Presentation at ASCO by Saladax Biomedical showing the benefits of TDM with 5-FU.

1. Pharmacokinetic (PK) guided optimization of 5-fluorouracil (5-FU) exposure in
colorectal cancer (CRC) patients: US based clinical practices experience.
Fadi Braiteh, M.D.1, Yunying Li, Ph.D.2, Jodi B. Courtney, B.S.2, Michael P. Duda, B.A.3, Steve Diamond, D.O.3, M. Craig Miller, B.S.2, and Salvatore J. Salamone, Ph.D.2
1 Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 2 Saladax Biomedical, Inc., Bethlehem, PA; 3 Saladax Biomedical Laboratories, Bethlehem, PA.
• 5-fluorouracil (5-FU) continues to be the backbone of the combination
chemotherapies used in the treatment of colorectal cancer (CRC).
• 5-FU has a narrow therapeutic window and marked inter-patient variability in
drug metabolism, including systemic clearance of 5-FU, resulting in
significant pharmacokinetic (PK) variability.
• As with other chemotherapy agents, the standard of care approach to
dosing 5-FU is based on body surface area (BSA). However, this approach
has been associated with 5-FU plasma level inter-variability as high as 10-
fold.
• There are multiple factors in addition to BSA which influence individual
patient drug exposure including tumor burden, organ function, genetic
composition, drug interactions, and other external influences.
• There is now a large body of evidence to show that the PK variability of 5-FU
systemic exposure is a major contributor to toxicity and treatment failure
and that monitoring and optimization of 5-FU exposure through PK-guided
dosing can reduce 5-FU related toxicities and improve clinical outcomes. 1-4
• Personalization of 5-FU dosing for individual patients has not been widely
utilized in oncology primarily due to lack of a fast, reliable, reproducible and
widely available testing method. Previous methods to monitor 5-FU levels,
such as HPLC-UV and LC-MS/MS assays, although sensitive, are not
amenable to widespread clinical use. 5-6
• With 5-FU PK testing now commercially available using a rapid, reliable
immunoassay, we present US-based oncologists’ experience with
individualizing 5-FU dosing based on PK in patients with adjuvant or
metastatic CRC.
• Between June 5, 2013 and May 1, 2014, Saladax Biomedical Laboratories (a
CLIA-certified lab) determined 5-FU plasma levels (My5-FU™ assay) in 1000
samples collected ~24±6 hours after the start of 5-FU continuous infusion.
• Samples were collected during 400 lines of therapy from 380 different CRC
patients being treated at over 70 different academic and community based
oncology practices by 99 different oncologists.
• The measured 5-FU concentration (ng/mL) was used to calculate area under
the curve [AUC in mg.hr/L] in order to assess systemic 5-FU exposure.
• Plasma concentration, calculated AUC, and dose adjustment
recommendations to achieve a target exposure range (AUC = 20 – 30
mg.hr/L) were reported back to the physicians. The dose adjustment
recommendations were based on a published algorithm (Kaldate, The
Oncologist 2012;17(3) 296-302).
• Evaluable cycle pairs, defined as two consecutive cycles with AUC results,
were used to follow the dose adjustments (if any) associated with the
laboratory reports.
• Actual vs. target AUC, recommended vs. actual dose adjustment, and ability
to adjust exposure to the target range were evaluated.
Recommended vs. Actual Dose Adjustment
• The initial exposure values (AUC) for 317 (67%) of the 473 evaluable cycle
pairs identified were outside the target range.
• Doses were decreased for 43% of the 65 patients above target range
• No dose change was made for 91% of the 142 patients within target range.
• Doses were increased for 52% of the 230 patients below target range.
Distribution of AUCs by Dose – 1st Sample Tested from Each Line of Therapy
• The majority of AUC results (62%) were outside the target range in the first
sample from each therapy line, irrespective of 5-FU dosing or regimen.
• For patients on the same dose (2,400 mg/m2; N=254), the PK (AUC) variability
was greater than 12 fold (CV% = 42%).
• Body surface area based 5-FU dosing results in frequent under dosing
(50%) of CRC patients receiving treatment with infusional 5-FU regimens.
• 5-FU exposure optimization is feasible in the US clinical setting,
consistent with other reports.
• The majority (63%) of dose adjustment recommendations were followed
in subsequent treatment cycles.
• PK-guided dose adjustment is a practical approach to personalization of
5-FU dosing for achievement of optimal 5-FU exposure.
• Saladax is currently conducting a separate retrospective study to collect
outcomes to demonstrate that following PK-guided 5-FU dosing
recommendations will improve outcomes without increasing toxicities.
