Download Pharmacokinetics of Vindesine Given as an

(CANCER RESEARCH 45, 464-469, January 1985]
Pharmacokinetics of Vindesine Given as an Intravenous Bolus and 24-Hour
Infusion in Humans1
Takao Ohnuma,2 Larry Norton, Alicja Andrejczuk, and James F. Holland
Department oÃ-Neoplastia Diseases, Mount Sinai School of Medicine, New York, New York 10029
ABSTRACT
MATERIALS AND METHODS
The pharmacokinetics of vindesine was examined after the
determination of serum drug levels by radioimmunoassay in
patients who received the drug either as an i.v. bolus or a 24-hr
VDS was supplied by Dr. R. Dyke of the Lilly Laboratories for Clinical
Research, Indianapolis, IN, as a lyophilized powder of 10 mg in 10-ml
infusion. After i.v. bolus, vindesine was eliminated from the serum
by triphasic decay. The central compartment was approximately
6 times the serum volume. The peak serum level achieved by
i.v. bolus was approximately 16 times that achieved by the 24hr infusion. The post-24-hr-infusion serum decay followed biphasic decay. Pharmacokinetic modeling, assuming a prolonged
infusion period, resulted in a triphasic decay curve, with an
extremely short distribution phase which would not be clinically
detectable. This was due to the incorporation of the distribution
phase into the infusion period. This explains the experimental
data of a biphasic decay curve observed after 24-hr infusion.
Pharmacokinetic parameters for the two phases observed after
24-hr infusion were similar to values calculated from i.v. bolus
data. The c x t for 24-hr infusion was identical to that after i.v.
bolus; theoretically, the c x f appears constant regardless of
infusion time. It is concluded that the rate of elimination and/or
the c x f, rather than the peak serum level, played a role in the
degree of hematological toxicity.
Vinca alkaloid vinblastine sulfate. Clinical studies have been
carried out in various institutions in the United States and Europe
(1,3,6, 7,10,14,19).
In our Phase I study of VDS, human dose
findings were done in 2 schedules, i.v. bolus and 24-hr infusion
lid or 0.69 ng/tube diluted with 0.02 M acetate buffer, pH 4.4) and 100
n\ rabbit anti-VLB antiserum (Lot No. 24-245-2-G, Eli Lilly Research
administered weekly. Major clinical side effects observed after
i.v. bolus and 24-hr infusion were myelosuppression and neurctoxicity. At identical dosage levels, degrees and parameters of
toxicity were indistinguishable (14).
During our Phase I study, we measured the serum drug
concentration by radioimmunoassay and compared the pharmacokinetic parameters of the 2 schedules. Attempts were made
to explain clinical toxicity in terms of pharmacokinetic parame
ters.
1Supported in part by Contract N01-CM-97275 from the Division of Cancer
Treatment, National Cancer Institute, NIH, Bethesda, MD; by USPHS Research
Grant CA 15936-03; by the United Leukemia Fund, Inc., New York, NY; and by T.
J. Marteli Foundation for Leukemia and Cancer Research, New York, NY.
' Chemotherapy Foundation Senior Clinical Investigator. To whom requests for
CANCER
renal impairment, but one (Patient 1) had a moderate third space fluids.
All patients had WBC counts more than 4,000//il and platelets more than
100,000//il. All but one patient (Patient 11) (Table 3) received 4 mg/sq m
of the drug. Patient 11 received 5 mg/sq m. One patient (Patient 6)
(Table 1) developed transient elevation of transaminases after each of 2
courses of i.v. bolus treatment.
After administration of VDS, either by i.v. bolus or 24-hr infusion,
until assay. Informed consent was obtained from each patient prior to
the study.
