Pharmacokinetics of Vincristine in the - Cancer Research

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[CANCER RESEARCH 41, 1466-1468, 0008-5472/81 /0041-OOOOS02.00

Pharmacokinetics

April 1981]

of Vincristine in the Cerebrospinal Fluid of Humans1

D. V. Jackson, Jr.,2 V. S. Sethi, C. L. Spurr, and J. M. McWhorter Oncology Research Center, Departments of Medicine [D. V. J., V. S. S., C. L S.] and Neurosurgery University, Winston-Salem, North Carolina 27103

MATERIALS

ABSTRACT Using a sensitive radioimmunoassay, concentrations of vincristine and its products were determined in cerebrospinal fluid (CSF) and corresponding blood samples from four patients with lymphoma and two patients with leukemia who had re ceived i.v. bolus injection of 2 mg vincristine. Serial samples of CSF were withdrawn from a CSF reservoir in two patients during a 24-hr period following injection. The first time point after injection at which measurable levels of vincristine were detected in the CSF was 30 min; the concentrations were within the lower range of sensitivity of the assay and were 20to 30-fold lower than were corresponding serum samples. Despite a prolonged terminal half-life of vincristine in the serum (14.4 to 37.5 hr) following i.v. bolus injection, concentrations of vincristine in the CSF ranged between undetectable within the limits of the assay and 1.1 x 10~9 M during the 24-hr period of observation. The highest CSF concentration of vin cristine (2.6 x 10"9 M) has been observed in a patient receiving cranial irradiation for active meningeal lymphoma. No measur able levels of vincristine or its products were detected in spot samples of CSF from three patients. Penetration of vincristine and its products into the CSF of humans after i.v. bolus injection appears to be very poor and may account for the uncommon occurrence of central neurotoxicity following its clinical use.

INTRODUCTION Vincristine, an alkaloid with antimitotic properties obtained from the plant Vinca rosea (L), has been widely used in cancer chemotherapy due to its lack of myelosuppression at conven tional dosage. Its principal limiting side effect has been neu rotoxicity which is usually manifested by a peripheral mixed sensory-motor neuropathy with symmetrical neurological signs and symptoms (8). Central neurological findings occur uncom monly and include confusion, depression, agitation, insomnia, hallucinations, psychosis, and hyponatremia as a result of inappropriate antidiuretic hormone secretion (8). Disruption of microtubules in neural tissue has been sug gested as the mechanism leading to neurotoxicity (4). However, little is known about the penetration of vincristine into the nervous system. Studies in the subhuman primate Macaca mulatta have shown rapid entry of this agent into the CSF3 with attainment of concentrations in the nM range (11 ). The current study was undertaken to investigate the pharmacokinetics of vincristine in the CSF of humans.

' Supported

in part by Grant CA 12197 from the National Cancer Institute,

NIH. 2 To whom requests for reprints should be addressed. 3 The abbreviations used are: CSF. cerebrospinal fluid; Received October 20, 1980; accepted January 13, 1981.

1466

i.t., intrathecal.

