Coadministration of neoral and the novel rapamycin analog, SDZ RAD, to ratlung allograft recipients - Potentiation of immunosuppressive efficacy andimprovement of tolerability by staggered versus simultaneous treatment
B. Hausen et al., Coadministration of neoral and the novel rapamycin analog, SDZ RAD, to ratlung allograft recipients - Potentiation of immunosuppressive efficacy andimprovement of tolerability by staggered versus simultaneous treatment, TRANSPLANT, 67(7), 1999, pp. 956-962
Background Neoral and rapamycin derivative (RAD) have complementary mechani
sms for inhibition of lymphocyte activation and are substrates for the same
pathways of drug metabolism. Therefore, we investigated treatment regimens
designed to minimize pharmacokinetic interactions and to potentiate immuno
suppressive efficacy in a highly stringent rat lung allograft model.
Methods. Lewis recipients of Brown Norway lungs received the following dail
y oral doses: (A) RAD at 2.5 mg/kg (n=9); (B) Neoral at 7.5 mg/kg (n=8); (C
) RAD at 2.5 mg/kg + Neoral at 7.5 mg/kg simultaneously (n=8); or (D) RAD a
t 2.5 mg/kg + Neoral at 7.5 mg/kg (n=6) staggered 6 hr apart. Rats were ass
essed by daily weights, chest radiographs, drug trough levels (highperforma
nce liquid chromatography/mass spectrometry), and blinded scoring of graft
histology at death (day 21), Results, Radiographs were completely opacified
in all grafts of control and RAD monotherapy groups on days 7 and 14, resp
ectively. Grafts were mildly opacified (Neoral monotherapy) and completely
clear (both RAD C Neoral groups) on day 21, Simultaneous or staggered combi
ned treatment dramatically reduced histologic rejection compared with treat
ment with either drug alone. Simultaneous treatment caused poor tolerabilit
y (poor grooming, lethargy) and significantly higher day-14 RAD and cyclosp
orine (CsA) trough levels (49+/-5 and 638+/-106 ng/ml; P<0.04) than in the
staggered group (28+/-3 and 318+/-25 ng/ml) in which all animals were clini
cally normal. RAD and CsA day-14 trough levels in the staggered group were
the same or lower than trough levels in animals treated with either drug al
one (RAD 27+/-3/Neoral 815+/-67 ng/ml),
Conclusions. (1) Administration of RAD + Neoral suppressed lung rejection m
ore effectively than treatment with either drug alone. (2) Trough levels di
d not differ between monotherapy and staggered combination therapy for RAD
but were lower for CsA, These results suggested that pharmacological, rathe
r than pharmacokinetic, interactions between the parent drugs were responsi
ble for the potentiation of immunosuppression when these drugs were coadmin
istered, 3) Staggered administration of RAD+Neoral avoided the pharmacokine
tic interactions that caused the elevated drug blood levels and poor tolera
bility caused by simultaneous administration. Thus, we could potentiate eff
icacy and improve tolerability by staggering administration of RAD and Neor
al.