VDS serum levels were measured by radioimmunoassay (12,13,16,
17). The reaction tubes (12- x 75-mm polystyrene tubes No. 2054;
Falcon Plastics, Oxnard, CA) consisted of 200 n\ of 0.2 M glycine buffer,
pH 8.8, which contained 0.25% human serum albumin (Plasmanate,
Cutter Laboratories, Berkeley, CA), 1.0% normal sheep serum (Antibod
ies, Davis, CA), and 0.0242% methiolate; 100 /il standard or unknown
serum (appropriately diluted with the glycine buffer, ¡fnecessary), 100 ^l
[3H]VLB solution (Amersham/Searie Corp., Arlington Heights, IL; 0.27
VDS3 is a new synthetic antineoplastic agent derived from the
vinWastine amidosulfate; Lilly Compound No. 99094, Eldisine); VLB, vinblastine;
VCR, vincristine.
Received January 11, 1982: accepted September 27, 1984.
after further diluting in one liter of 5% dextrose.
Serum VDS levels were measured in a total of 11 patients: 6 after i.v.
bolus, 4 after 24-hr infusion, and 1 after bolus and 24-hr infusions given
at a 3-week interval. None of the patients had preexisting hepatic or
blood samples were collected at selected time intervals (after bolus at 0,
5, 15, and 30 min and then 1, 2, 4, 6, 12, 24, 48, and 72 hr; with the
infusion schedule at 0 and 12 hr during infusion and after the infusion at
5 and 30 min and then 1, 2, 4, 8, 24, 48, and 72 hr) from an arm
contralateral to the site of the drug administration. Serum was separated
from coagulated blood samples by centrifugation and stored at -75°
INTRODUCTION
reprints should be addressed.
3 The abbreviations used are: VDS. vindesine sulfate (NSC 245467, CAS Regis
try No. 59917-39-4; 23-amino-O'-deacetyldemethoxyvincaleukoblastine,
deacetyl-
ampuls. The ampuls were refrigerated during storage. Just prior to use,
the drug was diluted with bacteriostatic sodium chloride injection solution
and was then administered either as a slow i.v. bolus (approximately 1
min) through the side arm of a running infusion, or as a 24-hr infusion
Laboratories, Indianapolis, IN: diluted 1:2500 with glycine buffer). The
contents of the tubes were mixed gently, and the tubes were capped
tightly and incubated for 4 days at 4°. At the end of the incubation
period, 500 n\ of dextran-coated charcoal suspension [1 % Nor it-A (Sigma
Chemical, St. Louis, MO) and 0.5% dextran 70 (Pharmacia, Upsala,
Sweden)] in glycine buffer were added to each tube, and incubation was
continued at room temperature for 30 min with gentle shaking twice.
The tubes were centrifuged at 1000 x g for 10 min, and the supernatant
was decanted directly into scintillation vials. One-half ml of NCS (Amersham) was added and heated at 50°for 20 min. The material was cooled
to room temperature. Ten ml of PCS (Amersham) were added, and the
vials were then counted in a liquid scintillation counter (Model LS-355,
Beckman Instruments, Palo Alto, CA). Standard solutions were made by
diluting VDS in acetate buffer with concentrations ranging from 0.2 to
100 Mg/liter. Control tubes included those containing glycine buffer and
[3H]VLB only ("total"), 100 ^l of nonimmune rabbit serum substituted for
the antiserum ("blank") and 100 fi\ of glycine buffer in place of the
standard or unknown ("bound"). The "blank" cpm were subtracted from
those of the "bound" to give the actual bound radioactivity, B. The "total"
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PHARMACOKINETICS
OF VOS IN HUMANS
cpm minus the "bound" cpm gave the actual free radioactivity, F. The
B/F based on "total," "blank," and "bound" should be close to 1.0. B/F
.80
for the standard and unknown was calculated as:
8 _ Sample cpm - "blank" cpm
F
"Total" cpm - sample cpm
(A)
B/F for the standard curve was plotted on a logit-log scale, and unknown
concentrations were read from the linear portion of the graph. The assays
were run in duplicate and repeated at least twice. All the serum drug
values were graphed semilogarithmically and curve fit by the method of
nonlinear least-square using the Meeter-Marquardt-Wood
algorithm (4).
