Clinical Cancer Research Vol. 6, 2677-2684, July 2000
© 2000 American Association for Cancer Research
Pharmacokinetic and Pharmacodynamic Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitor AG20341
Howard L. McLeod2,
James Cassidy,
Robert H. Powrie,
David G. Priest,
Mark A. Zorbas,
Timothy W. Synold,
Stephen Shibata,
Darcy Spicer,
Donald Bissett,
Yazdi K. Pithavala,
Mary A. Collier,
Linda J. Paradiso and
John D. Roberts
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 22D, United Kingdom [H. L. M., J. C., R. H. P., D. B.]; Medical University of South Carolina, Charleston, South Carolina 29425 [D. G. P.]; Agouron Pharmaceuticals, Inc., La Jolla, California 92037 [M. A. Z., Y. K. P., M. A. C., L. J. P.]; City of Hope Comprehensive Cancer Center, Duarte, California 91010 [T. W. S., S. S.]; University of Southern California, Los Angeles, California 90033 [D. S.]; and Medical College of Virginia, Richmond, Virginia 23298 [J. D. R.]
 |
ABSTRACT
|
|---|
Glycinamide
ribonucleotide formyltransferase (GARFT) is a component of the de
novo purine synthesis pathway. AG2034 is a specific inhibitor of
GARFT that was designed based on the GARFT crystal structure. In
conjunction with Phase I studies at four clinical centers in the United
States and United Kingdom, AG2034 pharmacology was evaluated in 54
patients receiving 1–11 mg/m2 AG2034 as a 2–5 min
injection. Blood samples were obtained just prior to and 5, 15, 30, and
45 min, and 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, and 96 h after
bolus injection during course 1. Limited sampling was also performed on
course 3. Plasma AG2034 was measured using a sensitive and reproducible
ELISA assay. AG2034 demonstrated a trimodal elimination pattern over
24 h, with median half-life (t1/2)
= 8.7 min,
t1/2ß = 72.6 min, and t1/2
= 364.2 min.
AG2034 systemic clearance ranged from 9.4–144.5 ml/min/m2,
and volume of distribution was 1.2–7.6 liters/m2. Course 1
AG2034 area under the concentration versus time curve (AUC)
had a linear relationship with dose (rs = 0.86).
Accumulation of AG2034 was evident, because course 3 AUC was higher
than course 1 in 23 of 23 evaluable patients, but was not associated
with an increase in erythrocyte AG2034. AG2034 systemic exposure had an
impact on toxicity, because course 1 and course 3 AG2034 AUCs were
significantly higher for patients with grade III/IV toxicity than
patients with less than grade II toxicity (P < 0.001
and P = 0.001 for course 1 and course 3,
respectively). This study demonstrates rapid systemic clearance of
AG2034 and suggests pharmacokinetic approaches that may minimize
patient toxicity and aid the development of this interesting class of
anticancer agents.
|
INTRODUCTION
|
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GARFT3
is an essential
enzyme in the de novo purine synthesis pathway. Most normal
tissues, with the exception of liver and activated T lymphocytes, are
thought to obtain purines primarily from the salvage pathway
(1)
. Tumor cells generally have elevated activities of the
de novo pathway and often have decreased activity of purine
salvage enzymes. This has led to the hypothesis that tumors have a
reliance on de novo purine biosynthesis, providing a
mechanism for selective targeting of tumor compared with normal tissue
using GARFT inhibitors (1)
. The first GARFT inhibitor to
undergo clinical evaluation was lometrexol. Lometrexol exhibited
promising preclinical activity and evidence for clinical objective
responses in a variety of solid tumors.(2
, 3)
. However,
its clinical development was limited by serious cumulative
hematopoietic toxicity (3
, 4)
. Dietary folic acid
supplementation was shown to modulate lometrexol toxicity, without
diminishing antitumor activity in preclinical models (5)
.
In clinical studies, concurrent folic acid supplementation increased
the MTD of lometrexol and seemed to attenuate some cumulative
toxicities (6, 7, 8, 9)
. Pharmacokinetics studies of
lometrexol observed that RBC, but not plasma, concentrations
correlated with the observed cumulative hematological toxicity
(10)
.
