Pharmacokinetics of metronomic chemotherapy

Divisione di Farmacologia
Dipartimento di Medicina Clinica and Sperimentale
Università di Pisa
U.O. Farmacologia Clinica
Azienda Ospedaliero Universitaria Pisana
Pharmacokinetics, pharmacodynamics
and pharmacogenetics of metronomic chemotherapy
Bocci Guido
Cancer Metronomic Therapy – AIOM Meeting
Milan ‐ February 26th 2016
Metronomic chemotherapy:
a new PK/PD definition
“Indeed, metronomic chemotherapy may be better defined as a frequent, regular administration of drug doses designed to maintain low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time without inducing excessive toxicities.”
Bocci & Kerbel. Nat Rev Clin Oncol 2016 in press
Pharmacokinetics of metronomic chemotherapy:
the neglected part of the story Despite more than 10 years of clinical studies on metronomic chemotherapy, very few clinical pharmacokinetic data are currently available
WHY ?
methodological issues such as long‐term sampling, availability of proper detecting methods (e.g. 4‐OH‐CTX), combinations of drugs
the underestimation of the importance of the relationship between plasma/tumor concentrations of metronomic drugs (and their active metabolites) and clinical activity Pharmacokinetics: a key aspect for the development of metronomic concept
The pharmacokinetic knowledge about metronomic chemotherapy regimens is essential to determine:
1.
a dose schedule that reaches an active concentration of drug
2.
the main mechanisms of action involved in the success of metronomic chemotherapy at a specific range of drug concentrations in plasma
3.
pharmacodynamic markers in oncology patients for such drug concentrations
4.
any possible pharmacokinetic interactions (positive or negative) with other drugs, such as tyrosine kinase inhibitors or therapeutic antibodies
Metronomic cyclophosphamide PK /PD
Metronomic daily oral dose: 20 mg/kg
Emmenegger et al. Mol Cancer Ther 2007;6:2280
Antiangiogenic activity
↓ number of vessels in matrigel plug
↓ number of viable CEP
Intermittent metronomic schedule: 140 mg/kg every 6 days
Activation of antitumor
innate immunity
↑ number of macrophages, dendritic cells and NK cells
Chen CS et al. Neoplasia 2014;16: 84
Dendritic cells
NK cells
Metronomic cyclophosphamide PK/PD ‐ II
Standard dose 600 mg/m2 i.v. Cmax 31.4±5.4 µg/ml Goodman & Gilman 2015
Daily oral dose CTX 50 mg
CTX Cmax 2.01 µg/ml
Antiangiogenic
activity
↓ number of vessels
CD31+
↓ expression of VEGF
Bazzola et al. Br J Cancer 2015;112: 52
Breast cancer
No available data about the active metabolites of cyclophosphamide (e.g. 4‐OH‐
CTX) and description of PK only after a single dose
Metronomic cyclophosphamide PK/PD ‐ III
Daily oral dose CTX 50 mg
Antiangiogenic
activity
Fontana et al. Clin Cancer Res 2009,15:4954
Calleri et al. Clin Cancer Res 2009,15: 7652
Prostate cancer
Responder patients had lower VE‐
cadherin expression
Breast cancer
Patients with lower VEGF levels after 2 mo of treatment had higher PFS
Metronomic cyclophosphamide PK/PD ‐ IV
Intermittent metronomic
schedule
Cyclophosphamide 100 mg/day,
1 week on and 1 week off
CTX and 4‐OH‐CTX
concentrations
?
Pharmacokinetics of metronomic oral vinorelbine
Standard dose 30 mg/m2 i.v. → Cmax 1130±636 ng/ml
Leveque et al. Clin Pharmacokinet 1996,31: 184
vinorelbine displayed linear pharmacokinetics
Briasoulis et al. Clin Cancer Res 2009;15:6454
Briasoulis E et al. BMC Cancer 2013;13:263
the blood Css for vinorelbine was attained after 14 days of treatment, and this compound did not show any evidence of accumulation during months of successive treatment 0.4
0.2
0
0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00
time (h)
N
30000
25000
20000
15000
*
10000
*P=0.0063
Bocci et al. 2016 unpublished data
on
N
R
es
p
Vinorelbine 30 mg p.o. three times a week in prostate cancer patients
R
↓ plasma VEGF
↑ plasmaTSP‐1
0.0
P<0.0001
re
sp
0.6
5000
on
0.8
*
10000
re
sp
Antiangiogenic
activity
15000
es
p
1.0
AUC 0-28 TSP1 [day  ng/ml]
VNR plasma levels [ng/ml]
Day 28
AUC 0-28 VEGF [day  ng/ml]
Metronomic oral vinorelbine PK/PD ‐ I
130
0.8
Non Responders
120
110
100
90
0
Immunological‐
mediated mechanism ?
1.0
Days
0.6
PFS (B7H3 concentration at day 28)
0.4
100
80
B7H3 < 30.25 pg/ml
B7H3 > 30.25 pg/ml
60
*Log-rank P=0.0298
0.2
0.0
0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00
time (h)
Percent survival
VNR plasma levels [ng/ml]
Day 28
Responders
11
2
Vinorelbine 30 mg p.o. three times a week in prostate cancer patients
140
28
% plasma B7H3 at day 0
Metronomic oral vinorelbine PK/PD ‐ II
40
20
0
0
Bocci et al. 2016 unpublished data
5
10
15
20
Time (months)
After 4 weeks of treatment, non responder patients showed increased plasma concentrations of the soluble form of B7‐H3, an inhibitor of prostate cancer immunity
Wang et al. Int J Cancer 2014, 134:2764
Metronomic UFT PK/PD
5‐FU 370 mg/m2 i.v. → Cmax 48.41±7.69 µg/ml
Bocci et al. Clin Cancer Res 2000,6: 3032
daily dose of 100 mg UFT p.o in combination with CTX 50 mg
< plasma VE‐cadherin
in SD
> plasmaTSP‐1 in SD
TSP‐1
Allegrini, Di Desidero et al. Angiogenesis 2012,15:275
Antiangiogenic
activity
VE‐cadherin
Pharmacokinetic parameters could be predictive of metronomic chemotherapy success ?