Abstract
#3574
BACKGROUND
METHODS
RESULTS (UPDATED THROUGH MAY 1, 2014)
CONCLUSIONS
• When the results of the test were used to make a dose adjustment, the
actual dose adjustments made were generally consistent with the
recommendations.
• In 158 cycle pairs where the initial AUC was out of target range and where a
dose adjustment consistent with the recommendation was made, 52% moved
into the target range in the following cycle as a result of the dose adjustment.
Consistent with earlier studies, some patients require 3-4 cycles of dose
adjustment to achieve target range.
PK guided dose adjustment helped an underdosed patient achieve target AUC
A ll D o s e s < 2 4 0 0 m g /m
2
2 4 0 0 m g /m
2
> 2 4 0 0 m g /m
2
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
In fu s io n a l 5 -F U D o s e
5-FUAUC(mg.h/L)
N
M e a n + S D
M e d ia n
% C V
A U C < 2 0
A U C 2 0 - 3 0
A U C > 3 0
4 0 0
2 1 + 1 0
2 0
49%
50%
38%
12%
1 0 8
1 8 + 1 2
1 5
69%
64%
24%
12%
2 5 4
2 2 + 9
2 0
42%
45%
43%
12%
3 8
2 2 + 7
2 2
31%
37%
50%
13%
A ll D o s e s < 2 4 0 0 m g /m
2
2 4 0 0 m g /m
2
> 2 4 0 0 m g /m
2
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
In fu s io n a l 5 -F U D o s e
5-FUAUC(mg.h/L)
N
M e a n + S D
M e d ia n
% C V
A U C < 2 0
A U C 2 0 - 3 0
A U C > 3 0
4 0 0
2 1 + 1 0
2 0
49%
50%
38%
12%
1 0 8
1 8 + 1 2
1 5
69%
64%
24%
12%
2 5 4
2 2 + 9
2 0
42%
45%
43%
12%
3 8
2 2 + 7
2 2
31%
37%
50%
13%
A ll D o s e s < 2 4 0 0 m g /m
2
2 4 0 0 m g /m
2
> 2 4 0 0 m g /m
2
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
In fu s io n a l 5 -F U D o s e
5-FUAUC(mg.h/L)
N
M e a n + S D
M e d ia n
% C V
A U C < 2 0
A U C 2 0 - 3 0
A U C > 3 0
4 0 0
2 1 + 1 0
2 0
49%
50%
38%
12%
1 0 8
1 8 + 1 2
1 5
69%
64%
24%
12%
2 5 4
2 2 + 9
2 0
42%
45%
43%
12%
3 8
2 2 + 7
2 2
31%
37%
50%
13%
0 5 0 0 1 0 0 0 1 5 0 0 2 0 0 0 2 5 0 0 3 0 0 0 3 5 0 0 4 0 0 0 4 5 0 0 5 0 0 0
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
5 -F U D o s e (m g /m
2
)
5-FUAUC(mg.h/L)
Underdosed
50%
Optimal
38%
Overdosed
12%
y = 0.9362x
R = 0.686
-90%
-60%
-30%
0%
30%
60%
90%
-30% -20% -10% 0% 10% 20% 30%
ActualDoseAdjustment
Recommended Dose Adjustment
57%
N=37
9% (N=14)
48%
N=122
43%
N=28
91%
N=142
52%
N=130
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Decrease No Change Increase
Recommended change for 5-FU dose in subsequent cycle
Followed Not Followed
0
10
20
30
40
50
60
70
First Cycle Subsequent Cyle
5-FUAUCmg.h/L
0
500
1000
1500
2000
2500
3000
3500
4000
4500
0
5
10
15
20
25
30
35
40
45
50
2 3 4 5 6
Infusional5-FUDosemg/m2
5-FUAUCmg.h/L
5-FU cycle number
Dose (mg/m²) 5-FU AUC (mg∙hr/L) Recommended Dose (mg/m²)
REFERENCES: 1. Gamelin E, et al. J Clin Oncol. 1998;16(4):1470-1478. 2. Gamelin E, et al. J Clin
Oncol. 2008;26(13):2099-2105. 3. Capitain O, et al. Clin Colorectal Cancer. 2012;11(4):263-267.
4. Kline CL, et.al. Clin Colorectal Cancer. 2014;13(2):119-126. 5. Beumer JH, et al. Ther Drug Monit.
2009;31(6):688-694. 6. Büchel B, et al. Clin Chem Lab Med. 2013;51(8):1681-1688.
confidential
Kevin Harter
Saladax Biomedical
Sep 02, 2015 09:13
confidential
Kevin Harter
Saladax Biomedical
Sep 02, 2015 09:13