AG2034 is a second generation GARFT inhibitor, designed using knowledge
of the X-ray crystal structure of GARFT from Escherichia
coli and of the GARFT domain of the human trifunctional enzyme
(11)
. Computational analysis of the GARFT active site
suggested that sulfur atoms should have particular affinity with two
regions of the folate cofactor binding site. Therefore, AG2034 was
designed to fulfill this condition, while retaining substrate activity
for the reduced folate carrier and FPGS. In preclinical studies, AG2034
was similar to lometrexol, in terms of GARFT inhibition and substrate
specificity for FPGS, but had higher binding affinity for the membrane
folate-binding protein (11)
. AG2034 demonstrated a broad
spectrum of antitumor activity in in vitro and in
vivo model systems, with greater potency than lometrexol
(11)
. In addition, AG2034 demonstrated preferential
cytotoxicity against tumor cells with mutant p53 (12)
.
On the basis of these findings, a Phase I program was designed to
evaluate AG2034 as a short i.v. infusion every 3 weeks. Phase I studies
were performed at clinical centers in the United States of America
(Massey Cancer Center, Virginia Commonwealth University, Richmond, VA;
The City of Hope Comprehensive Cancer Center; and University of
Southern California) and Europe (University of Aberdeen, Scotland). The
Phase I studies utilized a modified Fibonacci approach to define the
MTD of AG2034 in patients with advanced cancer, with a recommended
Phase II dose of 5 mg/m2. In this study, we describe
pharmacology studies conducted in conjunction with the Phase I trials,
to define the plasma pharmacokinetics of AG2034. In addition, the
influence of patient folate status on pharmacokinetics and
pharmacodynamics was evaluated.
|
MATERIALS AND METHODS
|
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Patients.
Pharmacological evaluation was conducted in 54 patients in the Phase I
development program (Table 1)
. Further
information on the clinical and toxicological findings of these studies
are published elsewhere (8
, 9)
. Patients received AG2034
as a 5-min i.v. infusion, with doses escalated from 1 to 11
mg/m2 (Table 2)
. Blood sampling for
pharmacokinetic analysis was performed prior to and 5, 15, 30, 45 min
and 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, and 96 h after bolus
injection during course 1. During course 3, limited blood sampling was
performed, with samples obtained before injection and 5 min, 1 h,
and 24 h after injection. Blood samples for analysis of AG2034 RBC
concentrations were obtained on days 1, 8, and 15 after each course
from seven patients treated at the 5 mg/m2 and 7.5
mg/m2 dose level. Following separation of plasma from whole
blood and removal of the buffy coat, the remaining red cell pellet was
washed twice with PBS and stored at -70°C until analysis.
Assay Development for Plasma AG2034.
Analysis of AG2034 in human plasma was performed using a sensitive and
reproducible ELISA assay, which was modified from a Good Laboratory
Practice ELISA assay developed for analysis of AG2034 in dog plasma at
Agouron Pharmaceuticals.4
An
AG2034 BSA conjugate was generated and used for coating microtiter
plates. Before each assay, plates were incubated with blocking solution
(PBS with 1% Casein). Plasma standards, quality control samples, and
patient samples were incubated with a rabbit polyclonal antibody
generated against AG2034 prior to incubation on the microtiter plate.
Each 96-well plate contained a standard curve in triplicate (0.1–1000
ng/ml) and triplicate quality control samples (4, 20, and 400 ng/ml). A
total binding (antibody alone) and blank nonspecific binding (no
antibody) control was included with each plate. After incubation,
plates were washed three times in PBST, incubated with a
secondary antibody conjugated to horseradish peroxidase, and color
developed using TMB peroxidase substrate. Microtiter plates were
read at 450 nm. Intra-assay coefficients of variation at 4, 20, and 400
ng/ml AG2034 ranged from 6.0–7.7%. The interassay coefficients of
variation at the same concentrations ranged from 6.7–8.2%. The lower
limit of detection was 0.5 ng/ml, and the lower limit of quantitation
was 1 ng/ml (2 nM). The assay was linear from 1–500 ng/ml
(r2 = 0.99). Evaluation of plasma dilution protocols
determined that linear sample prediction was achieved up to 1:200
dilution. Samples diluted 1:1000 gave a predicted AG2034 concentration
>20% of actual value (21.7%). There were no significant changes in
AG2034 concentration when left at room temperature for up to 4 h,
or after three freeze-thaw cycles. The assay was not cross-reactive
with folic acid or 5-methyltetrahydrofolate.
