azoles and tacrolimus sirolimus

advertisement
Tacrolimus and Sirolimus are commonly used in prophylactic treatment against GVHD in transplant patients. These two agents
are primarily metabolized by the CYP3A4 system. Often, with the concurrent use of CYP3A4 inhibitors such as the azoles in
fungal prophylaxis or as active treatment in transplant patients, the metabolism of tacrolimus and sirolimus can be altered and
may lead to supratherapeutic level. It is important to know the extent and clinical significance of these interactions. The
following table briefly summarizes the extent of interactions between tacrolimus, sirolimus with azoles. However, individual
adjustments are based on patient characteristics with close monitoring of drug levels.
Azoles
Tacrolimus
Sirolimus
Ketoconazole
50-60%
80-90%
(a)
Fluconazole
40%
50-70% (b)
Posaconazole
75-80% (b)
-----------Voriconazole
66%
90%
Itraconazole
50-60%
-----------Source: Saad AH et al. Pharmacotherapy. 2006
Dec;26(12):1730-44.
(a)Based
(b)Based
COH
Posaconazole: Recommend dose reduction of
guideline tacrolimus and sirolimus by 40 to 60% depending on
previous antifungal prophylaxis agent used,
concomitant agents, previous levels, and GVHD status
Voriconazole: Recommend dose reduction of
tacrolimus and sirolimus by 50 to 75% depending on
previous antifungal prophylaxis agent used,
concomitant agents, previous levels, and GVHD status.
on low dose fluconazole 100mg daily
on limited data
Tacrolimus Ketoconazole: A prospective RCT of 70 kidney transplant recipients receiving tacrolimus found that with addition
of 100mg/day will need reduction of tacrolimus dose by 58.7%(1). In a case report, the interaction was observed
after 1 day from start of therapy and persisted for 7 days after discontinuation of ketoconazole (4).
Fluconazole: A prospective study in kidney recipients where 9 out of 19 patients started on fluconazole
100mg/day found that within 5 days, tacrolimus dose resulted in 40% reduction with concurrent administration of
fluconazole(7).
Posaconazole: In a study of healthy subjects, administration of oral posaconazole 400mg BID for 8 days
resulted in 4.5-fold increase in Tacrolimus AUC. (6)
Voriconazole: In a study of healthy subjects, administration of voriconazole 400mg BID for 1 day followed by
200mg BID for 6 days tripled AUC of tacrolimus when only one dose of tacrolimus 0.1mg/kg was given.
Recommended a decrease of 66% for tacrolimus. (6)
Itraconazole: A single-institution, open-label prospective comparative pharmacokinetic study of itraconazole
and tacrolimus conducted on 17 allogeneic hematopoietic stem cell patients found that IV intraconazole of
200mg Q12H x 2 days, then 200mg daily, increased tacrolimus concentration by a mean of 83% (range from 49117%). The onset of interaction was found to occur within 48hrs to 72hrs and may require dose reduction of 50100%. For oral itraconazole and tacrolimus, case series have reported an increase of tacrolimus trough
concentration from 2-fold to 6.6-fold and required dose reductions of 45% to 75%.(2)
Sirolimus
Ketoconazole: In a study of healthy subjects, administration of 200mg/day for 10 days concurrently with oral
sirolimus 5mg/day decreased sirolimus clearance by 90%. (6)
Fluconazole: One case reported stated patient had preemptive reduction in dosage from 4-3 and then 2mg/day
4 days later, trough concentration still doubled by day 29 and tripled by day 32 with co-administration of
fluconazole 200mg/day. (6)
Posaconazole: In a phase I, open-label, multi-period, drug-interaction study with 12 healthy subjects, it was
found that co-administration with posaconazole 400mg BID increased sirolimus AUC by 8.9-fold and Cmax by
6.7-fold. (5)
Voriconazole: Co-administration is contraindicated according to manufacturer recommendation. This is due to
the result from a single blinded RCT where administration of oral voriconazole 400mg BID on day 1 follow by
200mg BID for 8 days increased AUC of sirolimus by 11-fold.(8) However, in a 2006 retrospective case series
study, 8 patients received concurrent voriconazole (median of 33 days) and sirolimus had similar trough
compared to previous values with a 90% decrease in sirolimus dose.(3)
Itraconazole: No substantial data, only single case reports
COH
Posaconazole: Recommend dose reduction of tacrolimus and sirolimus by 40 to 60% depending on previous
Guidelines antifungal prophylaxis agent used, concomitant agents, previous levels, and GVHD status
References
Voriconazole: Recommend dose reduction of tacrolimus and sirolimus by 50 to 75% depending on previous
antifungal prophylaxis agent used, concomitant agents, previous levels, and GVHD status.
1. el-Dahshan KF, Bakr MA, Donia AF, Badr Ael-S, Sobh MA. Co-administration of ketoconazole to tacrolimustreated kidney transplant recipients: a prospective randomized study. Nephrol Dial Transplant. 2004
Jun;19(6):1613-7. Epub 2004 Mar 19.
2. Leather H, Boyette RM, Tian L, Wingard JR. Pharmacokinetic evaluation of the drug interaction between
intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporin A in allogeneic hematopoietic
stem cell transplant recipients. Biol Blood Marrow Transplant. 2006 Mar;12(3):325-34.
3. Marty FM, Lowry CM, Cutler CS, Campbell BJ, Fiumara K, Baden LR, Antin JH.Voriconazole and sirolimus
coadministration after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006
May;12(5):552-9.
4. Moreno M, Latorre A, Manzanares C, Morales E, Herrero JC, Dominguez-Gil B, Carreño A, Cubas A, Delgado
M, Andres A, Morales JM. Clinical management of tacrolimus drug interactions in renal transplant patients.
Transplant Proc. 1999 Sep;31(6):2252-3.
5. Moton A, Ma L, Krishna G, Martinho M, Seiberling M, McLeod J.Effects of oral posaconazole on the
pharmacokinetics of sirolimus. Curr Med Res Opin. 2009 Feb 2.
6. Saad AH, DePestel DD, Carver PL. Factors influencing the magnitude and clinical significance of drug
interactions between azole antifungals and select immunosuppressants. Pharmacotherapy. 2006
Dec;26(12):1730-44.
7. Toda F, Tanabe K, Ito S, Shinmura H, Tokumoto T, Ishida H, Toma H.Tacrolimus trough level adjustment after
administration of fluconazole to kidney recipients. Transplant Proc. 2002 Aug;34(5):1733-5.
8. Vfend (package insert). New York:Pfizer, March 2008
Download