Using serum VDS levels after i.v. bolus, the first-order mass transfer
rate constant was calculated on the basis of a "first-pass" 3-compartrnent
model (Chart 1) (11,20). This model was chosen because animal studies
had indicated that the biliary excretion was the major route of VDS
elimination (2). Thus, the second compartment (Chart 1) is assumed to
be in equilibrium with the nepatobiliary system, and the elimination occurs
principally from the second compartment. The third compartment is
unidentified physiologically.
RESULTS
The VDS standard curve is shown in Chart 2. On the logit-log
scale, radioimmunoassay values of VDS were linear in the range
of 1.0 to 100 /¿g/liter.VDS is stable in 0.9% sodium chloride or
5% dextrose for more than 24 hr at room temperature.4 The
drug was also stable in frozen serum when repeatedly defrosted
and measured 2 to 3 times during a 6-month time span.
Serum VDS levels after i.v. bolus followed triexponential de
cay, as confirmed by the precise curve-fit of equation B:
+ Be-
= Pe-
(B)
where c,t,(f ) is the serum VDS concentration at time t after bolus
drug administration; P, A, and B are constants representing
intercepts on the ordinate at time zero; and ir, «,and ßare the
first-order disposition constants with ir > «> ß> 0. Pharmaco
kinetic parameters obtained from a single i.v. bolus administra
tion in 7 patients are shown in Tables 1 and 2. An example of
Dot t=o
2k2ik,2D¡koIk|3*k3l3
<20
3-compartment
.70
.60
.50
.40
.30
¡.20
.10
.02
1.0
100.0
10.0
VINDESINE (>ig/liter)
Chart 2. VDS radioimmunoassay standard curve. See "Materials and Methods"
for the assay. The "bound" (B) cpm/"free" (F) cpm ratio was plotted on a logit
0.2
scale on the ordinate.
the least-squares curve-fit of Equation B to the data is illustrated
in Chart 3. From these data, the initial half-life of serum drug
decay was approximately 9 min. The second serum half-life was
approximately 4 hr, and the third half-life was approximately 35
hr. Patient 6 had pharmacokinetic parameters essentially within
the values obtained from others, except ßof 0.0085 or the third
half-life of approximately 80 hr. The volume of distribution of the
central compartment (Chart 1, Compartment 1) was calculated
to be approximately 18 liters. VDS showed a high value for exit
rate constants (k,2 and ki3) from the central compartment, while
the elimination rate constant was quite low. This implied that
tissue distribution or inactivation rather than elimination was
primarily responsible for the drug clearance from the serum.
In contrast to i.v. bolus, the serum drug levels after 24-hr
infusion followed biexponential decay, as shown in Chart 4.
Least-squares regression fits precisely Equation C:
c„(f)
= A'e-°'v- " +
(C)
where cs,(f ) is the serum VDS concentration after 24-hr infusion,
7 is the infusion time (24 hr), and f is the time after the start of
infusion. A' and B' are constants representing y-axis values at
t = 7, and a' and ß'are the first-order disposition rate constants
with a' > ß'> 0. Pharmacokinetic parameters obtained after
24-hr infusion in 5 patients are shown in Table 3. Comparison of
pharmacokinetic parameters in Tables 1 and 3 shows that the
peak serum VDS concentration after the 24-hr infusion was
approximately 6% of the peak concentration obtained by i.v.
bolus. Noting that a and a' as well as ßand ,)" are equivalent
2k2ik|2'k|3k3l3
Chart 1. 'First-pass"
.90
open model used to calculate the phar-
macokinetic parameters presented In Tables 1 to 3. Upper scheme, i.v. bolus; lower
scheme, i.v infusion.
within the range of experimental variability, it is observed that,
after a 24-hr infusion of VDS, the ir phase of the serum is not
seen.