|
Pharmacokinetic Analysis
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Plasma concentrations after 24 h, were low and relatively
constant (8)
, with negligible contribution to the overall
AUC. Plasma AG2034 data from 0–24 h was analyzed using a
three-compartment linear pharmacokinetic model, implemented on ADAPT II
software (13)
. An iterative two-stage approach was used
with initial Bayesian starting primary pharmacokinetic parameters
(e.g. Vd, K10, K12,
K21, K13, and K31) from that
recently described for lometrexol (10)
. Primary estimates
were generated following three iterations, and secondary
pharmacokinetic parameters [CL, volume of distribution
(Vd), plasma half-life (t1/2), and AUC] were
derived from the model-generated primary estimates.
Analysis of HCY, MMA, pMF, and eMF.
Blood samples for analysis of patient folate status were obtained
immediately before the first dose of AG2034. Plasma HCY was
measured using a HPLC assay (14)
, whereas a gas
chromatography-mass spectroscopy assay was used for determination of
serum MMA (15)
. Plasma and RBCs were analyzed for
5-methyltetrahydrofolate content using an assay based on enzymatic
cycling of this reduced folate form to 5,10-methyltetrafolate, followed
by entrapment into a stable ternary complex with thymidylate synthase
and tritiated fluorodeoxyuridylate (16)
.
Analysis of RBC AG2034 Concentrations.
RBC AG2034 concentrations were measured using a newly developed
HPLC/electrochemical detection assay. The assay measures the
desglutamate form of AG2034, following enzymatic digestion with
carboxypeptidase G. The HPLC system consisted of a Shimadzu LC-10AS
solvent delivery pump (Shimadzu Inc., Columbia, MD), a SIL-10A
automatic injector, and a Coulochem II electrochemical detector (ESA
Inc., Chelmsford, MA). Separation was achieved using a C18
250 x 4.6-mm analytical column (Regis Technologies, Morton Grove,
IL) and a Nova-Pak C18 guard column (Waters Chromatography,
Milford, MA). The mobile phase was 17% acetonitrile in 0.05
M potassium phosphate buffer (pH 3.5) with 0.1
mM EDTA at a flow rate 1.2 ml/min. The total run time for
each sample was 26 min. The electrochemical settings were +0.9 V for
the guard cell, +0.4 V for electrode 1, and +0.6 V for electrode 2.
To determine intracellular levels of both AG2034 and its
polyglutamates, RBC samples were first lysed using three rapid
freeze-thaw cycles. The lysed cells were then treated with
carboxypeptidase G (Sigma Chemical Co., St. Louis, MO) to cleave all
intracellular drug species down to their common desglutamate form
(AG2057). Following enzymatic digestion, samples were extracted using 3
cc sulfonic acid cation-exchange cartridges (J. T. Baker,
Phillipsburg, NJ). The pH of the extracted samples was then adjusted to
4 using acetic acid, and 100 µl was injected on the HPLC. The
percentage conversion of AG2034 and AG2034-pentaglutamate to AG2057 was
115% and 92%, respectively. The standard curve for AG2057 was linear
in the range of 5–250 ng/ml (rs = 0.999). Intra-assay
coefficients of variation at 7.5, 75 and 200 ng/ml AG2057 ranged from
3.6–5.8%, whereas the interassay coefficients of variation at the
same concentrations ranged from 2.9–6.6%. The lower limit of
quantitation of the assay was 5 ng/ml, with a lower limit of detection
of 2 ng/ml.
Pharmacodynamic Analysis.
Both hematological and nonhematological toxicity (diarrhea,
fatigue, hyperbilirubinemia) were observed after treatment with AG2034
(8
, 9) . This toxicity was both acute and cumulative.
Therefore, the highest grade of toxicity during courses 1–3 were used
for each patient in the pharmacodynamic analysis.
Statistical Analysis.
