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Session 113
Poster Abstracts Pharmacology of Protease Inhibitors Wednesday, 1:30 - 3:30 pm Hall A |
Background: HAART has improved the
life expectancy of HIV-infected patients, allowing orthotopic
liver transplantation to become
a reasonable treatment option for selected patients with terminal liver
disease. This study was designed to manage drug-to-drug interactions with
immunosuppressive drugs such as tacrolimus and HAART.
Methods: This study, included 10 HIV+ patients transplanted for end-stage chronic hepatitis C. Criteria
for transplantation included: absence of
opportunistic infection, CD4-cell count greater than
150 cells/µL, and undetectable HIV plasma viral load (< 50 copies/mL).
HAART was stopped the same day of orthotopic
liver transplantation and was reintroduced 10 days after.
All patients received tacrolimus and prednisolone.
Targets for tacrolimus blood concentrations were 8 to 20 ng/mL
from day 0 until week 6, and 5 to 15 ng/mL after week 6. All patients received fluconazol 50 mg/day, trimetoprim
/ sulfametoxaxol, and ganciclovir. Tacrolimus pharmacockinetic
parameters were calculated by non-compartmental
method, in 8 of these patients on 2 occasions (period
A) when liver function normalized (about 10 days post-transplantation), and (period B) 10 days after
HAART reintroduction at standard doses (PI-nelfinavir
n = 2, lopinavir/r n = 3, or NNRTI-efavirenz
n = 2 + 2 nucleoside analogs)
or 3 NRTI (n = 1). Doses of tacrolimus were individually adjusted according to tacrolimus trough blood concentrations.
Results: Individual pharmacokinetic parameters of tacrolimus are listed in the table. All
patients had tacrolimus
blood concentrations at target range and HIV plasma viral load
of < 50 copies/mL.
|
Tacrolimus parameters |
Half-life h (Cmax to Cmin) |
Oral
clearance, L/h |
|
(A) (B) nucleoside analog |
9.9 9.1 |
9.4 6.4 |
|
(A) (B) efavirenz |
26.9, 8.1 12.1, 24.4 |
10.7, 10.5 14.9, 13.4 |
|
(A) (B) nelfinavir |
13.4, 14.8 27.7, 95.5 |
5.3, 12.0 3.0, 1.1 |
|
(A) (B) lopinavir/ritonavir |
6.3, 7.4, 9.1 120.7, 69.1, 233.7 |
33.1, 19.4, 15.6 0.5, 0.4, 0.9 |
Conclusions: Nucleoside analogues or efavirenz
lead to little change in tacrolimus pharmacokinetics, in contrast, nelfinavir and lopinavir/ritonavir
cause a large inhibition of tacrolimus first pass effect and clearance,
producing an important decrease in tacrolimus dosing. Management of
drug-to-drug interaction is feasible by attentive monitoring.
Keywords: protease inhibitors interaction; transplantation; tacrolimus
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