[J. M. M.]. Bowman Gray School of Medicine of Wake Forest

AND METHODS

Subjects. Four patients with non-Hodgkin's lymphomas (histiocytic, 1; mixed histiocytic-lymphocytic, 1; poorly differen tiated lymphocytic, 2) and 2 patients with acute lymphoblastic leukemia treated at the Bowman Gray School of Medicine were subjects of this study. Patient characteristics are given in Table 1. Meningeal involvement had been documented in each of the patients with lymphoma and was active in 2 of them at the time of study. One of the latter patients (W. G.) was receiving both cranial irradiation (900 rads) and i.t. methotrexate (15 mg given 5 days before study). Cranial irradiation consisting of 2300 rads had been administered to a second patient with lymphoma 7 months prior to study. Computerized tomography of the brain was performed in each of the patients with lymphoma and failed to demonstrate any evidence of mass lesions. Two pa tients with leukemia were investigated while receiving i.t. meth otrexate for central nervous system prophylaxis, of which the most recent injection was 7 days prior to study (K. M.). Sample Collection and Processing. Following i.v. injection of vincristine, serial samples of CSF were obtained from an indwelling ventricular catheter during a 24-hr period in 2 sub jects, and spot samples were collected by lumbar puncture in the 4 remaining patients. The total dose of vincristine used was 2 mg in each patient. Blood samples were obtained at intervals corresponding to CSF collection. Using a 23-gauge needle, periodic 1.0-ml samples of CSF were withdrawn from Rickham reservoirs (Extracorporeal Med ical Specialties, Inc., King of Prussia, Pa.) from 5 min to 24 hr following i.v. injection of vincristine in 2 patients with lymphoma (A. W. and E. M.). The first 1.0 ml of CSF was discarded prior to obtaining the test sample to ensure collection of a repre sentative ventricular specimen of CSF. Simultaneous venous blood samples were obtained by removal of 3 ml whole blood from the arm opposite injection or in the same arm below the site of vincristine administration. A 23-gauge scalp vein needle was attached to a heparin lock (Abbott Diagnostics, North Chicago, III.) from which blood samples were withdrawn after discarding the first 1.0 ml containing blood mixed with a dilute heparin solution. Blood samples were centrifuged, and the resultant sera were stored with the CSF samples at -20° until processed. In addition to determination of the concentration of vincris tine, CSF samples were analyzed for protein and glucose concentrations, cell count, cytology, and culture. In no patient was an accompanying bacterial meningitis present at the time of study. Radioimmunoassay and Pharmacokinetic Analysis. CSF and serum samples were analyzed for vincristine by radioim munoassay. The assay was originally developed by Root ef al. (13) and has been modified to allow a 5- to 7-fold greater sensitivity to 5 x 10~10 to 1 x 10"9 M (15). Appropriate dilution of the serum or CSF samples was made and assayed along CANCER

RESEARCH

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VOL. 41

Vincristine CSF Pharmacokinetics

lO-«3^

Table 1 Patient characteristics

involvementActiveActivePriorPriorNoneNoneCranial irradiationCurrent PatientW. (yr)546061661516SexMMMMMFDiagnosisLymphomaLymphomaLymphomaLymphomaLeukemiaLeukemiaMeningea! rads)NonePrior (900

G.W. M.W. M.A. W.S.S.K.

rads)NoneNoneNone (2300

I0'r-

M.Age

with standard vincristine sulfate samples (0.01 to 1.0 mg). From the known amount of vincristine sulfate and the percent age of bound radioactivity, a standard curve was plotted on a log-logit graph from which the amount of vincristine sulfate present in each diluted sample was determined. With the need to use undiluted samples in measuring concentrations <1 X 10~9 M, accurate measurements of concentrations in this lower

I &

10-

1

range of sensitivity have been difficult principally due to protein interference. The results are expressed as concentrations of vincristine which refer to vincristine equivalents (parent drug and its metabolic and degradation products). Kinetic modeling was performed according to the methods of Nagashima ef al. (12). i i i :

RESULTS Triexponential blood decay curves were observed following i.v. bolus injection of vincristine in 2 patients from whom serial blood samples had been obtained (Chart 1). Prolonged terminal half-lives of blood decay (14.4 and 37.5 hr) were noted in both patients (Table 2). Using a 3-compartment open model, large apparent volumes of drug distribution (202 and 313 liters) were observed for the slowly accessible compartment (C3), and the elimination rate constants (K3i) from this compartment into the plasma compartment were very slow. The prolonged terminal phase of blood decay and large final compartment of distribu tion associated with a very low elimination rate constant from this compartment suggest extensive tissue binding by vincris tine from which a slow release occurred. However, despite persistence of vincristine in excess of 10~9 M in the blood during the 24-hr period following i.v. injection, measurable CSF concentrations of vincristine remained between 0.8 and 1.1 X 10~9 M (Chart 1). Peak serum concentrations of vincristine, 1.9 and 8.9 x 10~7 M, were noted at the first observation points (5 and 8 min after injection, respectively). Measurable levels of vincristine in the CSF were not detected until 30 min following i.v. injection and were 7.6 and 9.5 x 10~10 M with corresponding serum levels of 1.4 and 2.7 x 10~8 M, respec tively. Spot samples of CSF were obtained in 4 other patients by lumbar puncture at time periods from 2.0 to 4.0 hr following i.v. bolus injections of vincristine. Concentrations of vincristine >5.0 x 10~9 M were obtained in each of the corresponding serum samples (Table 3). However, measurable concentrations of vincristine were not detectable in any of the CSF collections with the exception of the 3-hr sample in Patient W. G. who had active meningeal lymphoma at the time of study. In addition, the latter patient had received 900 rads cranial irradiation at the time of study. There was no correlation between vincristine levels in the CSF and concentrations of glucose and protein or cell count in

