Effect of ketoconazole on plasma concentrations of saquinavir

Julio Collazos*, Eduardo Martínez, Jose Mayo and Maria-Soledad Blanco

Section of Infectious Diseases, Hospital de Galdakao, 48960 Vizcaya, Spain

Dear Sir,

Saquinavir has poor bioavailability owing to its limited absorption and extensive first-pass metabolism by the cytochrome CYP3A4 isozyme.1 To evaluate the usefulness of co-administration with ketoconazole, an inhibitor of CYP3A4, trough and peak plasma concentrations of saquinavir were measured in a group of human immunodeficiency virus (HIV)-infected patients before and after treatment with two different dosages of ketoconazole.

Seven HIV-infected men with a median age of 36 years, and a median CD4 cell count of 478 cells/µL were included in a study over 3 weeks. Patients received saquinavir, 600 mg tds with meals, in addition to two other antiretroviral drugs. No patient received drugs known to influence the saquinavir concentrations. Seven days later, ketoconazole, 200 mg/day, was added for 1 week, and then increased to 400 mg/day for an additional week. Blood samples were obtained after 7 days of saquinavir treatment before ketoconazole, after 7 days of ketoconazole 200 mg/day and after 7 days of ketoconazole 400 mg/day.

Trough blood samples were obtained 9–10 h after the last dose, and peak samples 3 h after the intake of saquinavir with breakfast.1,2 Saquinavir concentrations were measured by high-performance liquid chromatography (reverse-phase column Lichrospher C8 Select B, Darmstadt, Germany). Paired t-test and Friedman's test were used to compare two and three sequential measurements, respectively.

The FigureGo shows the patients' trough and peak values of saquinavir. The mean trough saquinavir concentration before ketoconazole was 42 ng/mL, after 200 mg of ketoconazole 44.3 ng/mL and after 400 mg of ketoconazole 36.8 ng/mL. The mean peak concentrations were 253.5, 255.7 and 269.9 ng/mL, respectively.



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Figure. Peak (upper panel) and trough (lower panel) plasma saquinavir concentrations before ketoconazole (week 1), after 200 mg/day of ketoconazole (week 2) and after 400 mg/day of ketoconazole (week 3).

 
There were no significant differences between any two of the three trough (P = 0.39, P = 0.53 and P = 0.8) or peak (P = 0.69, P = 0.88 and P = 0.98) measurements. The comparison of the three measurements considered altogether was also non-significant for the trough (P = 0.65) and peak (P = 0.86) determinations. On the contrary, there were significant differences in the mean saquinavir values between the trough and peak measurements before ketoconazole, after 200 mg/day and after 400 mg/day of ketoconazole (P = 0.015, P = 0.019 and P = 0.022, respectively).

Although it is commonly accepted that ketoconazole increases the plasma concentrations of saquinavir, we have not found any report dealing with this association. Unpublished data from the manufacturer (Roche, Madrid, Spain) suggest that concomitant use of ketoconazole, 200 mg/day and saquinavir causes a 1.5-fold increase in plasma concentrations of saquinavir.3 However, we failed to reproduce such findings even with higher doses of ketoconazole.

Jordan4 found a greater drop in viral load in patients receiving saquinavir and 200 mg/day of ketoconazole as compared with those receiving saquinavir alone. Although Jordan evaluated the virological response after 3 months of treatment, and our study lasted only 3 weeks, our patients reached the steady state, and the pharmacokinetics of the drug does not seem to change with chronic administration.2 Unfortunately, Jordan did not measure the plasma saquinavir concentrations, and no mention is made about other antiretrovirals used and compliance in each group, factors that could have influenced the results. Alternatively, the results of Jordan4 could perhaps be explained by the subset of patients who seemed to have increased saquinavir levels after ketoconazole treatment.

We observed a great inter-subject variability, as high as 5- to 10-fold in some determinations. Other authors reported similar findings, which have been attributed to the variability of CYP3A4.5 This suggests that the plasma saquinavir concentrations cannot be predicted in an individual patient, and that this variability may result in very low saquinavir levels and perhaps little antiviral effect in some patients. In fact, trough concentrations below 25 ng/mL were found in five of the 21 measurements in our series, and in 30.3% of patients in another series.5 Consequently, a fixed therapeutic regimen may not be adequate for all patients, and the dosage should probably be tailored individually by measuring the plasma drug levels to avoid subtherapeutic concentrations of the drug.

We conclude that ketoconazole does not seem to consistently increase the saquinavir concentrations at the doses used in this study, and that the inter-subject variability in both peak and trough levels is substantial.

Notes

J Antimicrob Chemother 2000; 46: 151–153

* Corresponding author. Tel: +34-94-400-7005; Fax: +34-94-400-7133; E-mail: jcollazos{at}hgda.osakidetza.net Back

References

1 . Noble, S. & Faulds, D. (1996). Saquinavir. A review of its pharmacology and clinical potential in the management of HIV infection. Drugs 52, 93–112.[ISI][Medline]

2 . Vanhove, G. F., Kastrissios, H., Gries, J. M., Verotta, D., Park, K., Collier, A. C. et al. (1997). Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy. Antimicrobial Agents and Chemotherapy 41, 2428–32.[Abstract]

3 . Productos Roche, S. A. (1996). Invirase (saquinavir mesylate) prescribing information. Madrid, Spain.

4 . Jordan, W. C. (1998). The effectiveness of combined saquinavir and ketoconazole treatment in reducing HIV viral load. Journal of the National Medical Association 90, 622–4.[ISI][Medline]

5 . Barry, M. G., Merry, C., Lloyd, J., Halifax, K., Carey, P., Mulcahy, F. et al. (1998). Variability in trough plasma saquinavir concentrations in HIV patients—a case for therapeutic drug monitoring. British Journal of Clinical Pharmacology 45, 501–2.[ISI][Medline]