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editorial
. 1999 Jul;43(7):1815. doi: 10.1128/aac.43.7.1815

Ritonavir-Fluoxetine Interaction

S Eralp Bellibas 1
PMCID: PMC89375  PMID: 10438337

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, Peyton A L, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther. 1992;51:239–248. doi: 10.1038/clpt.1992.18. [DOI] [PubMed] [Google Scholar]
  • 2.Medical Economics Company. Physicians’ desk reference. 51st ed. Montvale, N.J: Medical Economics Company; 1997. Prozac product information; pp. 935–940. [Google Scholar]
  • 3.Ouellet D, Hsu A, Qian J, Lamm J E, Cavanaugh J H, Leonard J M, Granneman G R. Effect of fluoxetine on pharmacokinetics of ritonavir. Antimicrob Agents Chemother. 1998;42:3107–3112. doi: 10.1128/aac.42.12.3107. [DOI] [PMC free article] [PubMed] [Google Scholar]
Antimicrob Agents Chemother. 1999 Jul;43(7):1815.

AUTHORS’ REPLY

Daniele Ouellet 1,2, Ann Hsu 1,2

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 (1-1–1-3).

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

  • 1-1.Bergstrom R F, Peyton A L, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther. 1992;51:239–248. doi: 10.1038/clpt.1992.18. [DOI] [PubMed] [Google Scholar]
  • 1-2.Dista Products and Eli Lilly and Company. Prozac, package insert. Indianapolis, Ind: Eli Lilly and Company; 1996. [Google Scholar]
  • 1-3.El-Yazigi A, Chaleby K, Gad A, Raines D A. 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. 1995;35:17–21. doi: 10.1002/j.1552-4604.1995.tb04740.x. [DOI] [PubMed] [Google Scholar]

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