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Rapid Responses: Rapid Responses published:
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The side effects from the cholesterol lowering drugs may offset their benefit.
- Uffe Ravnskov (19 August 2001)
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Lesson # 1: Mandate Phase IV studies
- I Dan Dattani (20 August 2001)
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Cerivastatin (Lipobay ®, Baycol®) and the ABC of pharmacokinetics and pharmocodynamics
- Hartmut Glossmann (27 August 2001)
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Uffe Ravnskov Magle Stora Kyrkogata 9, S-22350, Lund, Sweden
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To withdraw cerivastatin (Lipobay®, Baycol®) because of 31 fatal side effects in the US is a wise decision, but why has the Federal Drug Administration and Bayer Corporation not reacted before? Did they consider 30 deaths as a rare, but acceptable side effect? The benefit from statin treatment is rare also, in particular when “treating” healthy people. In the WOSCOP trial, for instance, the odds of escaping a fatal heart attack in five years for healthy people with high cholesterol was 98.4 %, which improved non-significantly to 98.8 % after pravastatin treatment.1 As the effect of the statins on mortality is trivial, fatal side effects may easily counteract their benefit. Bear in mind that the reported number of side effects is the top of the iceberg; few doctors report side effects of their treatment, or they may view them as natural manifestations of old age. It is therefore praiseworthy that the European Agency for the Evaluation of Medicinal Products has announced a review of all cholesterol lowering drugs. For instance, the agency should ask for the final result of the first statin trial, EXCEL, where total mortality probably was significantly higher in the lovastatin group (0.5% versus 0.2%; no other figures were given) already after one year.2 They should also ask why recurrence of breast cancer, the only side effect noted significantly more often in the pravastatin trial CARE,3 is not mentioned on the drug label. Such unfortunate results are particularly worrying considering that the new guidelines for treating high cholesterol, recently published by the US National Cholesterol Education Program, recommend treatment with cholesterol lowering drugs for a considerable part of mankind.4 Uffe Ravnskov 1. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7. 2. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-22. 3. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9. 4. Ravnskov U. New cholesterol guidelines for converting healthy people into patients. 2001; http://www.ravnskov.nu/ncep_guidelines.htm |
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I Dan Dattani, Ambulatory Care Physician Acadia Medical Centre,3510-8th St East,Saskatoon.Sask.Canada S7H 0W6
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The unfolding cerivastatin story has a lesson for all of us. Mandate genuine phase IV studies. The spirit of such large surveillance studies is to capture adverse events in a naturalistic community setting which would otherwise be less apparent in a restrictive phase III study. |
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Hartmut Glossmann, Full Professor and Chairman Institute of Biochemical Pharmacology, Medical Faculty, University of Innsbruck, Austria
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Cerivastatin
(Lipobay ®, Baycol®) and the ABC of pharmacokinetics and pharmocodynamics EDITOR – the commentaries on cerivastatin’s withdrawal
from the market emphasize the potentially dangerous interaction of this statin
with other drugs. However, there is an alternative viewpoint. 1.
The therapeutic target organ of the
statins (to lower LDL-cholesterol) is the liver. Here, LDL-receptor expression is
to be stimulated leading to accelerated clearance of expanded LDL-cholesterol
pools. If a statin reaches the general circulation , favourable as well as
adverse effects are to be expected, among other in smooth and striated muscle. 2.
It is well known, that statins favor
apoptosis in muscle 1,2. Statins can lead to rhabdomyolysis,
especially when other drugs (gemfibrozil, ciclosporin, diltiazem, erythromycin)
block first pass metabolism and increase systemic bioavailability of lovastatin,
simvastatin or atorvastatin, with the possible exception of pravastatin 3.
Normally some statins reach the general circulation with only a minor
percentage of an oral dose: lovastatin and simvastatin with less than 5%. Other
statins have higher systemic bioavailability: atorvastatin 12%, pravastatin
17%, fluvastatin 24%. However, the champion is undoubtedly cerivastatin with
60% 4. 3.
Cerivastatin was developed as an
extremely potent, lipophilic blocker of the HMG – CoA-reductase. Its
dissociation constant (Ki value) must be in the picomolar range as cerivastatin
is 200 times more potent than lovastatin, which has a Ki between 0.1
to 1.0 nanomolar. Consequently the dissociation half-life from the enzyme
renders cerivastatin almost an irreversible blocker. Cerivastatin has a high
systemic bioavailability and interactions with other drugs, blocking first-pass
metabolism “should be negligible“ – argues a correspondent, who consulted for
BAYER 4. This point is well taken – however, here is the other side
of the coin: There is overwhelming evidence that adverse reactions of statins
including myopathy and toxic destruction of muscle are more frequent and severe
the higher the amount is that reaches the general circulation 3,5,6. 4.
It is disturbing to learn that two
of the 28 patients receiving 0.8 mg cerivastatin in a BAYER supported study had
elevations of creatine kinase, one of them up to 8-fold 7. This
extremely high incidence of myopathy clearly underlines the “biological activity”
of cerivastatin outside of the prime target the liver. Did the developers of this
drug base hope on favourable effects on bone or vascular smooth muscle that are
unrelated to LDL-cholesterol reduction and almost forgot the skeletal muscle? Now
consider a simple calculation-comparing lovastatin and cerivastatin. Let us
assume that we would like to have the same systemic effects (outside of the
prime target) with old-fashioned lovastatin as with 0.8 mg cerivastatin, from
which 0.5 mg reach the systemic circulation. As cerivastatin is 200 times more
potent we need 100 mg lovastatin systemically each day to achieve
“bioequivalence in potency”. With a bioavailability of 5% the patient must
swallow fifty 40 mg tablets lovastatin as a single daily evening dose. Of
course, by blocking first pass metabolism almost completely by adding one or
more of the above mentioned interacting drugs, three 40 mg lovastatin-tablets
will suffice to mimick the 0.8 mg cervastatin daily dose! The question arises if the experts of the regulatory
agencies knew the ABC? Hartmut
Glossmann professor hartmut.glossmann{at}uibk.ac.at Competing interests: None declared 1 J Lipid Res (1997), 38, 1639-48 2 Atherosclerosis (2000) 152, 217-227 3 Arch Intern Med (2000) 160, 2273-2280 4 Arch Intern Med (2001), 161,1012-1013 5. AmJ.Cardiol
(2001) 87, 1074-1079 |
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