For the determination of c x t, there were insufficient data
points to allow curve-fitting during the infusion period. However,
the VDS serum level at the 12th hr after the start of the infusion
was 88% of the value within 15 min after the end of infusion in
4 patients. Using this observation plus the shape of the decay
curve, with the absence of the ir phase, an overall serum VDS
curve may be estimated which can then be used to approximate
c x i. Theoretically (20), for an infusion of length 7, the serum
concentration cs/(f) for f > 7 is given by:
P(7)e-
4 R. L. Nelson, personal communication.
CANCER
+ A(T)e-
' + B(T)e-
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(D)
PHARMACOKINETICS
OF VOS IN HUMANS
where P(T), A(T), and B(T) are pharmacokinetic
which are functions of the infusion time 7":
"constants"
tO CO CO ^~ O N«
8 iß
SSS
(E)
•(«
- 7r)(ir - 0)
CM
CO O»<D
(D
^ ^- CM O CM IO CÑI
r^i ö^" öS
cj cöW
(F)
«(0- «)(«
ifo [(£2- |8)(^31
O
*- O
»- CM *
i-
f~
O r-
m
V, \
ß(a-
(Dose)/T
and
r-
The pharmacokinetic values /fzo, ta, ta, T, a, and ßfrom
Tables 1 and 2 were calculated, not from the "true" bolus
00
administration but, rather, from a T = Vfeo-hrinfusion. Therefore,
it is preferred to calculate P(T), A(T), and B(T) for all 7 > Veotir
from P, A, and B as follows:
in
ÃŽ3
»-
i-cg^cocnoor*;
P(7) = P x |P(7-)/P('/6o)|=
ÌÌ
2
(1 - e-4437)
559 1- (1 -- e -°1757)
\A(T)IA(V«,)\ = —
A(T) = AX
8(7) = S x jB(7)/B(Veo)| = 422
— -2 (1 -
in OD <O
CNJ O CNJ
p p p p pp
(G)
O
en evi c\j co «-;co p
o o o ö o ö ö
CO CO CO 00
i- C\J OJ *-
-1)
- ir)
p
7)
(H)
(I)
(J)
o o ö ö ö ö ö
CQ :
The values of P(24), /A(24). and 8(24), calculated directly from
Equations H, I, and J, were 4.23, 22.9 and 6.68, respectively. Of
note is the observation that the value of P(24) = 4.23 is suffi
ciently small, and the decay e~*<' ~ 24)sufficiently rapid, so as to
ooo
<o "Õ
. . . tg. *~.*R
to ID cn ro ^ CNJco
reduce the impact of the w phase on the serum concentration of
VDS after termination of the infusion. It is also of confirmatory
importance that calculated -4(24) = 22.9 and 3(24) = 6.68 are
close and proportional to the measured values ¿'= 26.4 ±3.32
and B' = 7.5 ± 1.06 from the infusion (7 = 24) data (from
SaSKSts °
^Cgt^r^CVIi-;^
+1
o o ööo o ö
in
Equation C) as summarized in Table 3. The measured values are
probably higher than the estimates by virtue of the incorporation
of the "hidden" P(24). In this regard, the calculated value of C.X24)
ö
CD
CNiinoipoioicn
oöinoSr-'cxjco^
h-min^rininco
T- OO CM i-
â„¢
"H
^
or P(24) + A(24) + 8(24) = 33.8 corresponds nicely with the
measured value of 33.9 (Table 3, Cs,(f = 7)).
At time 7, by reference to Equation D, the heights of compo
nents IT, a, and ßare given by P\T), A(T), and B(T), respectively.
Thus, at time Veo < t < T during an infusion of length 7, the
serum concentration should equal P(t ) + A(t) + B(t), where these
values are calculated from Equations K, L, and M below, which
are modifications of Equations H, I, and J.
IO IO tO
pcncnooincxicn
a' IA tf> v- (Q CVÃŽ
O
o> r^ p Å“ O) in
TT CO CO LO CM Öl
<+1
P(t)
N.
A(t)
101.6 (1 - e-44»)
559.1
(K)
(L)
O CD CO CO (D CM CM
<D U) (0 (O N K N
B(t) =
I-
o o o ooo
(M)
o
These equations are valid because the total dose administered
by time f is —=r—-so that
»-CMco^-incoi^
+|
Dose-f
CANCER
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1985
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PHARMACOKINETICS
OF VOS IN HUMANS
Table 2
First-order mass transfer rate constant (see Chan 1) to lit serum vindesine levels after i.v. bo/us
(hr1)0.6016.761.451.543.644.054.923.28
Patient1234567Mean*«
(hr1)0.02580.05260.03770.02470.03340.01350.04720.0336
(liters/hr/kg)0.1200.2790.0980.1940.06170.1280.04490.1
±0.83"*2,(hr1)0.8440.7440.3210.2351.620.8131.010.799
32 ±0.03
+ 0.161ft*
54 ±0.0255Clearance
±0.00513*M(hr1)0.2240.1710.08210.1220.2600.0920.1240.1
±0.174ft«(hr1)0.09711.310.2720.1570.1410.2170.3190.359
"Mean±S.E.
This concept allows for the simulation of the serum concentration
both during the infusion and after f = T.
Õ
If Veo< t < T, then P(f) + A(t) + B(t).
10therwise, PfTJe-*' " n + ^(TJe-^' ~ n + S(T)e,-«'
-
(N)
Simulations of Equation N are illustrated in Charts 5 and 6 for
T = Veoand 24 hr, respectively. Confirming the validity of this
model is the calculation that the ratio cs,(12)/cs/(f) varies between
0.84 and 0.95 for values of / between 0 and 15 min after the end
of the infusion at T = 24. This corresponds with the measured
value of 0.88.
The c x f for the infusion data can now be estimated by
integrating Equation N (see "Appendix"). This has been per
formed for the mean infusion data (see Table 3, footnotes) and
the bolus data (see Table 1, footnotes). It is to be noted that the
c x f for the 24-hr infusion was identical to that for bolus
24
48
56
72
HOURS AFTER START OF INFUSION
administration.
Chart 3. Serum clearance of VDS after 4 mg/sq m i.v. "bolus" (V«o-hr
infusion)
as measured by radioimmunoassay (Patient 4). The ordinate is expressed as a
natural logarithm of VDS concentration in >ig/titer. Each point represents a mean
of the assay run in duplicate and repeated at least twice. The line represents
computer-generatednonlinear least-squares to fit Equation B.
7
e
5
4
3
2
DISCUSSION
The radioimmunoassay used in the present study is a sensitive
one, but it also cross-reacts with other Vinca alkaloids (12,16).
This implies that the method might cross-react not only with the
parent VDS but probably with some metabolite(s) present in the
biological material. In this context, what we expressed as VDS
should more accurately be called VDS equivalents. We have
used the term VDS in this treatise in order to avoid confusion
when one compares the data produced from different institu
tions; most of the earlier Vinca alkaloid pharmacology data using
radioimmunoassay were derived by the use of a method devel
oped by Root ef a/. (17).
Nelson ef a/. (12, 13) and Owellen ef al. (16) reported pharmacokinetic parameters of VDS in humans obtained by similar
radioimmunoassay. They have shown that the central compart
ment was compatible with the total blood volume. In contrast,
the central compartment obtained in this report is approximately
4-fold greater. The reason for this discrepancy is unclear. In
order to avoid extravasation of the drug, we administered it in a
slow i.v. bolus (over approximately 1 min) through the side arm
of running infusion. This might have caused a low P + A + B
value (by Equations K, L, and M) and, consequently, a high V,.
