Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir

Abstract

Objectives: The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir-boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation.

Patients and methods: We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels.

Results: Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohn's disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged.

Conclusions: Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction.

Figure 1

Tacrolimus blood levels during 12 or 24 h pharmacokinetic assessment in patients concomitantly treated with different types of HIV therapies. (a) Case 1 was treated with ritonavir, saquinavir and lopinavir when receiving a single dose of 0.5 mg of tacrolimus every 2 weeks (circles) and at a later timepoint with 0.06 mg of tacrolimus once daily (squares). (b) Two patients were treated with 400 mg of raltegravir and 1 mg (squares, Case 4) or 2 mg (circles, Case 5) of tacrolimus, all given twice daily. (c) Case 3 was treated with ritonavir, darunavir and tacrolimus (0.01 mg in the morning and 0.02 mg in the evening). The horizontal lines show the lower and upper limits of the therapeutic range of tacrolimus blood concentrations, from 5 to 10 ng/mL.

Figure 2

Graphs show tacrolimus trough levels from three patients after orthotopic liver transplant, treated with: (a) 0.06 mg of tacrolimus once daily (unless otherwise indicated) with ritonavir, lopinavir and saquinavir; (b) 0.08 mg of tacrolimus once daily with ritonavir and fosamprenavir; or (c) 0.03 mg of tacrolimus daily with ritonavir and darunavir. The horizontal lines show the lower and upper limits of the therapeutic range of tacrolimus blood concentrations, from 5 to 10 ng/mL. QD, once daily; BID, twice daily.