shock and coma, occlusive artery disease;

Excessive Muscular Stress:

• Marathon runners, military training, status epilepticus with prolonged myoclonus or dystonia, agitation, delerium.

Physical Damage:

• Heat stroke, burns;

Infections:

• Viral (coxsackie, herpes, echo, influenza); bacterial (Clostridia, Legionella, typhoid, Staphylococci);

Electrolyte and Water Imbalances:

• Hypokalemia, Hypernatremia (elevated Na), hypophosphatemia, hyperosmolar states, endocrine dysfunction);

Genetic Effects:

• Deficiencies in glycolytic enzymes, cartinine palmitoyl transferase deficiency;

Neuropathy:

• Polyneuropathy, motor neuron diseases

Although incomplete, there have been some case reports and clinical trials showing cases of rhabdomyolysis and other cases of elevated CPK and liver transaminase levels. Some of these are indicated below.

Case Reports and Clinical Studies:

• 11 Patients with Baycol-induced rhabdomyolysis in three hospitals but no cases related to other statins (Ravan et al, 2002).
• US FDA Adverse Event Reports on Statin-Associated rhabdomyolysis: of 871 cases of statin-associated rhabdomyolysis in a 29-month time frame, 31.9% of the cases could be attributed to Baycol (cerivastatin); death in 38 cases overall (Omar, 2002).
• An 82 year old white male had been on gemfibrozil for several years and was started on Baycol. After one month, he was diagnosed with rhabdomyolysis secondary to his medications (Bruno-Joyce et al, 2001).
• Combination Baycol-gemfibrozil therapy resulted in rhabdomyolysis, followed by renal failure and death (Ozdemir et al, 2000).
• Other cases involving Baycol-gemfibrozil interactions resulting in rhabdomyolysis (Lau et al, 2001; Bermingham et al, 2000).
• 1,170 patients treated with either 0.8 mg Baycol, 0.4 mg Baycol or placebo demonstrated symptomatic elevations of creatine kinase (ten times upper limit of normal) in 1%, 1.5% and 0%, respectively. Elevations (> three times upper limit of normal [ULN]) of serum hepatic transaminases occurred in 0.3-0.5%, 0.5% and 0% of patients, respectively. (Isaacsohn et al, 2001).
• Clinical trial involving 1,170 patients demonstrated elevated (> ten times ULN) serum creatine kinase levels of 0%, 1%, and 0.9% in patients dosed with placebo, cerivastatin at 0.4 mg and at 0.8 mg (Insull et al, 2000).
• Clinical trial involving cerivastatin showed transient elevations in serum creatine phosphokinase, and hepatic amino transferases (Betteridge, 1999).
• Multicenter clinical trial showing <1% of patients on cerivastatin showed elevated serum hepatic transaminases (three times ULN) or creatine phosphokinase (> five times ULN) (Stein, 1998).
• Clinically significant increases in hepatic transaminases and creatine phosphokinase in 751 patients treated with cerivastatin (Farnier, 1998).

Prepared by: Richard A. Parent, PhD, DABT, RAC, ERT
Consulting Toxicologist and President
Consultox, Limited
89 Bristol Road, PO Box 1239
Damariscotta, ME 04543

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