On the other hand, we noticed that our V, value for VDS is
similar to the reported V, for VCR (12) and VLB (12,15). Our V2
and V3 values are in accord with those reported by Owellen ef
al. (16). The mean terminal serum half-lives in our study are
greater than the reported values (12, 16) but clearly less than
2
e
e
24
4e
66
72
HOURS AFTER START OF INFUSION
Chart 4. Postinfusion serum clearance of VOS, 5 mg/sq m given as a 24-hr
infusion i.v. (Patient 11). The ordinate is expressed as a natural logarithm of VDS
concentration in ¿ig/liter.
Eachpoint represents a mean of the assay run in duplicate
and repeated at least twice. The line represents computer-generated nonlinear
least-squares to fit Equation C.
CANCER
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PHARMACOKINETICS
OF VOS IN HUMANS
Table 3
Pharmacokinetic parameters obtained from a 24-hr infusion of vindesine
Biexponentia! serum decay curve followed Equation C.
DosePatient7*8
m)4.04.0
(/•g/Kter)19.2 (HO0.268
6.0
9
10
11(mg/sq
Mean
4.0
6.08.4
4.0
5.0(mg)7.2 9.0A'
35.0
24.0
27.4
18.6a'
26.4 ±3.32a'c
0.163
0.182
0.157
0.242B'
Oig/liter)5.85
(hr1)0.0201
= T)
to/liter)"25.0
8.33
5.69
10.1
4.14»'
0.0245
0.00342
0.01937
0.00616c-(f
43.3
29.7
37.5
22.7
0.202 ±0.025 7.50 ±1.06"
0.0147 ±0.00417 33.9 ±4.06e
* Patient 7 in Table 1 was also studied for 24-hr infusion.
" Mean ±S.E.
c Data from Patient 11, who received a different dose from the others, were not used for calculation.
The c x r. estimated by integration of Equation N (see "Appendix"), is 1083 (pg/hr/liter).
8
24
43
56
72
HOURS AFTER START OF INFUSION
24
40
56
72
HOURS AFTER START OF INFUSION
Chart 5. Simulation of the VOS serum concentration after i.v. "bolus" (V«o-hr
infusion) based on Equation N. The ordinate is expressed as a natural logarithm of
VDS concentration in fig/liter. The values of P, A, and B are intercepts of each of
the 3 straight lines to the x-axis.
those reported for VCR. The discrepancy of the half-life obtained
from this study and the earlier report is not clear. Our data are
partially influenced by a value in Patient 6, who had a terminal
half-life of 80 hr.
The reasons why Patient 6 had a prolonged terminal half-life
are unclear. The only difference in clinical course of this patient
from the others is the transient elevation of transaminases after
each course of VDS administration. He might have had preexist
ing subclimcal hepatic impairment. The dose we used (4 mg/sq
m) is larger than those reported by Nelson et al. (13); thus, this
could possibly be a dose-dependent phenomenon. Owellen et
al. used the doses ranging from 1.5 to 4.0 mg/sq m (16), but the
number of patients in each dose level is too small to conclude
the dose dependence. All the patients we studied had platelets
more than 100,000/^1, whereas the reported study did not men
tion the platelet value. A possibility of platelet binding as a factor
influencing the half-life could not be excluded.
Somewhat wide fluctuations of pharmacokinetic parameters
from one patient to the other were noted for both bolus and 24hr infusion. We noted that the P value of Patient 1 is smaller than
are the P values of the other patients. This patient had a large
retroperitoneal sarcoma and a moderate amount of leg edema.
CANCER
Charte. Simulation of the VDS serum concentration during and after 24-hr
infusion based on Equation N. The ordinate is expressed as a natural logarithm of
VDS concentration in ng/liter. P. A, and S are the values on the y-axis at t = 24 hr
for each of the 3 lines.
