Pharmacokinetic Interaction between Saquinavir and Cyclosporine

1 December 1998 | Volume 129 Issue 11 Part 1 | Pages 914-915

TO THE EDITOR:

An HIV-positive kidney transplant recipient who was receiving cyclosporine and prednisone started zidovudine and lamivudine therapy shortly after kidney function had stabilized. When protease inhibitors became available, saquinavir was added; levels of both drugs were monitored.

Without saquinavir, the cyclosporine trough levels in this patient were stable at a dosage of 150 mg twice daily (150 to 200 µg/L). Within 3 days after saquinavir therapy began at a dosage of 1200 mg three times daily, the patient reported fatigue, headache, and gastrointestinal discomfort and the trough level of cyclosporine tripled to 580 µg/L. After cyclosporine and saquinavir dosages were decreased to 75 mg twice daily and 600 mg three times daily, respectively, the symptoms subsided. Time curve analysis showed that an area under the concentration-time curve (AUC₀–12) seen with 75 mg of cyclosporine during treatment with saquinavir was 90% of the AUC₀–12 seen with 150 mg of cyclosporine alone (Figure 1, top). Meanwhile, saquinavir showed an AUC₀–12 4.3 times higher than the average value of five control patients who were receiving an identical saquinavir dosage of 600 mg twice daily without cyclosporine (Figure 1, bottom) and 11.1 times higher than the AUC₀–12 reported in the literature (0.47 h per mg/L) [1].

View larger version (17K): [in this window] [in a new window]   Figure 1. Time-curve analyses of cyclosporine and saquinavir concentrations.Top. Area under the concentration-time curve (AUC0–12) alone and combined with saquinavir (SQV) (5.48 h per mg/L and 4.93 h per mg/L, respectively). Bottom. AUC0–12 of saquinavir in the case-patient combined with cyclosporine (5.20 h per mg/L) and the average AUC0–12 of saquinavir in five controls not receiving cyclosporine (1.21 h per mg/L).

 

This observation confirms the anticipated pharmacokinetic interaction between protease inhibitors and cyclosporine. This inhibitory interaction is most likely explained by the similar metabolism of both drugs via CYP3A. An additional explanation might be that both drugs also display high affinity for the drug-transporting P-glycoprotein [2, 3] and might therefore increase the absorption or decrease the clearance of the other drug, as was recently postulated by others [4, 5].

This interaction has not previously been reported in the literature or in the records of the drug manufacturer. This report reemphasizes the importance of pharmacokinetic interaction between protease inhibitors and concomitantly administered drugs.

Author and Article Information

Top Author & Article Info References

University Hospital Nijmegen; Nijmegen, the Netherlands

References

Top Author & Article Info References

1. Merry C, Barry MG, Mulcahy F, Ryan M, Heavey J, Tjia JF, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS. 1997; 11:F29-33.

2. Sonneveld P, Durie BG, Lokhorst HM, Marie J, Solbu G, Suciu S, et al. Modulation of multidrug-resistant multiple myeloma by cyclosporin. Lancet. 1992; 340:255-9.

3. Washington CB, Duran GE, Sikic BI, Blaschke TF. Saquinavir is a high affinity substrate for the multidrug transporter, P-glycoprotein [Abstract]. Clin Pharmacol Ther. 1997; 61:193.

4. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest. 1998; 101:289-94.

5. Lee CG, Gottesman MM. HIV-1 protease inhibitors and the MDR1 multidrug transporter. J Clin Invest. 1998; 101:287-8.

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