Cut‐off = 0.501 µg/ml
Sensitivity = 81.82%
Specificity = 76.92%
Cmax 5-FU (g/ml)
1.5
1.0
*
0.5
SD
PD
0.0
day 1 of treatment
PFS according to 5-FU Cmax at day 1
80
60
100
Cmax 5-FU > 0.501*
Median PFS: 4.5 ms (95%C.I.1.5-7.5)
Cmax 5-FU < 0,501*
Median PFS: 2 ms (95%C.I. 0.1-3.9)
*ROC curve
Log-rank P=0.0222
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Percent survival
Percent survival
100
OS according to 5-FU Cmax at day 1
Cmax 5-FU > 0.501*
Median OS: 9.5 ms (95%C.I. 5-14)
Cmax 5-FU < 0.501*
Median OS: 5.65 ms (95%C.I. 3-8.3)
80
60
*ROC curve
Log-rank P=0.0172
40
20
0
0
2
4
6
time (months)
8 10 12 14 16 18 20 22
time (months)
Allegrini, Di Desidero et al. Angiogenesis 2012,15:275
5‐FU prodrugs pharmacokinetics: why we
should go ahead…
Despite the limitation of this analysis due to the small number of patients, these results identified a pharmacokinetic cut‐off value in a clinically relevant population UFT pharmacokinetic parameters may be used from the very first administration of the drug to predict the efficacy and the survival of colorectal patients undertaking the metronomic schedule.
…and capecitabine ?
Metronomic capecitabine
Capecitabine 1250 mg/m2 p.o.→ Cmax 10.74±6.77 µg/ml
Farkouh et al. Anticancer Res. 2014;34:3669
Yasuno et al. Oncol Rep. 2013;29:451
Which is the prevalent mechanism of action for these drug concentrations?
Direct cytotoxic activity
on tumor cells
PK of 1 patient
plasma levels (g/ml)
10
8
Cape
5DFCR
5DFUR
5FU
6
Antiangiogenic activity
4
2
0
0
1
2
3
4
5
time (h)
dose of 800 mg capecitabine p.o
Bocci et al. 2016 unpublished data
Activation of antitumor
innate immunity
?
Pharmacokinetic interactions between topotecan
and pazopanib in patients
with pazopanib
Significant differences of topotecan PK at standard doses
Kerklaan et al. Br J Cancer 2015, 113:706
NO significant differences of topotecan PK at metronomic doses
Turner et al. Anticancer Res 2013, 33:3823
Pharmacokinetic interactions between metronomic topotecan and pazopanib in preclinical studies
Kumar et al. Clin Cancer Res 2011, 17:5656
NO significant differences of
topotecan PK at metronomic
doses
Jedeszko et al. Sci Transl Med 2015, 282ra50
but…
Increased intracellular
accumulation of topotecan in cancer and endothelial cells
Metronomic chemotherapy pharmacogenetics:
the available pieces of the puzzle
Is the genetic background involved in the efficacy or resistance to metronomic
therapies? Are somatic mutations of
tumors involved in the efficacy
or resistance to metronomic
therapies? Gene polymorphisms as
possible predictive
biomarkers for
metronomic
chemotherapy
?
Prostate cancer patients harbouring the germline
VEGF ‐634CC genotype were not responsive to
metronomic cyclophosphamide
Progression‐free survival
CC
CG/GG
VEGF -634 CC: median PFS 2.2 ms
(C.I. 95% 0.45-3.95)
100
P=0.0485
48.84%
20
39.53%
15
10
11.63%
5
% of survival
number of patients
25
VEGF -634 CG/GG: median PFS 6.25 ms
(C.I. 95% 3.28-8.62)
75
50
P=0.0042
25
0%
0
Responders
Non Responders
0
0
5
10
15
20
25
30
time (months)
Clinical response: decrease of PSA≥50%
Median PFS 2.2 vs. 6.3 months
Orlandi et al. Br J Cancer 2013,109:957
A possible hypothesis from this pilot study….
Orlandi et al. Br J Cancer 2013,109:957
Hypothesis
Could be the beginning for a personalized metronomic
chemotherapy?
Urgent need for a prospective
validation trial…
but
metronomic chemotherapy is
given in combination with an
antiangiogenic drug and after MTD chemotherapy…
It will be the same?
Conclusions
1) Different metronomic drug concentrations ‐ and schedules ‐
may determine different prevalent mechanisms of action
(selection of therapy and patient based on the prevalent effect?)
2) Pharmacokinetic parameters should be extensively investigated
in relation to pharmacodynamics (PK/PD approach)
3) Therapeutic drug monitoring (TDM) of metronomic
chemotherapy to maintain drug concentrations in the “activity
range”
4) Randomized, prospective, pharmacogenomic/pharmacogenetic
clinical studies should be performed to achieve a personalized
metronomic chemotherapy
Acknowledgements
My team
Teresa Di Desidero
Paola Orlandi
(Anna Fioravanti)
Romano Danesi
University of Pisa
Alfredo Falcone
and collaborators
Mario Giorgi and Alessandro Saba
General Hospital of Pontedera
Giacomo Allegrini and collaborators
University of Toronto
Robert S. Kerbel
and collaborators
Urban Emmenegger
University of Texas at El Paso
Giulio Francia
Thanks to grants from: