Disposition of mitoxantrone in patients

Cancer Treatment

Reviews

Disposition

(1983)

10 (Supplement B), 23-27

of mitoxantrone

David S. Alberts,‘f$§T Yei-Mei and David L. Woodward 11

PengJy

in patients* Susan

Leigh,$f/

Thomas

P. Davis!jl

ISection of Hematology and Oncology, Department of Internal Medicine, #Department of Pharmacology, BCancer Center, College of Medicine, University of Arizona, Tucson, A< 85724 and I[Medical Research Division, American Cyanamid Co., Lederle Laboratories, Pearl River, N. T. 10965, U.S.A.

Introduction Mitoxantrone, or 1,4-dihydroxy-5,8-bi( ((2-[(a-hydroxyethyl)amino]ethyl)amino))-9,10anthracenedione dihydrochloride (NSC 301,739) is an investigational anthracene derivative which has shown significant activity in the treatment of metastatic breast cancer, unfavorable histology non-Hodgkin’s lymphoma, and acute leukemia (3, 5, 14, 16, 18). Mitoxantrone has been very well tolerated, causing a very low incidence of nausea, vomiting and alopecia, and virtually no phlebitis (2, 17). Its dose-limiting toxicities have been rapidly reversible leukopenia and to a lesser extent thrombocytopenia (2, 17). In patients, but not animals, mitoxantrone has been associated with a significant but low incidence of cardiotoxicity ( 1, 13, 15). We (7, 8) and others (6, 9) have developed high performance liquid chromatographic (HPLC) assays for mitoxantrone in order to evaluate its disposition in patients.

Materials Eight head were All

and methods

patients with histopathologically proven diagnoses ofdisseminated solid tumors (four and neck cancers, two renal cell cancers, one ovarian cancer, and one melanoma) entered into phase II trials ofmitoxantrone after standard forms oftherapy had failed. patients had normal renal and hepatic blood chemistry values prior to the

* This work was supported in part by grants CA 17094 and CA 23074 from the National Institutes of Health, Bethesda, MD 20205, and by a grant from the Medical Research Division, American Cyanamid Co., Lederle Laboratories, Pearl River, N.Y. 10965. t To whom requests for offprints should be addressed at the Section of Hematology and Oncology. 0305%7372/83/10B0023+05

$03.00/O

fQ 1983 Academic 23

Press Inc.

(London)

Limited

D. S. ALBERTS

24

ET

AL.

pharmacokinetic studies. Three patients had received prior doses of mitoxantrone, and all others were studied during the first dose administration. Each patient was administered a single intravenous dose of “C-labelled mitoxantrone (4.83 ,&X/mg), 12 mg/m2, over 3&35 min in a 150-250 ml volume of 5% dextrose in water. Blood samples were obtained during and at varying time intervals from 1 min to 96 h after the termination of mitoxantrone infusion. Blood samples were drawn into heparinized tubes, immediately placed on ice, and then quickly processed to separate plasma, RBCs, and WBCs which were then frozen at -20°C for analysis. Ascorbic acid was added to plasma samples to inhibit mitoxantrone’s oxidative degradation (9). Total urinary and fecal outputs were collected for up to 5 days post-dosing. A recently reported HPLC assay for mitoxantrone (12) was used to quantitate mitoxantrone concentrations in all plasma and urine samples. This HPLC method uses a commercially available mini-cartridge with Crs reversed-phase packing to isolate the drugs from biological matrix prior to HPLC. The average mitoxantrone recovery of the assay was 98 + 6% with a coefficient ofvariation ofless than 7%. The sensitivity of the assay was 1 rig/ml for mitoxantrone. Fecal material, blood, and bone marrow formed elements, tumor and autopsy tissues were analyzed for i4C-mitoxantrone equivalent concentrations.