Evaluation of the relationship between age, folate status (HCY, MMA,
pMF, eMF), or dose and either Vd or CL were made using the
Spearman’s rank test. The influence of gender on Vd, CL,
HCY, MMA, pMF, and eMF was assessed using the Mann-Whitney test.
Differences between pharmacokinetic parameters or folate status in
patients from the United States or United Kingdom were evaluated by
using the Mann-Whitney test. The change in AG2034 AUC between course 1
and course 3 was analyzed with the Wilcoxon signed ranks test. The
Mann-Whitney test was also used to evaluate differences in AUC, CL,
HCY, MMA, pMF, eMF or age in patients with grade II toxicity or less or
grade III/IV toxicity.
|
RESULTS
|
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Course 1 Plasma Pharmacokinetics.
Plasma pharmacokinetic data from the first course of AG2034
administration was available for 54 patients (Table 2)
. Plasma CL was
rapid with a median value of 38.1 ml/min/m2 (Table 2)
.
AG2034 pharmacokinetics demonstrated a triphasic elimination profile,
with a rapid initial distribution phase (median t1/2 = 8.7 min)
and a prolonged terminal elimination phase (median t1/2 = 364.2
min; Fig. 1
and Table 2
). AG2034 AUC
demonstrated a linear relationship with dose (Fig. 2
; rs = 0.86;
P < 0.001).
AG2034 CL decreased with increasing age (rs = -0.32;
P = 0.018) and increasing pMF concentration
(rs = -0.47; P = 0.001) (Fig. 3)
. CL did not seem to be influenced by
HCY or MMA concentrations. A 5.6-fold range in Vd was
observed (Table 2)
. Vd was not associated with patient age,
BSA, AG2034 dose, HCY, MMA, or eMF. However, a significant inverse
relationship between Vd (ml/m2) and pMF was
observed (rs = -0.44; P = 0.004).
This Phase 1 study was conducted at three United States centers and one
United Kingdom center. Differences in folate status was apparent, with
lower pMF and eMF and higher HCY in United Kingdom patients (Table 3)
.
Plasma MMA was not different between the two countries. The impact of
altered folate status on AG2034 was less apparent, because there was no
significant difference between AG2034 CL (P = 0.22) or
Vd (P = 0.25) between the two countries.
AG2034 Accumulation.
Information on plasma AG2034 pharmacokinetics was available for
course 3 in 23 patients. Evidence for drug accumulation was apparent,
because AG2034 AUC demonstrated a median 212.7% increase from course 1
to course 3 (P < 0.001; Fig. 4
). The course 3 AUC was
higher than course 1 in 23 of 23 patients. A strong correlation between
course 1 and course 3 AG2034 AUC was observed (rs =
0.88, P < 0.001). There was no evidence for
disproportional intracellular accumulation of AG2034. RBC AG2034
concentrations during the first three courses were low (<4.5 to 13.9
ng/ml) and mirrored that observed in plasma.
AG2034 Pharmacodynamics.
Grade III/IV toxicity was observed in 14 of 23 total patients
(United States, 11; United Kingdom, 12) receiving the top three dose
levels (6, 7.5, and 11 mg/m2). Grade III/IV hematological
toxicity occurred in seven patients, with grade III/IV nonhematological
toxicity in 14 patients. Unlike lometrexol, anemia was not a dominant
hematological toxicity of AG2034 (8
, 9)
. The patients were
equally distributed by country for nonhematological toxicity (United
States 7 of 11; United Kingdom, 7 of 12). Grade III/IV hematological
toxicity seemed to occur more frequently among the United Kingdom
patients (United Kingdom, 5 of 12, and United States, 2 of 11 patients
at 6, 7.5, and 11 mg/m2), although this did not reach
statistical significance (P = 0.22). The incidence of
systemic toxicity was significantly higher among patients with greater
than the median course 1 AG2034 AUC value (12 of 27 patients with
toxicity versus 2 of 27 patients whose AUC was less than the
course 1 median P = 0.005). Course 1 AG2034 AUC was
significantly higher in patients with hematological (P = 0.001) and nonhematological (P < 0.001) toxicity. No
other pretherapy demographical or biochemical variable was associated
with nonhematological toxicity, whereas a higher pretherapy HCY
concentration was observed in patients with grade III/IV hematological
toxicity (P = 0.024). When toxicity in any tissue was
considered, course 1 median AG2034 AUC was significantly higher in
patients with grade III/IV toxicity compared with other patients (toxic
198,515.6 versus nontoxic 70,441.2 ng/ml*min,
P < 0.001; Fig. 5
). The influence of
AG2034 systemic exposure on toxicity was also evident among the 23
patients with course 3 AUC measurements (P = 0.001,
Fig. 5
). The degree of increase in AG2034 AUC between courses 1 and 3
was not different between nontoxic and toxic patients
(P = 0.88).
