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  • (CANCER RESEARCH 46, 1513-1520, March 1986]

    Human Pharmacokinetics, Excretion, and Metabolism of the AnthracyclineAntibiotic Menogaril (7-OMEN, NSC 269148) and Their Correlation withClinical Toxicities1

    Merrill J. Egorin,2 David A. Van Echo, Margaret Y. Whitacre, Alan Forrest, Lawrence M. Sigman,

    Kathrin L. Engisch, and Joseph Aisner

    Divisions of Developmental Therapeutics [M. J. E., K. L. E., A. F., L. M. S.] and Medical Oncology [D. A. V. E., M. Y. W., J. A.], University of Maryland Cancer Center,Baltimore, Maryland 21207

    ABSTRACT

    In a Phase I study, menogaril (7-OMEN) was administereddaily for 5 days/course, every 21-28 days. Dosages of 3.5, 7,11.5, 17, and 31.5 mg/m2 were infused over 1 h, and dosagesof 42,50, and 56 mg/m2 were infused over 2 h. Pharmacokinetics

    was studied at all dosages. Plasma and urine samples werecollected from 24 patients, and bile samples were also collectedfrom 2 patients. 7-OMEN and metabolites were measured byhigh performance liquid chromatography. 7-OMEN was the major

    plasma fluorescent species at all times, with only trace amountsof N-demethyl menogaril observed. 7-OMEN disappeared from

    plasma biexponentially with f./, a 0.19 0.04 (mean SE) h andtv, 13.22 1.54 h. Plasma pharmacokinetics of 7-OMEN waslinear from 3.5-56 mg/m2; area under the curve increased pro

    portionally with dosage. Total body clearance of 7-OMEN was28.18 3.33 liter/nf/h, Vcwas 224 30.8 liter/m2, and Vsswas370 25.7 liter/m2. Plasma pharmacokinetics of 7-OMEN stud

    ied on multiple days of a given course were similar. Urinaryexcretion of 7-OMEN and fluorescent metabolites accounted for

    5.4 0.4% of the daily dose. Parent compound still represented>80% of urinary drug fluorescence after 24 h. W-demethyl men

    ogaril was the only other fluorescent drug species detected inurine. In two patients with biliary tract drains, biliary excretion ofdrug fluorescence accounted for 2.2-4.2% of the daily dose.Only 7-OMEN and A/-demethyl menogaril were detected in bile

    by high performance liquid chromatography and thin layer chromatography. 7-OMEN was the major fluorescent biliary species,but, by 24 h, A/-demethyl menogaril accounted for approximately

    40% of biliary drug fluorescence. When considered in light ofeach patient's observed toxicities, excellent relationships were

    observed between the plasma area under the curve of 7-OMEN

    and the percentage of decreases in WBC and absolute neutrophilcount. These latter findings should be useful in developing moreprecise and intelligent dosing schemes for 7-OMEN.

    INTRODUCTION

    Anthracycline antibiotics, of which doxorubicin and daunorub-

    icin (Fig. 1) are the most important representatives, are a majorclass of antitumor agents. However, these two agents produce

    Received 6/27/85; revised 11/8/85; accepted 11/11/85.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 inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    'This work was supported in part by Contract NO1CM27541, and Grant

    IP50CA32107 awarded by the National Cancer Institute, Department of Health andHuman Services, Bethesda, MD 20205.

    2To whom requests for reprints should be addressed.

    considerable toxicity and have limited efficacy against manyneoplasms. Therefore, the search continues for anthracyclineantibiotics with improved therapeutic indices, altered spectra, oractivity of both (1).

    7-OMEN3 is a semisynthetic derivative of the anthracycline

    antibiotic nogalamycin (Fig. 1), a drug with significant experimental antitumor activity but prohibitive toxicity in animals (2). 7-

    OMEN has been introduced into Phase I clinical trials based onits broad spectrum of in vivo activity against animal tumors, itsdemonstrated activity after p.o. as well i.v. administration (2, 3),and its reduced cardiotoxic potential (4).

    The mechanism of action of 7-OMEN may differ from that ofdoxorubicin. 7-OMEN is most toxic to cells in d phase, whereas

    doxorubicin is most toxic to cells in S phase (2). In addition,while doxorubicin interacts strongly with DNA, 7-OMEN interactsonly weakly with DNA and is highly cytotoxic at concentrationswhich do not inhibit nucleic acid synthesis (2, 5). Finally, whenvarious tumor lines are incubated in vitro with 7-OMEN ordoxorubicin, 7-OMEN fluorescence is localized mainly in the

    cytoplasm, whereas doxorubicin fluorescence accumulates primarily in the nucleus (2, 6). Previous studies have described theplasma pharmacokinetics of 7-OMEN in beagle dogs (7), rabbits

    (8), and mice (9, 10), while our laboratory has defined the organdistribution of 7-OMEN in mice and rabbits (8, 9), and the urinaryand biliary excretion of 7-OMEN by rabbits (8).