Results Plasma kinetic data for mitoxantrone and “C-mitoxantrone equivalents were obtained in seven of the eight study patients. The mitoxantrone concentration time data were computer fitted using NONLIN with a data weighting of 1ly’. In five of the seven patients the mitoxantrone plasma disappearance curves measured by HPLC were best described by a three compartment model. The mean pharmacokinetic parameters for these five patients are shown in Table 1. Because the data from the remaining two patients were adequately described by a two compartment model they have not been included in this analysis. In the five study patients the initial phase of the decrease in plasma was rapid (t$2 = 0.1 h). The second phase (412) was somewhat longer with a half-life of one hour. The mean terminal phase plasma half-life (ti,2) was 42.6 h. The mean apparent volume of the central compartment (V,) was 12.2 l/m2, while the mean apparent volume of dis-

Table

1. Mitoxantrone parameters*

Parameter

(h)

1.0 42.6 (m/ml)

V, Wd

1875

(I/min/m*)

CLR (ml/min) *Based

on pharmacokinetic

0.1

Maximum 0.2

0.7

1.5

20.8

69.3

0.3 12.2

Vny Wm2) CL,

Minimum

0.1

tY,,, (h) AUC

pharmacokinetic

Mean

62 (h) tf,,

mean

3.9 1072

0.6 70

0.3 35

data from

five patients.

67.8 2930 0.9 122

DISPOSITION

OF

MITOXANTRONE

IN

PATIENTS

25

tribution based on the t:,, was 1875 l/m2. The clearance rate of mitoxantrone from the plasma (CL,) was 0.6 l/min/m2 and the renal clearance rate was 70 ml/min. The concentration of “C-mitoxantrone-related material in the blood formed elements (FE) was at all time points greater than that in the plasma. The FE/plasma ratio of radioactivity ranged from 2 : 1 to 10 : 1 at various intervals after mixotantrone administration. The mean urinary recovery of mitoxantrone was only 6.5% (range 5.2-7.9%) of the total administered dose, recovered over 5 days (Table 1). The majority (90%) of mitoxantrone recovered was during the first 24 h with the first 4 h contributing 62%. The recovery of i4C-labelled material for seven ofeight patients ranged from 0.8 to 1.6 times the HPLC measured mitoxantrone recovery. In those patients who had more than one bowel movement during the 5-day collection period, the mean percent recovery of i4C-labelled mitoxantrone from feces was 18.3% (range 13.6-24.8%) of the administered dose. Tissue concentrations of 14C-labelled mitoxantrone-related material from four patients are shown in Table 2. Note that the tumor tissue from two of three patients contained only picogram quantities of mitoxantrone per million cells. Neither of these patients showed a response to mitoxantrone therapy although the tumor from one (patient 8, Table 2) had been predicted to be exquisitely sensitive to mitoxantrone on the basis of in vitro testing using a clonogenic assay (10). In contrast approximately twenty times higher mitoxantrone concentrations were observed in bone marrow white cells and lymph node cancer cells obtained from two other patients (patients 2 and 4, respectively). Patient 2 experienced lifethreatening leukopenia (i.e., neutrophil count < 500/mm3) 10 days following mitoxantrone therapy and patient 4 had a 25% reduction in the size of her metastatic lymph node disease. Organ specimens were obtained from patient 2 who died of progressive kidney cancer 35 days after mitoxantrone administration. Even at 35 days, the liver, pancreas, thyroid, spleen, and heart contained relatively high mitoxantrone equivalents per gram of tissue (wet wt). On the basis of “C-mitoxantrone distribution per whole organ, the liver contained the highest number of counts followed by the bone marrow, heart, lungs, spleen, kidney, and thyroid glands in that order. Adding the total amounts of mitoxantrone retained in each of the seven organs evaluated as much as 15% of the administered dose could be accounted for in these tissues at 35 days. Discussion

We have shown that the plasma disappearance of mitoxantrone measured by HPLC can be described in the majority of patients by a three compartment model with a prolonged Table

2. “C-labelled

Patient number

mitoxantrone-related

material

in bone

marrow

we

(h)

Bone marrow white cells Squamous cell cancer metastatic to neck Adenocarcinoma (ovary) metastatic to supraclavicular node Melanoma metastatic to wrist* 10 rig/ml for 1 h exposure, reduced prior to mitoxantrone treatment).

tumor

Time interval after mitoxantrone

Tissue

*Mitoxantrone, melanoma nodule

and

melanoma

colonies

samples mitoxantrone equivalents (rig/l x 1 O6 cells)

6 5.25

1.13 0.06

6 22.25

1.32 0.03

to < 1% control

(biopsy

obtained

from

26

D. S. ALBERTS

ET

AL.