30 60

8 12 16 TIME (hours)

( min x I hr )

20

24

Chart 1. Blood decay kinetics of vincristine equivalents following i.v. bolus injection of 2 mg vincristine in Patients E. M. O and A. W. (O) with their corresponding concentrations of vincristine equivalents in the CSF: •E. M.; •, A. W. A, time points at which samples of CSF were collected but did not contain any detectable vincristine equivalents within the extreme lower limits of the assay (~5 x 10~'° M). Accurate measurements of concentrations <1 x 10~9 M may not be possible due to protein interference described in the text.

in undiluted

samples of CSF as

Table 2 Pharmacokinetic

parameters of vincristine in the blood

Half-life (min)

Apparent compartment (liters)

volumes

')0.0021

PatientA. W. E. M.a2.9

3.7ß34.7 34.7Y864.0 2250.0C12.48 3.03C211.90 8.25C3201.57 313.62(min0.0014

K3i, elimination rate constant from C3 to C1 ; C1, plasma volume; C2, wellperfused tissues; C3, slowly accessible compartment. Table 3 Concentrations PatientS.S. W. G. K. M. W. M.Sample

of vincristine equivalents in spot samples of blood and CSF time (hr)2.0 3.0 3.5 4.0[Serum]

(M)5.0 x 2.8 x 2.8 X 5.5 X

(M)NDa 10'" 10"8 10~8 10"9[CSF]

2.6 X 10~9 NO NO

ND, not detectable.

this fluid. Of the 2 patients with active meningeal lymphoma, vincristine was detected in the CSF of one of them (W. G.). DISCUSSION Neurotoxicity following administration of vincristine has been observed in the mouse, rat, rabbit, chicken, and monkey (1, 6, 16) as well as in humans. Penetration of this agent into the CSF and brain of several mammalian species has been investigated with tritiated vincristine. El Dareer et al. (5) have found low

APRIL 1981

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1467

D. V. Jackson, Jr., étal. concentrations of vincristine and its products in the brain tissue of the mouse, dog, and monkey compared to the amount found in other major organs. Castle et al. (3) also observed low concentrations of vincristine in rat brain but were unable to detect it or related species in brain tissue or CSF of dogs. Examination of serial CSF samples obtained from monkeys with Ommaya reservoirs has shown rapid entry of tritiated vincristine and its products into the CSF following i.v. bolus injection (11). However, the concentration range in this fluid (0.7 to 9.6 x 10~9 M) was considerably lower than that in the

relative to the concentration of this agent in the blood and may account for the uncommon development of central neurological side effects compared to the high incidence of peripheral neuropathy observed with its clinical use. Furthermore, such low CSF concentrations of vincristine and its products (~10~9 M) are unlikely to be lethal to tumor cells (9). The influence of active meningeal disease and cranial irradiation on vincristine pharmacokinetics in the CSF remains unclear and is worthy of further investigation.

serum during the first 24 hr after injection (11). Similarly, in the present study, low CSF concentrations of vincristine and its products have been observed during a 24-hr period following injection and have ranged from undetectable within the limits of the assay to 2.6 x 10~9 M. In addition to intraspecies

ACKNOWLEDGMENTS

variation, differences in the methods of assaying vincristine between the monkey and human investigations might account for the somewhat dissimilar CSF concentrations. Also, fluctua tion of the CSF concentrations seen in Chart 1 probably reflects the difficulties of accurate measurement of these very low concentrations of vincristine equivalents in the lower range of sensitivity of the radioimmunoassay. The highest concentration of vincristine in the CSF (2.6 x 10~9 M) has been attained in a patient with active meningeal

