Plasma and Cerebrospinal Fluid Pharmacokinetic Study of Topotecan by mercy2beans125

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									[CANCER RESEARCH 53. 725-727. February 15. 199.11


Advances in Brief


Plasma and Cerebrospinal Fluid Pharmacokinetic Study of Topotecan in Nonhuman
Primates
Susan M. Blaney,1 Diane E. Cole, Frank M. Balis, Karen Godwin, and David G. Poplack
Waller Reed Army Medical Center. Washington, DC 20307 ¡S.M. B.]. and The Pediatrie Branch. National Cancer Institute. Bethesda. Maryland 20892 ¡D.E. C.. F. M. B.. K. G..
D. C. P.I


Abstract                                                                                            Topotecan has demonstrated preclinical activity against several re
                                                                                                 fractory murine tumors including B16 melanoma, colon carcinomas
    Topotecan, a water soluble semisynthetic analogue of camptothecin, is
                                                                                                 38 and 51, and multidrug resistant p388 leukemia (2). Significant
a topoisomerase I inhibitor that has recently entered phase II clinical
                                                                                                 preclinical activity, including cures, have also been observed follow
trials. Topotecan has shown significant preclinical activity in refractory
                                                                                                 ing topotecan in mice with rhabdomyosarcoma and osteosarcoma
murine tumors and in human tumor xenograft models. In addition, ob
jective antineoplastic activity has been observed in recent adult phase I                        xenografts (4). In addition, in phase I studies of topotecan objective
clinical trials. Topotecan is unstable in solution and is rapidly and spon                       complete and partial responses have been observed in patients with
taneously converted to a less active open ring form which predominates at                        non-small cell lung cancer, cisplatin resistant ovarian carcinoma,
physiological pH. This study was undertaken to better define the phar-                           small cell lung cancer, and metastatic colorectal cancer (5-8).
macokinetic behavior of this highly unstable compound in both plasma                                Topotecan is unstable in solution and undergoes spontaneous hy
and cerebrospinal fluid (CSF) and to measure the degree of CSF penetra                           drolysis at physiological pH to a less active open ring species (Fig. 1).
tion of this novel antineoplastic agent.                                                         The hydrolysis is pH dependent with the equilibrium favoring the
   Three nonhuman primates with indwelling Ommaya reservoirs re                                  open-ring form at a pH > 7.0 and the lactone form in acidic condi
ceived 10 ing/iir i.v. topotecan administered as a Ili-min infusion. Fre
                                                                                                 tions. Pharmacokinetic studies of topotecan have been performed in
quent plasma and CSF samples were obtained and immediately extracted
                                                                                                 adult and pediatrie patients (7-12) but have been limited by the
and assayed with a reverse phase high performance liquid chromatogra-
                                                                                                 instability of the parent drug in solution. In addition, the CSF2 pen
phy assay to quantitate the concentration of topotecan (lactone). Samples
were then acidified and reinjected to quantitate total drug (lactone ring                        etration of this novel antineoplastic agent has not been characterized.
plus open ring).                                                                                 The CSF penetration of camptothecin appears to be negligible. CSF
   Peak plasma concentrations of topotecan ranged from 0.27 to 0.45 UM.                          camptothecin levels were not detected in the limited number of pa
Plasma disappearance of the lactone ring was biexponential with a distri                         tients in whom CSF samples were obtained during phase II trials of
                       of                                                  o
bution half-life «i/z«) 22 ±5 min and an elimination half-life (t,/2ß) f                     this drug (13). In this study the plasma and CSF pharmacokinetics of
1.3 ±0.1 h. Total body clearance of topotecan was 72.1 ±15.8 liters/h/m2.
The volume of distribution at steady state was 88.6 ±33.2 liters/in -•.
                                                                       Peak
                                                                                                 topotecan in nonhuman primates are examined.
CSF concentrations of topotecan occurred at 30 min following drug ad
                                                                                                 Materials and Methods
ministration and ranged from 0.044 to 0.074 UM.CSF disappearance par
alleled that in plasma. The mean ratio of the area under the CSF concen                            Drugs. Topotecan (hydrochloride salt, adjusted to pH 3 to 4) was supplied
tration-time curve to that in plasma was 0.32 (range, 0.29 to 0.37).                             by the Division of Cancer Treatment. National Cancer Institute (Bethesda.
    The mean CSF penetration of topotecan exceeds 30%, which is signif                           MD) in 5-mg vials which were reconstituted in 2 ml of sterile water. The
icantly greater than the penetration of most structurally similar chemo-                         appropriate dose of drug was further diluted with 12.5 ml of 5% dextrose which
therapeutic agents. The impact of chemotherapy on the survival of pa                             was administered over 10 min through either a peripheral venous or central
tients with primary or metastatic central nervous system malignancies is                         venous catheter.
very limited. Therefore, this novel antineoplastic agent is an excellent                            Monkeys. Three adult male rhesus monkeys (Macaca mulatta) ranging in
candidate for further study in patients with high risk or refractory central                     weight from 6.9 to 9.7 kg were used in these experiments. The animals were
nervous system tumors.                                                                           fed NIH Open Formula Extruded Non-Human Primate Diet twice daily and
                                                                                                 group housed in accordance with the Guide for the Care and Use of Laboratory
Introduction                                                                                     Animals (14). Blood samples were drawn through a catheter placed in either
                                                                                                 the femoral or the saphenous vein opposite from the site of drug administra
   Topotecan [(S )-9-dimethy laminomethyl-10-hydroxycamptothecin
                                                                                                 tion. CSF samples were obtained from a chronically indwelling Puden/. cath
hydrochloride, SK&F 104864-A, NSC 609699] (Fig. 1), a campto                                     eter attached to a s.c. implanted Ommaya reservoir (15).
thecin analogue that inhibits topoisomerase I, is currently undergoing                              Experiments. The plasma and CSF pharmacokinetics of topotecan were
extensive phase II clinical evaluation. Topoisomerase I is an intranu                            studied in 3 animals following an i.v. dose of 10 mg/nr administered over 10
clear enzyme which relaxes supercoiled DNA by creating single                                    min. Blood was collected in heparinized tubes prior to the dose and at 5, 15,
strand DNA breaks which are subsequently religated by this enzyme                                30 min, at 1. 1.5. 2. 3 h. and at 30- to 60-min intervals thereafter until parent
(1). Topoisomerase I inhibitors, like topotecan, produce cytotoxicity                            drug could no longer be quantitated in the plasma. Plasma was separated
by stabilizing the covalent complex between topoisomerase I and                                  immediately by centrifugation at 12,000 x g for 2 min in a rapid acceleration/
                                                                                                 deceleration centrifuge. CSF samples were collected from an Ommaya reser
DNA which results in enzyme linked DNA breaks that cannot be
                                                                                                 voir at the same time points as plasma. The reservoir was pumped 4 times
religated in the presence of drug (2, 3).
                                                                                                 before and after each sample collection to ensure adequate mixing with ven
                                                                                                 tricular CSF.
   Received 11/25/92; accepted 12/31/92.
   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 lo indicate this fact.                                                 - The abbreviations used are: CSF. cerebrospinal fluid: HPLC. high performance liquid
    1To whom requests for reprints should be addressed, at Pediatrie Branch. National            chromatography: AUC. area under the drug concentration-time curve; CL-IB. total body
Cancer Institute. Building 10. Room I3N240. 9000 Rockville Pike. Bethesda, MD 20892.             clearance; Vd„.volume of distribution at steady state.
                                                                                           725
                                                      PHARMACOKINETICS       OF TOPOTECAN         IN NONHUMAN      PRIMATtS

