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Antimicrobial Agents and Chemotherapy, July 1999, p. 1815-1815, Vol. 43, No. 7
0066-4804/99/$04.00+0
LETTERS TO THE EDITOR
Ritonavir-Fluoxetine Interaction
 |
LETTER |
I read with interest the report of the clinical study by Ouellet
et al. (3) in which the effect of fluoxetine on
pharmacokinetics of ritonavir was investigated. Although the article
presented some interesting findings, I would like to comment on a
methodological flaw with the study.
This is a study aiming to look at a pharmacokinetic interaction between
two drugs being used in clinical practice. To assess this type of
interaction, the most important rule is achieving steady state. The
fluoxetine dosing scheme is not appropriate to reach steady state. Even
though the authors mention that steady state is achieved in clinical
practice after 4 to 6 weeks of therapy with fluoxetine at 20 mg daily,
they administered 60 mg daily for 8 days before assessing interaction.
Fluoxetine has a relatively long half-life of 1 to 3 days after acute
administration or 4 to 6 days after chronic administration. Its active
metabolite, norfluoxetine, has a longer half-life: 4 to 16 days after
acute or chronic administration (2). It is not possible to
reach steady state in a shorter time by using higher doses. The study by Bergstrom et al. (2), cited in support of this approach, suffers from the same error. Ouellet et al. underestimate the full
impact of interaction when fluoxetine is given under steady-state conditions.
Although steady state was not reached, Ouellet et al. obtained a
statistically significant increase (19%) in ritonavir area under the
curve with concomitant fluoxetine administration. A greater interaction
may be seen in clinical settings, and dosage adjustment of ritonavir
may be necessary.
| |
REFERENCES |
| 1.
|
Bergstrom, R. F.,
A. L. Peyton, and L. Lemberger.
1992.
Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.
Clin. Pharmacol. Ther.
51:239-248[Medline].
|
| 2.
|
Medical Economics Company.
1997.
Prozac product information, p. 935-940.
In
Physicians' desk reference, 51st ed. Medical Economics Company, Montvale, N.J.
|
| 3.
|
Ouellet, D.,
A. Hsu,
J. Qian,
J. E. Lamm,
J. H. Cavanaugh,
J. M. Leonard, and G. R. Granneman.
1998.
Effect of fluoxetine on pharmacokinetics of ritonavir.
Antimicrob. Agents Chemother.
42:3107-3112[Abstract/Free Full Text].
|
| | | | |
S. Eralp Bellibas
Division of Clinical Pharmacology and Experimental Therapeutics
Box 1220
University of California, San Francisco
San Francisco, California 94143
E-mail: bellibas{at}rocketmail.com
|
| |
AUTHORS' REPLY |
The ritonavir-fluoxetine interaction study was designed to achieve
fluoxetine concentrations similar to those observed at steady state
after administration of clinical doses. On the second day of
administration of ritonavir, i.e., after 8 days of 60 mg of fluoxetine
daily, fluoxetine and norfluoxetine concentrations ranged between 103 and 291 ng/ml and between 45.1 and 187 ng/ml, respectively. These
concentrations are similar to those observed clinically at steady state
(1-3).
The fact that ritonavir was not at steady state is appreciated. It
should be noted that ritonavir induces its own metabolism, which is
mediated primarily by CYP3A and, to a lesser extent, by CYP2D6. As
stated in the article, the mechanism by which fluoxetine increased
ritonavir's area under the curve was most likely mediated by
inhibition of the CYP2D6 enzyme. Since ritonavir is also metabolized by
CYP3A, the effect at steady state may be smaller since CYP3A metabolism
is induced with ritonavir, thereby decreasing the impact of the CYP2D6
pathway (which is not inducible) with multiple dosing. A greater
interaction, suggested by Dr. Bellibas, is theoretically unlikely, in
our opinion.
| |
REFERENCES |
| 1.
|
Bergstrom, R. F.,
A. L. Peyton, and L. Lemberger.
1992.
Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.
Clin. Pharmacol. Ther.
51:239-248.
|
| 2.
|
Dista Products and Eli Lilly and Company.
1996.
Prozac, package insert.
Eli Lilly and Company, Indianapolis, Ind.
|
| 3.
|
El-Yazigi, A.,
K. Chaleby,
A. Gad, and D. A. Raines.
1995.
Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone.
J. Clin. Pharmacol.
35:17-21[Abstract].
|
| | | | |
Daniele Ouellet
Department of Pharmacokinetics, Dynamics and Metabolism
Parke-Davis Pharmaceutical Research
Ann Arbor, Michigan
|
| | | | |
Ann Hsu
Abbott Laboratories
Abbott Park, Illinois
|
Antimicrobial Agents and Chemotherapy, July 1999, p. 1815-1815, Vol. 43, No. 7
0066-4804/99/$04.00+0
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