Published Online, 15 November 2005, www.theannals.com, DOI 10.1345/aph.1G015a.
The Annals of Pharmacotherapy: Vol. 39, No. 12, pp. 2141. DOI 10.1345/aph.1G015a
© 2005 Harvey Whitney Books Company.
Comment: supratherapeutic response to ezetimibe administered with cyclosporine
Matthew K Ito, PharmD FCCP BCPS1
1 Professor and Chair of Pharmacy Practice, College of Pharmacy, Portland
Campus at Oregon Health and Science University, Oregon State University, 840
SW Gaines Rd., Portland, OR 97239-3098, fax 503/494-8797,
itom{at}ohsu.edu
Published Online, November 15, 2005. www.theannals.com, DOI 10.1345/aph.1G015a
TO THE EDITOR: I read with interest the article by Koshman et
al.1 I agree,
as mentioned in the article, that this particular patient appears to have had
a "supratherapeutic" response to ezetimibe. However, I suspect
that this response may not be due—or at least, not entirely—to the
interaction with cyclosporine. As pointed out in the article, an interaction
between ezetimibe and cyclosporine deemed to be clinically significant has
been reported. However, the data concerning lipid alterations were not
reported. A premarketing dose-ranging study of ezetimibe that included 243
subjects who received doses between 0.25 and 40 mg/day demonstrated a
flattened dose-response
curve.2,3
Mean low-density lipoprotein cholesterol (LDL-C) was reduced by 9.9%, 12.6%,
16.4%, 18.7%, and 20.0% in the patients randomized to receive ezetimibe 0.25,
1, 5, 10, 20, and 40 mg, respectively, after 8 weeks of treatment.
Similarly, 190 patients were administered a structural analog (active
metabolite) of ezetimibe (SCH 48461) with doses ranging from 1 to 400
mg.4 Mean
LDL-C reduction ranged from 0.6% to 15.5%. These data suggest that if
cyclosporine had increased serum total ezetimibe or ezetimibe glucuronide
within the range of the doses studied above, the LDL-C response in Koshman et
al.'s1 case
would not be due to the drug-drug interaction.
An alternative hypothesis is that this patient is a hyper-absorber of
cholesterol and, therefore, falls on the extreme end of the Gaussian curve for
LDL-C responses to an inhibitor of cholesterol
absorption.5
These types of patients tend to have a lower rate of cholesterol synthesis and
fall on the opposite end of the Gaussian curve for LDL-C responses to statins.
In this
case,1 the
patient's baseline LDL-C was 156 mg/dL when he was started on atorvastatin 10
mg/day. The dosage was gradually titrated to 60 mg/day, which resulted in an
LDL-C level of 103 mg/dL. This represents an LDL-C change of only 34%, which
was considerably less than expected based on the manufacturer's prescribing
information (50% for 40 mg and 60% for 80
mg).6 Thus,
this patient had a less-than-expected response to statin therapy.
Ziajka et
al.7
demonstrated that the initial response to a statin predicted the subsequent
response to the addition of ezetimibe (r = 0.77; p < 0.001). In this
retrospective analysis, the patient's actual response was compared with
predicted response (manufacturer's prescribing information) for the agent and
dose used. The additional decrease in LDL-C after the addition of ezetimibe
ranged from 6% to 60%. Patients who responded poorly to a statin had the
largest reduction in LDL-C when ezetimibe was added. We have found similar
results in a prospective, randomized study of ezetimibe and simvastatin that
was designed to confirm data presented at the 2005 Annual Meeting of the
American College of Clinical
Pharmacy.8
Patients in our study will be phenotyped for absorption efficiency in an
effort to aid in a more suitable drug selection. This case provides a good
opportunity to educate clinicians on the importance of variability in
cholesterol absorption and synthesis on the observed response to
lipid-lowering agents.
Footnotes
Dr. Ito has served as a consultant and speaker for Kos Pharmaceuticals,
Merck & Co., Merck/Schering-Plough Pharmaceuticals, and AstraZeneca and
has received research grants from Kos Pharmaceuticals and Merck & Co.
References
- Koshman SL, Lalonde LD, Burton I, Tymchak WJ, Pearson GJ.
Supratherapeutic response to ezetimibe administered with cyclosporine.Ann Pharmacother
2005;39:1561-5. Epub 19 Jul 2005. DOI10.1345/aph.1G015[Abstract/Free Full Text]
- Bays H, Drehobl M, Rosenblatt S, Toth P, Dujovne C, Knopp R, et al.
Low-density lipoprotein cholesterol reduction by SCH 58235 (ezetimibe), a
novel inhibitor of intestinal cholesterol absorption in 243
hyper-cholesteremic subjects: results of a dose-response study (abstract).Atherosclerosis
2000;151:133.
- Data on file. Merck/Schering-Plough Pharmaceuticals,
North Wales, PA.
- Dujovne CA, Bays H, Davidson MH, Knopp R, Hunninghake DB, Stein EA,
et al. Reduction of LDL cholesterol in patients with primary
hyper-cholesterolemia by SCH 48461: results of a multicenter dose-ranging
study. J Clin Pharmacol 2001;41:70-8.[Abstract]
- Thompson G, O'Neill F, Seed M. Why some patients respond poorly to
statins and how this might be remedied. Eur Heart J 2002;23:200-6.[Free Full Text]
- Product monograph and prescribing information. Lipitor
(atorvastatin). New York: Pfizer.
www.lipitor.com/pi/default.asp
(accessed 2005 Sept 8).
- Ziajka PE, Reis M, Kreul S, King H. Initial low-density lipoprotein
response to statin therapy predicts subsequent low-density lipoprotein
response to the addition of ezetimibe. Am J Cardiol 2004;93:779-80.[CrossRef][Medline]
- Cheung RJ, Ito MK, Henry RR. Is the cholesterol lowering response
to a statin and a cholesterol absorption inhibitor inversely related? A
prospective, randomized, cross-over design study. Presented at: 2005
Annual Meeting of the American College of Clinical Pharmacy, Oct 26, 2005, San Francisco, CA.
