Everolimus in Pulmonary Transplantation: Pharmacokinetics
and Exposure–Response Relationships
John M. Kovarik, PhD,
a
Gregory I Snell, MD,
b
Vincent Valentine, MD
c
Robert Aris, MD,
d
Charles KN Chan, MD,
e
Heinz Schmidli, PhD,
a
and Ulrich Pirron, PhD
a
Background: In this study we evaluated exposure, safety and efficacy data from an international trial of
everolimus. We sought to identify a tolerated and efficacious range for blood levels of this agent in
maintenance lung transplant recipients.
Methods: In a randomized, double-blind, multicenter trial, 213 maintenance lung transplant recipients
received either everolimus 1.5 mg twice daily (n = 101) or azathioprine 1 to 3 mg/kg/day (n = 112)
with cyclosporine and corticosteroids. At 15 visits over the first 2 years of the trial, we obtained 826
everolimus trough (C
0
) blood samples. We used median-effect analysis to assess relationships
between everolimus C
0
vs efficacy and safety responses.
Results: Everolimus administration began at 1.5 mg twice daily and was progressively lowered over the first
2 months to an average of 1.2 0.4 mg twice daily, which was maintained thereafter. This dose
yielded median C
0
levels of 6.6 ng/ml (10th to 90th percentiles: 2.8 to 11.8 ng/ml). Over this range
of everolimus C
0
, freedom from a decline in pulmonary function with bronchiolitis obliterans
syndrome and freedom from biopsy-proven acute rejection were both 88%. The incidence of
increased cholesterol (6.5 mmol/liter), increased triglycerides (2.9 mmol/liter) and transiently
decreased platelet count (100 10
9
/liter) rose significantly with increasing C
0
. Infections and
drug-related adverse events were not significantly related to exposure.
Conclusions: A tolerated and efficacious concentration range for everolimus in maintenance lung transplantation
appears to be 3 to 12 ng/ml when used in conjunction with cyclosporine and corticosteroids. This
range should be prospectively assessed with possible refinement as more clinical experience is
gained. J Heart Lung Transplant 2006;25:440 – 6. Copyright © 2006 by the International Society for
Heart and Lung Transplantation.
Chronic allograft dysfunction and rejection are major
challenges in the care of lung transplant recipients. In
lung transplantation, chronic dysfunction manifests as
obliterative bronchiolitis due to fibroproliferation and
leads to an inexorable decline in pulmonary function.
Given the difficulties in the histologic diagnosis of
obliterative bronchiolitis, bronchiolitis obliterans syn-
drome (BOS) can be considered the best available
surrogate marker for obliterative bronchiolitis and is
predictive of graft and patient survival.
1
BOS is charac-
terized clinically by progressive airflow obstruction on
the basis of pulmonary function tests. There is currently
no treatment that can prevent the development or
progression of obliterative bronchiolitis or BOS.
Everolimus is an immunosuppressant for the preven-
tion of acute allograft rejection after kidney and heart
transplantation.
2
Everolimus inhibits growth factor–
stimulated proliferation of lymphocytes and mesenchy-
mal cells
3,4
and proliferation of human lung fibroblasts
in vitro.
5
Given the fibroproliferative processes under-
lying obliterative bronchiolitis, a role for everolimus in
preventing the decline of pulmonary function and onset
of BOS in maintenance lung transplant recipients was
assessed in a 3-year multicenter, randomized, double-
blind clinical trial comparing everolimus with azathio-
prine.
6
In brief, the protocol-specified primary study
end-point was an efficacy failure composite of 15%
decline in forced expiratory volume in 1 second (FEV
1
15%), graft loss, death or loss to follow-up 12 months
after the first dose. The incidence of efficacy failure was
significantly lower in the everolimus group compared
with the azathioprine group (21.8% vs 33.9%, p =
0.046). Other end-points significantly reduced with
everolimus included change from baseline FEV
1
15%,
change from baseline FEV
1
15% with BOS, and acute
From
a
Novartis Pharmaceuticals, Basel, Switzerland;
b
Alfred Hospital,
Melbourne, Australia;
c
Ochsner Clinic Foundation, New Orleans, LA,
USA;
d
University of North Carolina at Chapel Hill, Chapel Hill, NC,
USA;
e
University of Toronto, Toronto, Ontario, Canada
Submitted July 21, 2005; revised November 29, 2005; accepted
December 10, 2005.
Reprint requests: John M. Kovarik, PhD, Clinical Pharmacology,
Novartis Pharmaceuticals, Building WSJ 103.426, Basel 4002, Swit-
zerland. Tel: 41-061-324-8239. Fax: 41-061-324-3074. E-mail: john.
kovarik@novartis.com
Copyright © 2006 by the International Society for Heart and Lung
Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/
j.healun.2005.12.001
440