|
DISCUSSION
|
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AG2034 pharmacokinetics were best described by a three-compartment
model over the first 24 h after initial injection. A prolonged
terminal elimination phase was observed with a median t1/2 of
364.2 min, and AG2034 AUC was linear with dose. CL was highly variable
and seemed to be influenced, at least in part, by patient age and
pretherapy pMF concentration. Overall, AG2034 pharmacokinetics were
similar to the first generation GARFT inhibitor lometrexol
(10)
. Lometrexol has demonstrated a triphasic pattern of
elimination, which is not influenced by folic acid or leucovorin
pretreatment (10
, 17) . AG2034 and lometrexol have a
similar CL value (median 38.1 versus 22.6–26.7
ml/min/m2) and Vd (median 3.6 versus
8.6–8.9 liter/m2) (10
, 17)
. Because previous
studies of lometrexol have not included measures of patient folate
status, regulation of pharmacokinetics by pMF cannot be compared
between the two agents.
AG2034 pharmacokinetics seem to be influenced by both age and pMF. Cl
illustrated an inverse relationship between both age and pMF, whereas
Vd was inversely related to pMF alone. AG2034 is a
substrate for both the reduced folate carrier and FPGS and has high
binding affinity for membrane folate-binding protein (11)
.
Therefore, it can be hypothesized that patients with high pMF will have
a greater cellular competition for both intercellular uptake and efflux
of AG2034. The linear relationship between CL and Vd may
reflect coregulation by patient folate status. A precise physiological
basis for the interaction between pMF and both AG2034 CL and
Vd remains to be defined. The influence of age on AG2034 CL
is likely a surrogate of renal function. AG2034 seems to be eliminated
unchanged in the urine, and no metabolites were apparent in plasma with
HPLC analysis.5
Because there
is a well-defined relationship between increasing age and decreasing
kidney function, the correlation between age and CL is likely
explained. The definitive measures of patient creatinine clearance
(24-h urine collection or radioisotope evaluation) were not available
from patients on this Phase 1 study.
Significant differences in pMF, eMF, and HCY were observed between
United States and United Kingdom patients. This is not surprising
because folic acid fortification of bread and other foodstuffs is not a
common practice in the United Kingdom. In addition, vitamin
supplementation is less frequently used in the United Kingdom than
United States. There was no significant difference in AG2034
pharmacokinetic parameters between countries. However, the incidence of
hematological toxicity was higher in United Kingdom patients, although
this did not reach statistical significance. The MTD was also identical
between the two countries (8
, 9)
. This makes the
significance of differences in folate status unclear. Caution may need
to be used when extrapolating drug dosage across populations,
especially for anticancer agents that involve folate pathways.
Drug accumulation was apparent for AG2034 between course 1 and course
3. AG2034 AUC increased from course 1 to course 3 in all 23 evaluable
patients. The median change in AG2034 AUC was 212.7%, with a range
from 20–389% increase from course 1 to course 3. This is similar to
that previously described for lometrexol. However, unlike lometrexol,
the accumulation of AG2034 in RBCs was not apparent (10)
.
This may suggest that delayed elimination from plasma, rather than
enhanced tissue retention, may be responsible for the alteration in
AG2034 AUC. Alternatively, RBC accumulation may not be a good surrogate
for tissue accumulation of AG2034.
