Transcript Role of Bortezomib in Kidney Transplantation

Role of Bortezomib in Kidney
Transplantation
Reference: Raghavan R, Jeroudi A, Achkar
K, et al. Bortezomib in kidney
transplantation. J Transplant. 2010;1–6.
• In most stage five chronic kidney disease patients,
transplantation has been observed to be the common
treatment of choice.
• In sensitized patients with any panel reactive antibody
(PRA) level, it is difficult to carry out transplantation, and
thus these patients have to wait longer prior to
transplantation.
• The process of removing or reducing preformed antibodies
in such candidates is known as desensitization.
• The two desensitization protocols backed by proven clinical
efficacy include highdose intravenous immunoglobulin
(IVIG) or low-dose IVIG with either plasmapheresis (PP) or
immunoadsorption.
• Although existing therapies for treatment of
antibodymediated rejection (AMR) and pretransplant
desensitization have recorded some success, they do
not particularly reduce plasma cells producing
antihuman leukocyte antigen antibodies (see Fig. 1).
• The role of plasma cells in mediating humoral rejection
has not been effectively addressed.
• Bortezomib, a proteasome inhibitor, which has been
approved for the treatment of multiple myeloma,
could be considered as an alternative option to deplete
plasma cells through proteasome inhibition.
The Biological Effect of Bortezomib
• Bortezomib, which was first synthesized in 1995,
is an FDA approved drug for the treatment of
multiple myeloma, a plasma cell dyscrasia. Since
2005, Bortezomib has been used off label in the
transplantation setting to lower donorspecific
antibodies (DSAs) in highly sensitized patients
and in AMR as an adjunct therapy.
• Bortezomib (C19H25BN4O4) has a central boron
atom that unites the catalytic site of the 26S
proteasome with high specificity and affinity.
• Bortezomib’s interference with nuclear factor
kappa B (NFkB) (regulatory protein) and IkB
(transcription factor) leads to the accretion and
aggregation of unfolded proteins and ultimate
apoptosis of plasma cell.
• Bortezomib indirectly affects the circulating B
cells and TH cells.
• The drug may lead to T-cell cycling blockade,
thereby causing apoptosis of TH cells and
lowering of bone marrow interleukin-6 that may
decrease the B-cell numbers.
Bortezomib Pharmacokinetics,
Pharmacodynamics, and Side-Effects
• Bortezomib has a rapid and broad distribution, hepatic
cytochrome P-450 (CYP) isoenzyme metabolism and an
extended elimination half life.
• Following a fast distribution half life of about 10 min,
peak plasma bortezomib concentrations vary from 60
to 120 ng/mL after repeated doses of 1–1.3 mg/m2.
• Total body clearance reduces from 102 to 112 L/h after
the initial dose and from 15 to 32 L/h following
repeated doses.
• Subsequent elimination half-life ranges from 40 to 190
h.
• Following intravenous bortezomib administration, the
highest percentage of 20S proteasome inhibition is
observed after 5 min, reaching a mean of 70−84%
inhibition.
• Bortezomib-related adverse effects reported in phase II and
phase III studies include neurotoxicity, thrombocytopenia,
and other common side-effects like nausea, diarrhea,
fatigue, and mild gastrointestinal disturbances.
• The Bortezomib dosing is similar irrespective of the route of
administration.
• The drug does not require hepatic or renal dosing
alterations, and the drug is not detectable within 30 min of
injection.
Bortezomib Use in Kidney
Transplantation
• There are numerous published case reports and series
detailing bortezomib’s use in kidney transplantation.
• Studies suggest that bortezomib can be employed to
reduce donor specific antibodies (DSA) levels with
minimal toxicity.
• The drug may also have a role in reducing complement
fixation.
• However, owing to bortezomib’s mild effect on PRA for
pretransplant desensitization, it may indicate the need
for adjunct modalities that target antibodies such as PP
and IVIG, and further investigation of bortezomib in
transplant desensitization.
• Studies also back the use of bortezomib in rejection
protocols.
• It has been observed that bortezomib therapy aids in
prompt rejection reversal (within days to weeks) and
improved renal function and reduction in DSA levels.
• Bortezomib has also shown efficacy in lowering bone
marrow plasma cells, antibody production (including
DSA), and number of plasma cell allospecificities in the
bone marrow aspirates.
• Bortezomib-based regimens could be an advantageous
adjunct therapy option in the acute AMR setting, as
compared to common modalities like PP.
Conclusion
• The ability of bortezomib in targeting the antibody-producing plasma cell
has evoked the use of it in pretransplant desensitization and in an AMR
setting.
• Bortezomib offers potential insight into kidney transplantation management
in highly sensitized patients who are on the kidney transplant waiting list.
• Novel therapeutic modalities targeting the DSA reduction and management
of AMR could offer opportunities for these patients.
• However, limited use of bortezomib in such settings may be an issue of
concern.
• In addition, the use of bortezomib along with other accepted
desensitization modalities like PP, IVIG, and rituximab may make it difficult
to tease out bortezomib’s role in transplant desensitization and treatment
of AMR.
• As more and more clinical data and well-designed clinical trials become
available bortezomib’s role in transplant desensitization will be elucidated
better.