Protease inhibitors significantly increase levels of ciclosporin.Ciclosporin may increase time to maximum nelfinavir levels
A HIV-positive patient taking ciclosporin 250 to 350mg twice daily (to maintain a therapeutic ciclosporin trough level of 300 to 400 nanograms/mL) was restarted on his usual HAART regimen of tenofovir,lamivudine and fosamprenavir 1.4 g twice daily on day 12 post-liver transplantation. Within 2 days, ciclosporin level had increased to 600 nanograms/mL, requiring a ciclosporin dose reduction to 100mg twice daily (See reference number 1).
A pilot study in 7 HIV-positive subjects taking nelfinavir 1.25 g twice daily found that a single 4-mg/kg oral dose of ciclosporin increased time to maximum serum level for nelfinavir from 2.6 to 3.2 hours. The AUC of nelfinavir was also increased but this was not significant. In same study, a single 2-mg/kg intravenous dose of ciclosporin given over
5 hrs had little effect on pharmacokinetics of oral nelfinavir. Nelfinavir did not significantly affect pharmacokinetics of either oral or intravenous ciclosporin (See reference number 2)
Three HIV-positive patients who had undergone liver transplantation required reductions in their ciclosporin doses when they started taking ritonavir-boosted HAART. One patient taking ciclosporin 150mg twice daily had an increase in his ciclosporin levels to 900 nanograms/mL when ritonavir-boosted HAART was started,and needed a dose reduction of 95 % to maintain a usual ciclosporin trough level of 75 to 150 nanograms/mL. A second patient also required a similar reduction. The third patient needed a dose reduction of 80 % when taking ritonavir-boosted lopinavir,but no further ciclosporin dose alteration was needed when his treatment was changed to ritonavir-boosted indinavir (See reference number 3).
An HIV-positive patient taking lamivudine and zidovudine,and ciclosporin for a kidney transplant, started taking saquinavir 1.2 g three times daily. Within 2 days he started to complain of fatigue,headache and gastrointestinal discomfort. On investigation his ciclosporin level was found to have risen from a range of 150 to 200 nanograms/mL up to 580 nanograms/mL,and his saquinavir AUC was increased 4.3-fold (by comparison with subjects not taking ciclosporin). His ciclosporin dose was reduced from 150mg twice daily to 75mg twice daily,and his saquinavir dose was reduced to 600mg three times daily, which resulted in ciclosporin levels similar to those achieved previously (See reference number 4).
All protease inhibitors can inhibit cytochrome P450 isoenzyme CYP3A4 to varying degrees, see Antivirals, . Ciclosporin is extensively metabolised by CYP3A4,so any inhibition of this isoenzyme is likely to increase ciclosporin levels. Ciclosporin and protease inhibitors are substrates for P-glycoprotein, which may explain raised nelfinavir and saquinavir levels.
The increase in ciclosporin levels seen with ritonavir may occur irrespective of whether it is used as an antiretroviral in its own right or as a pharmacokinetic enhancer with other antiretrovirals(See reference number 5) (usually in a lower dose of 100mg twice daily). The inhibition of ciclosporin metabolism by other protease inhibitors,either alone or in combination with ritonavir, may lead to significant increases in ciclosporin levels. Therefore, ciclosporin levels should be carefully monitored and dose adjusted accordingly during concurrent use, bearing in mind that large dose reductions may be required in some patients, as seen with ritonavir. It is also important to reduce or alter ciclosporin dose should protease inhibitor be stopped or changed to avoid ciclosporin toxicity. The clinical significance of effects of ciclosporin on nelfinavir pharmacokinetics are unclear, and further study is needed.
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