The small P value may be related to this. The low P value did
not influence the c x f value, however. Determinants for phar
macokinetic parameters for VDS of possible importance include
tumor load and earner protein concentration (5); these and other
such factors as nutritional status and concurrent medications
might have affected the pharmacokinetic parameters.
Pharmacokinetic parameters from postinfusional blood curves
have been assessed for other drugs (8). Although a mathematical
equation which enables one to determine the parameters iden
tical to an i.v. bolus by utilizing the postinfusion curve has been
presented (8), the present study clearly indicates the limitation
of such an approach because of the likelihood that, after a
prolonged infusion, distribution phase constants P and w may
not be recognizable from experimental data.
Increased toxicity in patients with major hepatic impairment
(14) and increased terminal half-life in Patient 6 suggested that
the liver plays a major role in VDS excretion or metabolism.
Determination of the influence of preexisting hepatic dysfunction
on serum VDS pharmacokinetics would be of interest. Neurolog
ical toxicity was more insidious and difficult to quantify. Ob
viously, pharmacokinetic parameters obtained after the first
course of chemotherapy are inadequate to explain the delayed
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PHARMACOKINETICS
OF VOS IN HUMANS
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15. Owellen, R. J., Hartke, C. A., and Hains, F. 0. Pharmacokineticsand metab
olism of vinblastine in humans. Cancer Res., 37: 2597-2602,1977.
16. Owellen, R. J., Root, M. A., and Hains, F. O. Pharmacokineticsof vindesine
and vincristine in humans. Cancer Res., 37:2603-2607,1977.
17. Root, M. A., Gerzon, K., and Dyke, R. W. A radioimmunoassayfor vinblastine
and vincristine.Federationof AnalyticalChemistryand SpectroscopySocieties.
Abstract 183, p. 125, October, 1975.
18. Sethi, V. S., Castle, M. C., Surratt, P.,Jackson, D. V., and Spurr, C. L. Isolation
and partial characterization of human urinary metabolites of vincristine sul
phate. Proc. Am. Assoc. Cancer Res., 22:173,1981.
19. Valdivieso, M., Richamn.S., Burgess, A. M., Bodey, G. P., and Freinch. E. J.
Initial clinical studies of vindesine. Cancer Treat. Rep., 65: 873-875,1981.
20. Wagner, J. G. Fundamentalsof clinical pharmacokinetics, pp 114-117. Ham
ilton, IL: Drug IntelligencePublications, 1975.
21. Yap, H. Y., Blumenschein,G. R., Bodey, G. P., Hortobagyi, G. N., Buzdar, A.
U, and DiStefano, A. Vindesine in the treatment of refractory breast cancer:
improvement in the therapeutic index with continuous 5-day infusion. Cancer
Treat. Rep., 65: 775-779,1981.
neurological toxicities.
We noted that the comparison of the 2 schedules is a practi
cable method to correlate the relationship between pharmacokinetic data and clinical toxicity. Thus, our pharmacokinetic eval
uation revealed that the 24-hr infusion of VDS produced only
one-sixteenth of the peak serum level achieved by i.v. bolus,
whereas the c x t value after 24-hr infusion was identical to that
after i.v. bolus. Since the observed hematological toxicities were
essentially similar for the 2 schedules (14), it may be concluded
that the toxicity is less related to the peak serum levels than that
immunoassayable c x f and/or the elimination half-life.
The observation that the c x i for the bolus administration is
identical to that after 24-hr infusion should be of interest. This
was mathematically confirmed. Theoretically, c x f would be
constant, regardless of infusion time. One might be tempted to
carry out prolonged infusion in attempts to correlate c x t and
biological effects.