REFERENCES

lymphoma who was receiving cranial irradiation. That active meningeal disease or cranial irradiation was responsible for the somewhat higher CSF concentration of vincristine observed in this patient remains only speculation. However, increased pen etration of another antitumor agent, methotrexate, into the CSF of humans during active meningeal leukemia (2) and into brain tissue of rats following cranial irradiation has been observed (7). The significance of low concentrations of vincristine and its products in the central nervous system is unclear. Concentra tions of vincristine <2 x 10~9 M are unlikely to be lethal to tumor cells (9), but such concentrations might be injurious to microtubule-rich neural tissue to which vincristine binds avidly (8). The long terminal phase of its disappearance from the blood as demonstrated in the 2 patients in the current study (14.4 to 37.5 hr) might allow prolonged exposure of neural tissue, particularly peripheral nerves, to low concentrations of vincristine and its products with resultant microtubular disrup tion and neurotoxicity (4). This may relate to the clinical obser vation that some patients with preexisting liver disease have had unusually severe neuropathies after receiving relatively small doses of vincristine (14). Hepatic dysfunction might result in delayed excretion of vincristine and its products with result ant prolonged exposure of neural tissue since the biliary system is responsible for the major route of elimination of this agent and its products in humans (10). In summary, the penetration of vincristine into the CSF of humans following i.v. bolus injection appears to be very poor

1468

The authors appreciate the technical assistance of Paulette Surratt. Debbie Rosenbaum, Vicki O'Brien, and Bonita Scott.

1. Adamson, R. H., Dixon, R. L., Ben, M., Crewa. L., Shohet. S. B., and Rail, D. P. Some pharmacologie properties of vincristine. Arch. Int. Pharmacodyn. Ther., 157: 299-311, 1965. 2. Bleyer, W. A., Drake, J. C., and Chabner. B. A. Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia. N. Engl. J. Med., 289. 770-773, 1973. 3 Castle. M. C., Margileth, D. A., and Oliverio, V. T. Distribution and excretion of [3H]vincristine in the rat and the dog. Cancer Res., 36. 3684-3689.1976. 4. Creasey, W. A. Vinca alkaloids and colchicine. In: A. C. Sartorelli and D. G. Johns (eds.), Antineoplastic and Immunosuppressive Agents II, pp. 670694. Berlin: Springer-Verlag, 1975. 5. El Dareer. S. M., White, V. M., Chen, F. P.. Mellet, L. B., and Hill. D. L. Distribution and metabolism of vincristine in mice, rats, dogs, and monkeys. Cancer Treat. Rep., 61: 1269-1277, 1977. 6. Folk, R. M., Peters, A. C., Parker, K. L., and Swenberg, J. A. Vincristine
13. 14.

15.

16.

partment model to the analysis of the dose-dependent kinetics of bishydroxycoumarin elimination. J. Pharm. Sci.. 57. 1888-1895, 1968. Root, M. A., Gerzon, K., and Dyke, R. W. A radioimmunoassay for vinblastine and vincristine. Fed. Anal. Chem. Spectrosc. Soc., 125, 1975. Sandier, S. G., Tobin, W., and Henderson, E. S. Vincristine-induced neurop athy. A clinical study of fifty leukemic patients. Neurology, 19: 367-374, 1969. Sethi, V. S.. Burton, S. S.. and Jackson. D. V. A sensitive radioimmunoassay for vincristine and vinblastine. Cancer Chemother. Pharmacol., 4: 183-187, 1980. Todd, G. C.. Griffing, W. J., Gibson, W. R., and Morton, D. Animal models for the comparative assessment of neurotoxicity following repeated admin istration of Vinca alkaloids. Cancer Treat. Rep., 63. 35-41, 1979.

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RESEARCH

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VOL. 41

Pharmacokinetics of Vincristine in the Cerebrospinal Fluid of Humans D. V. Jackson, Jr., V. S. Sethi, C. L. Spurr, et al. Cancer Res 1981;41:1466-1468.

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Pharmacokinetics of Vincristine in the - Cancer Research

[CANCER RESEARCH 41, 1466-1468, 0008-5472/81 /0041-OOOOS02.00 Pharmacokinetics April 1981] of Vincristine in the Cerebrospinal Fluid of Humans1 D...

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