    During the performance of a Phase I study at our center, wehad the opportunity to define the human plasma pharmacokinetics and urinary excretion of 7-OMEN and its metabolites at

    multiple dosages, and to investigate the biliary excretion of thesecompounds in two patients with biliary drains. Finally, when weanalyzed these plasma pharmacokinetic data and comparedthem with the toxicity observed in each patient, an excellentrelationship was apparent between the plasma pharmacokineticsof 7-OMEN in any patient and the pharmacodynamics resultingfrom 7-OMEN therapy of that patient. This paper presents these

    results.

    MATERIALS AND METHODS

    Patient Selection. All patients entering this trial had to fullfill thefollowing criteria: histological proof of malignant disease which had failedconventional chemotherapy or for which no conventional therapy existed,recovery from all toxicities from prior treatments and passage of at least4 weeks from any prior chemotherapy or radiotherapy, a minimal life

    3The abbreviations used are: 7-OMEN, menogaril; HPLC, high performanceliquidchromatography;TLC, thin layerchromatography;AUC,areaunder the curveof plasmadrug concentration versus time; Vc,volume of the central compartment;V,steady-state volumeof distribution.

    CANCER RESEARCH VOL. 46 MARCH 1986

    1513

    on July 15, 2018. 1986 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

    http://cancerres.aacrjournals.org/

  • 7-OMEN PHARMACOKINETICS AND TOXICITIES

    DounorublcinCH3Doxorubicin

    CH2OHNoqolomycin

    CH3Menogoril

    CH3N-DemethylMenogonlHNogorol0

    CH]7-Deoxynogarol

    CH3N-Demethyl-7-Deoxynogarol

    HNogalose

    COOCH3OCHj

    HOCH3

    HOH

    HH

    HH

    H

    Fig. 1. Structures of doxorubicin, daunorubicin, nogalamycin, 7-OMEN, andsome metabolites of 7-OMEN. Nogarene (Nogarol') corresponds to 7,8-9,10-

    bisanhydronogarol.

    expectancy of 12 weeks, a Karnofsky performance status >60%, adquate bone marrow function (WBC >3,500 cells//!),and platelet count>100,000/--l,adequate liver function (bilirubin 45% at

    rest. Objective measurable disease was desirable, but not required.Written informed consent in accordance with Federal and institutionalpolicies was obtained from all patients prior to their entry onto study.

    Before entry onto study, each patient had a detailed history taken anda physical examination performed. Tumor measurements were madeand performance status was assessed. Laboratory studies relevant tothis paper included pretreatment and weekly complete and differentialblood counts and platelet counts.

    Dosage Preparation and Administration. 7-OMEN (NSC 269148),was supplied in freeze-dried dosage form by the Investigational DrugBranch, National Cancer Institute, Bethesda, MD. 7-OMEN was recon

    stituted by adding 10 ml of sterile water for injection (DSP) to each vial.The resulting solution contained 50 mg of 7-OMEN, 100 mg of mannitol,and 16.6 mg of L-lactic acid. This was further diluted with sterile 5%dextrose in water. Dosages of 3.5 to 31.5 mg/m2 were diluted to 150 mland were infused i.v. over 1 h, while dosages of 42, 50, and 56 mg/m2

    were diluted to 250 ml and were infused over 2 h. 7-OMEN was admin

    istered i.v. on 5 consecutive days with courses repeated after 4 weeks.Sample Acquisition. Heparinized blood samples were obtained before

    and at multiple times during and after the 7-OMEN infusion. Specifically,on day 1 of the 5-day course, blood was obtained prior to and at 0.5-hintervals during the 7-OMEN infusion. In addition, samples were obtained

    at 5, 10, 20, 30, and 60 min, and at 2, 4, 6, 12, 18, and 24 h aftercessation of the infusion. Blood samples were also obtained before the7-OMEN infusion on days 2,3,4, and 5 of each course. In some patients,

    a repeat of the intensive sampling scheme performed on day 1 was alsoperformed on day 4 or 5 of a course to investigate whether the phar-

    macokinetics on later days of a course were similar to that on the firstday. Blood samples were immediately centrifuged at 1000 x g for 10min, and the resulting plasma supernatant was immediately removedand frozen at -20C until analyzed. During the first 24 h after drug

    administration, urine was collected as voided and stored as 4-h aliquotsin opaque containers at 4C. Subsequently, a portion of each 4-hcollection was frozen and stored at -20C until analyzed.