Implications of these observations on the therapeutic effects
remain to be elucidated. In our Phase I study, none of the patients
went into partial or complete responses (14). It is noteworthy
that remissions were reported to be induced in patients with
acute leukemia with a 48-hr infusion, whereas a twice-daily i.v.
bolus regimen did not produce a response (10). Similarly, contin
uous infusion of VDS for 5 days appeared to be more efficacious
than was the bolus schedule in the treatment of patients with
refractory breast carcinoma (21). The improved therapeutic effi
cacy of VDS infusion over bolus cannot be explained from
available pharmacokinetic parameters alone. In this context, the
following considerations may be offered. First, it is possible that
pharmacokinetic parameters (c x f, half-lives, etc.) from 48-hr
infusion or 5-day continuous infusion are entirely different from
those of 24-hr infusion. This possibility is, however, unlikely
because c x t appears constant regardless of infusion time.
Second, therapeutic efficacy may be related to a biological
concentration-effect window (biologically effective drug concen
tration x exposure time) rather than mere c x i. Third, Ndesformyl-VCR, an inactive metabolite, was identified in the urine
Appendix: Integration of c x (
The c x f for infusion data are defined as the definite integral of c„(f
) (Equation
N) over the interval from zero to infinity. Let P(t) = K,(i), A(t) = KJ(t), and B(f) =
K¿t),where a, = T, «2
= a, and «3
= ß.Specify z-, = 101.6, Z2= 559.1, and z3 =
422.4. Then, Equations K, L, and M may be written:
of a patient receiving VCR (18). It is possible that such a
metabolite may be present in radioimmunoassayable VDS, and
intracellular metabolism of VDS may be independent of serum
c x f. In-depth pharmacokinetic studies of VDS for both bolus
and infusion in patients with VDS-sensitive tumors might give
insight into the relationship between pharmacokinetic parame
ters and therapeutic efficacy.
(O)
and Equation N reduces to
Õ3
If V«o
< f < 24, then £K,(i).
3
M
Otherwise, I K,(24)e^"
ACKNOWLEDGMENTS
(P)
~ r).
I
We thank Dr. Mary Root of Eli Lilly Research Laboratories, Indianapolis,IN, for
the gift of rabbit anti-VLB antibodies.
Since
JL ÕK.<0*=•
f ÕK.(0* = i {z, + (-^)<e-" •slfiO1-1
REFERENCES
1. Blum, R. H., and Dawson, D. M. Vindesine: Phase I study of a Vinca alkaloid.
Proc. Am. Assoc. Cancer Res., 17:108, 1976.
2. Gulp, H. W.. Daniels,W. D., and McMahon, R. E. Dispositionand tissue levels
of [3H]vindesinein rats. Cancer Res., 37:3053-3056,1977.
3. Currie, V., Wong, O., Krakoff, I. H., and Young, C. W. Phase I trial of vindesine
in patients with advanced cancer. Cancer Treat. Rep.. 62: 1333-1336,1978.
4. Daniel,C., and Wood, F. S. Fitting Equationsto Data, pp. 320-333. New York:
Wuey-lntersoence, 1971.
5. Domgian,D. W., and Owellen, R. T. Interaction of vinblastine, vincristine, and
colchicine with serum proteins. Biochem. Pharmacol.,22: 2113-2119,1973.
6. Dyke, R. W., and Nelson, R. L. Phase I anticancer agent vindesine (deacetyl
CANCER
RESEARCH
and
**)
|_1
b-1 I
\*l ' /
1)
(Q)
r!K,(De-«-"*=i^ =Ã]-(^y«'
-D
•X M
i-1
/ti
1-1
I
\IC|77
then
f-
i
**
3
c„(f)cff
= £z, «1083, which is independent of T for all T > Veo
>-i
These results may be confirmed by numerical integration of Equation N (9).
VOL. 45 JANUARY
1985
469
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1985 American Association for Cancer Research.
(S)
Pharmacokinetics of Vindesine Given as an Intravenous Bolus
and 24-Hour Infusion in Humans
Takao Ohnuma, Larry Norton, Alicja Andrejczuk, et al.
Cancer Res 1985;45:464-469.
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