                                  Table 1 I'hurmacokinetii•parameters following u I0-ntg/nr     i.v. bolus dose of topotecun in 3 animal*

                                                      (betone)AUC                                                                              dotai
                                                                                                                                         drug)AUC

                                  CSF                        Plasma                                                 CSF                         plasma
    MonkeyCH955CH94U           <MM-h)U.I                  (uwh)0.361                                             (UM-h)0.249                  (UM-h)1.123             plasma0.22
                                  029
                               0.0894                 0.2390.2750.292                0.37                        0.185                       0.684                 0.270.240.24
   CH843Mean               008340.0926                                           0.310.32                    0.145O.I                    0.6170.808

          ±
           SDAUC                   0.009Topoteean
                                  ±                        ±
                                                             0.063CSF:plasma0.28        ±0.05AUC                93 ±0.052Topoteean            ±
                                                                                                                                                 0.275CSF:               0.03
                                                                                                                                                                        ±



   Sample Analysis. Topotecan (laclone ring form and total drug) was mea                    1.2-1.4 h). Total body clearance was 72.1 ±15.8 liters/h/m2 (range,
sured in plasma and CSF by using a recently deseribed reverse phase HPLC                                                          was
                                                                                            55.1 - 86.4 liters/h/m-) and the Vi/„ 88.6 ±33.2 liters/nr (range,
assay.' Plasma samples were immediately extracted with the use of activated
                                                                                            52.6 - 188 liters/nr). Plasma disappearance of the total drug was also
Fisher PrepSep-C,« columns. Topotecan and its open ring metabolite were
                                                                                            best fitted by a biexponential equation with a mean t,,2a of 41 ±10
eluted from the column with methanol and an aliquot of the eluant was                                                                     of
                                                                                            min (range. 30 - 50 min) and a mean /|/2ß 3.8 ±1.6 h (range, 2.1
immediately injected onto the HPLC. Samples were extracted and injected                     - 5.4 h). Total drug CI,,, was 28.9 ±8.4 liters/h/m2 (range 19.5 - 35.5
onto the HPLC in less than IO min. Following injection of an aliquot of eluant
                                                                                                                       w
                                                                                            liters/h/m2) and the Vd„ as 40.9 ±13.1 liters/m2 (range, 26.2 - 50.4
for quantitation of topotecan (lactone). the remaining cartridge eluant was
acidified with 2'7r phosphoric acid in order to quantitate the total drug (lactone          liters/m2). The plasma and CSF AUCs for both the lactone and
and open-ring species). The acidified eluant was injected after it had been at              the total drug following i.v. topotecan administration are shown in
room temperature tor at least 2 h. The concentration of the open ring hydrolysis            Table 1.
product was obtained indirectly by subtracting the concentration of lactone in                 CSF topotecan concentrations peaked at 30 min and ranged from
the unacidified sample from the total lactone in the acidified sample. CSF                  0.044 to 0.074 UMfor the lactone and 0.065 to 0.097 UMfor the total
samples were analy/ed for topotecan {lactone) by immediate direct injection of              drug. CSF disappearance paralleled that in plasma. The mean ratio of
a 100-ul aliquot of CSF onto the HPLC column. A second aliquot of CSF was
                                                                                            the area under the CSF concentration-time curve to that in plasma was
acidified with concentrated phosphoric acid and the concentration of the open
                                                                                            0.32 (range, 0.29 to 0.37) for the lactone and 0.24 (range, 0.22 to 0.27)
ring hydrolysis product was obtained as described above. Topotecan was
                                                                                            for total drug. A representative concentration-time profile of the lac
detected by using a fluorescence detector (Applied Biosystems) at a Acvof 375
nm and a A,.,,,of 470 nm (cutoff filter). Under these conditions, the open ring             tone form of topotecan in plasma and CSF is shown in Fig. 2.
metabolite eluted with the solvent front and the lactone eluted at 4 min.                      The hydrolysis of topotecan to the open ring form was rapid.
Standard curves in the monkey's plasma and CSF were prepared for each
                                                                                            Greater than 60% of total drug in plasma was in the open ring form by