terminal elimination phase half-life of approximately 43 h. Previous investigations have reported either shorter (4) or similar (11, 12) durations of this important pharmacokinetic parameter. Our highly sensitive HPLC assay (8) has allowed us to measure mitoxantrone plasma concentrations for up to 72 h after drug administration, and thus, accurately determine the duration of the terminal elimination phase half-life. While the estimate of this half-life (i.e., range of 20.8 to 69.3 h) is longer than that reported by others (4), it is likely that the elimination half-life is much longer based on the body content of drug 35 days after dosing. These data provide a pharmacologic rationale for an every-3-week dosing schedule. Mitoxantrone appears to distribute into a deep tissue compartment from which it is slowly released as evidenced by its prolonged plasma terminal half-life, extremely large volume of distribution (Vn), and the relatively large amount of mitoxantrone ( > 15% of administered dose) retained in autopsy tissues 35 days after dosing. Even though mitoxantrone (and/or mitoxantrone related material) persists in the body for prolonged periods, repeat dosing at 3-week intervals for as many as 12 courses had no noticeable effect on the calculated pharmacokinetics. Considerable evidence exists to suggest that mitoxantrone undergoes extensive metabolism. Firstly, the mean AUC (i.e. area under the plasma disappearance curve) for r4Clabelled material was significantly larger than that determined by HPLC. Secondly, the recovery of r4C-labelled material in the 5-day urine collections was significantly larger than that of the HPLC measured parent compound. Finally, urine HPLC chromatograms revealed up to three polar metabolites, which appeared identical to those previously observed in rat, dog, and monkey bile. The most important route of mitoxantrone elimination appears to be fecal. Total drugrelated material recovered averaged 28% of the administered dose in 5 days; 10.1 o/o in the urine (6.5% as mitoxantrone and an additional 3.6% as 14C-labelled material) and 18% in the feces. Because of the relatively low urinary excretion of mitoxantrone it is unlikely that the standard drug dose must be reduced in the presence ofcompromised renal function. On the other hand, since the drug appears to be metabolized in the liver, future studies must be carried out to determine the effect of liver dysfunction on the disposition and toxicity of mitoxantrone. References 1. Aapro, M., Mackel, C., Alberts, D. & Woolfenden, J. (1982) Phase II cardiotoxicity study of mitoxantrone hydrochloride using exercise radionuclide evaluation of the left ventricular cardiac ejection fraction (LVEF). Proc. Am. SOC. Clin. 0~. 1: 14. 2. Alberts, D. S., Griffith, K. S., Goodman, G. E., Herman, T. S. & Murray E. (1980) Phase I clinical trial of mitoxantrone: a new anthracenedione anticancer drug. Cancer Clmnother. Pharmacol. 5: 11-15. 3. Estey, E. H., Keating, M: J., McCreadie, K. B., Bodey, G. P. & Freireich, E. J. (1982) Phase II trial of dihydroxyanthracenedione in acute leukemia. Proc. Am. Assoc. Cancer Res. 23: 113. 4. Neidhart, J., Stabus, A., Young, D. & Malspeis, L. (1981) Pharmacokinetic studies of dihydroxyanthracenedione (DHAD, NSC 301,739) with clinical correlations. Proc. Am. Assoc. Cuncer Rcs. 22: 363. 5. Neidhart, J. A. & Roach, R. W. (1982) A randomized study of mitoxantrone (M) and adriamycin (A) in breast cancer patients failing primary therapy. Proc. Am. SOG. Clin. Oncol. 1: 86. 6. Ostroy, F. & Gams, R. A. (1980) An HPLC method for the quantitative determination of 1,4-dihydroxy-5,8 bis( (2-((2-hydroxyethyl)amino)ethyl)amino)9, lo-anthracenedione (DHAD, Lederle Labs., CL 232,315, NSC 301,739) in serum. 3. Liq. Chromafog. 3: 637-644. 7. Peng, Y.-M., Davis, T. P. & Alberts, D. S. (1981) High performance liquid chromatography of a new anticancer drug, ADCA-physicochemical properties and pharmacokinetics. Life .Sti. 29: 361-369.

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