AG2034 pharmacokinetics demonstrated a significant influence on
toxicity. AG2034 AUC after courses 1 or 3 were significantly higher in
patients demonstrating either grade III/IV hematological or
nonhematological toxicity (Fig. 5)
. Indeed, 12 of 14 patients with
systemic toxicity had a course 1 AG2034 AUC greater than the median
value. All toxic patients were treated at the three highest dose levels
(6, 7.5, and 11 mg/m2), reflecting the linearity of the
AG2034 dose-AUC relationship. A correlation between AUC and toxicity is
not surprising, because lometrexol systemic exposure has been
associated with the degree of hematological toxicity (10)
.
Similar pharmacodynamic relationships have also been described for
other antifolates, including methotrexate (18
, 19)
.
Although drug accumulation and cumulative toxicity was evident for
AG2034, the high correlation of AUC between the courses made course 1
AUC a strong predictor for systemic toxicity. This provides a useful
tool for future development of this class of compounds.
The results of the AG2034 pharmacodynamic analysis provide further
support for the selection of 5 mg/m2 AG2034 as the Phase II
dose, based on clinical toxicity information. Based on the AG2034
pharmacokinetic data in Table 2
, 5 mg/m2 would give an
estimated median AUC 131,580 ng/ml*min, whereas 6 mg/m2
would result in a median 157,900 ng/ml*min. The estimated AG2034 AUC
(±10%) from 5 mg/m2 would be predicted to be well
tolerated, as none of four patients in that range experienced toxicity.
The 6 mg/m2 AUC estimate was associated with toxicity in
two of four patients. The schedule dependence of antimetabolite
anticancer agents do not allow the use of simulation experiments based
on this data to predict the toxicity profile that would be observed
with alternative administration schedules.
Whereas higher AG2034 AUC is associated with increased systemic
toxicity, it does not seem to be the only factor regulating AG2034
pharmacological activity. A degree of overlap in AG2034 AUC values was
observed between toxicity groups (Fig. 5)
. A high pretherapy HCY value
was associated with greater hematological toxicity, but did not seem to
influence nonhematological toxicity. This may reflect the finding that
HCY was higher in United Kingdom patients than United States patients,
and a high proportion of patients with hematological toxicity were from
the United Kingdom center (five of seven patients). Demographic
variables, including prior treatment with leucovorin, did not have an
apparent influence on the incidence of AG2034 toxicity. However,
preclinical studies have identified other variables that influence
AG2034 cytotoxicity, including hypoxanthine concentrations, FPGS
activity, and expression of reduced folate carrier and membrane
folate-binding proteins (11
, 20)
. In addition, AG2034
seems to be preferentially cytotoxic to cells with mutant p53 protein
(12)
. Variability in the reliance on the p53-mediated
apoptosis pathway (or a related p53-mediated checkpoint) between normal
tissues may be an additional influence on AG2034 systemic toxicity.
|
ACKNOWLEDGMENTS
|
|---|
This study could not have been completed without the important
contributions of the Research Nurses, Data Managers, Clinical Research
Associates, and other team members at the clinical centers and Agouron
Pharmaceuticals. The technical skills of Robert Anderson and Peter
Mackie were greatly appreciated. Special thanks to Dr. Lisa DiMolfetto
for her efforts.
|
FOOTNOTES
|
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by a research grant from Agouron
Pharmaceuticals. 
2 To whom requests for reprints should be
addressed, at Department of Medicine and Therapeutics, Institute of
Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25
2ZD, United Kingdom. Phone: 44-1224-552730; Fax: 44-1224-273066;
E-mail: h.l.mcleod{at}abdn.ac.uk
3 The abbreviations used are: GARFT, glycinamide
ribonucleotide formyltransferase; AUC, area under the concentration
versus time curve; CL, systemic clearance; eMF, erythrocyte
5-methyltetrahydrofolate; FPGS, folylpolyglutamate synthetase; HCY,
homocysteine; HPLC, high-performance liquid chromatography; MMA,
methylmalonic acid; MTD, maximum tolerated dose; PBS,
phosphate-buffered saline; pMF, plasma 5-methyltetrahydrofolate; RBC,
erythrocyte.
4 M. A. Zorbas, unpublished data.
5 Unpublished data.
Received 2/ 2/00;
revised 3/21/00;
accepted 3/27/00.
|
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ABSTRACT
INTRODUCTION