experiment by addition of known amounts of topotecan to plasma or CSF,
respectively. Standard curves were linear (/- > 0.995) over a range of 0.002 to
       T
l U.M. he lower limit of quantitation was 0.002 UM.
   Pharmacokinetic Analysis. Plasma concentration versus time data from
the topotecan bolus experiments were fit to mono- (;i = I ) and (»exponential
(n = 2) equations:
                                                                                                                                       OH             HO
                                                                                                                                        H*

                               C(r)=


using MLAB. a nonlinear curve fitting program, where C is the plasma con
                                                                                                                                                             Open-Ring Form
centration of topotecan at time t. A, the coefficients, and A, the rate constants
(16). Akaike's information criterion (17) was used to determine which equation
                                                                                                 Fig. 1. Strueture of topoteean undergoing pH dependent hydrolysis to its open-ring
best fit the data. The half-life for each phase of elimination was calculated by              form.
dividing 0.693 by the rate constant (A,) for that phase. Noncompartmental
methods were used to calculate other pharmacokinetic parameters. The AUC
                                                                                                          1 -q
was derived by the linear trapezoidal method (18), and extrapolated to infinity
by adding the quotient of the final plasma concentration divided by the ter
minal rate constant (A,,). Total body clearance (CITB) was determined by
dividing the dose by the AUC. The volume of distribution at steady state ( Vi/,,)
was calculated by using the area under the moment curve ( 19). The fraction of
                                                                                                       0.1 -
drug penetrating into the CSF was derived from the ratio of the AUCs in CSF
and plasma.

Results
   Plasma and CSV Pharmacokinetics.       Peak plasma concentrations                                  0.01 -
                                                                                                                                       CSF
of the lactone form of topotecan following an i.v. 10-min infusion of
10 mg/m2 ranged from 0.27 to 0.45 UM.Plasma disappearance was
best fitted by a biexponential equation with a mean tu2ct of 22 ±5
min (range, 16-25 min) and a mean tu2ßof 1.3 ±0.1 h (range.
                                                                                                    0.001
                                                                                                                                                 3
   ' S. M. Blaney, F. M. Balis. D. E. Cole, C. Craig. J. Reed. J. Ames. G. Reaman. D.
                                                                                                                                             TIME [hr]
Hammond, and D. G. Poplaek. Pediatrie Phase I Trial and Pharmaeokinetie Study of
Topoteean Administered as a Twenty-tour Hour Continuous Infusion. Cancer Res.. 53: in          Fig. 2. Representative coneentration-time curves of topoteean (laetone) from a single
press, 1993.                                                                                animal (No. 955) in plasma and CSF following a I0-mg/m2 i.v. 10-min infusion.

                                                                                        726
                                                        PHARMACOKINETICS     Op TOPOTECAN            IN NONHUMAN       PRIMATES


                                                                                               anticancer drugs. For example. CSF levels of etoposide are less than
                                                                                               5 to 10% of simultaneously drawn plasma levels (21). and doxorubi-
              1 -
                                                                                               cin. another highly protein bound antineoplastic agent, is not detect
                                                                                               able in CSF (22).
                                                                                                  The poor prognosis of patients with primary or metastatic central
                                                 Total Drug
                                                                                               nervous system malignancies is in part related to the lack of effective
           0.1 -                                                                               chemotherapeutic agents that penetrate the blood-brain barrier. Topo
                                                                                               tecan is a new anticancer drug with a novel mechanism of action. The
                                                                                               results of the present study document that topotecan has substantial
                                                                                               CNS penetration, and suggest that it should be evaluated in patients
 0       0.01                                Lactone                                           with central nervous system tumors.

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