    Two of the patients on this study had indwelling biliary tract drainsand provided the opportunity to collect and analyze the biliary excretionof 7-OMEN and its metabolites. The first of these patients had completelynormal serum liver function tests (bilirubin, 0.8 mg/dl; aspartate amino-

    transferase, 35 units/liter; alanine aminotransferase, 7 units/liter; lactate

    dehydrogenase, 136 units/liter; alkaline phosphatase, 292 units/liter;total protein, 6.9 g/dl; and albumin, 4.2 g/dl). The second patient hadmoderate hepatic dysfunction as assessed by serum liver function tests(bilirubin, 5.4 mg/dl; aspartate aminotransferase, 56 units/liter; alanineaminotransferase, 38 units/liter; lactate dehydrogenase, 143 units/liter,alkaline phosphatase, 1102 units/liter, protein, 6.2 g/dl, and albumin, 2.9g/dl). Each patient had bile collected on ice and stored frozen as 4-haliquots during the first 24 h after initiation of 7-OMEN therapy. The

    second of these patients also had the subsequent 4 days of biliaryexcretion collected and stored frozen as 24-h aliquots.

    Extraction and Chromatographie Analysis of 7-OMEN and Metabolites. 7-OMEN and metabolites were analyzed by the method of Mc-Govren ef al. (11). Briefly, 1-ml samples of plasma, urine, or bile weredeproteinized with 0.2 ml of 0.05 M glucuronic acid and 2.4 ml acetoni-trile:methanol, 1:1 by volume, containing 0.25 MM7-con-O-ethyl nogarol

    as an internal standard. Internal standard was graciously provided by Dr.J. P. McGovren of the Upjohn Co., Kalamazoo, Ml. Samples weresubsequently centrifuged at 27,000 x g for 15 min at 4C.The resulting

    supernatant fraction was transferred to prechilled, screw-cap vials,shielded from light, and stored at 4Cuntil injection onto the HPLC.

    The HPLC system used in these studies consisted of a Waters M45pump (Waters Associates, Milford, MA) and a C8 radial compressioncartridge (Waters Associates) held in a Z module (Waters Associates).7-OMEN and metabolites were eluted with a mobile phase of 0.2 M

    acetic acid, 0.015 M methane sulfonic acid:acetonitrile, 3:2 by volume,pumped at 1.5 to 4 ml/min. Fluorescent materials were detected with anAminco fluoromonitor (SLM Instruments, Urbana, IL), fitted with 470 nmexcitation and 550 nm cut-off emission filters. 7-OMEN concentrationswere determined by comparison of the areas of 7-OMEN peaks with that

    of the corresponding internal standard.In addition to HPLC, bile and urine samples were also analyzed by

    TLC. TLC analyses utilized 250 firn Silica Gel 60 TLC plates (E. Merck,Darmstadt, West Germany), that were developed for 15 cm, in anascending fashion, in chloroform:methanol:acetic acid:water, 80:20:14:6by volume. Fluorescent spots were identified under 254 nm light (UVS-

    54 Mineralight, Ultraviolet Products, San Gabriel, CA). Known standardsof 7-OMEN, W-demethyl menogaril, 7-deoxynogarol, nogarol, and nogar-

    ene were also run on each TLC plate.Pharmacokinetic Analysis. Computer modeling of the decline in

    plasma concentrations of 7-OMEN was performed with the MLAB pro

    gram (12), and pharmacokinetic parameters were calculated from themodeled data. The relationships between changes in WBC and AUCwere modeled with ADAPT (13), another program which uses iterative,weighted, nonlinear, least squares regression.

    RESULTS

    At all dosages, plasma concentrations of 7-OMEN rose pro

    gressively during the drug infusion, after which they decayed inbiexponential fashion with tv, a 0.19 0.04 h (mean SE) andtv, 13.22 1.54 h (Fig. 2; Table 1). The pharmacokinetics of7-OMEN was linear over the dosage range studied, the AUC

    increasing linearly with increased dosage (Fig. 3; Table 1). Ascan be inferred from this, the total body clearance of 7-OMEN,28.18 3.33 liter/h/m2, was not altered by increasing the dose

    (Table 1). Similarly, neither the volume of the central compartment, 224 30.8 liter/m2, nor the steady-state volume of distribution, 370 25.7 liter/m2, were altered by increasing the

    amount of drug infused. These plasma pharmacokinetic parameter values did not change with repeated dosing since thosedetermined on day 4 or 5 of a course were unchanged fromthose observed in that same patient on day 1.

    At all times, 7-OMEN was the major fluorescent species pres-

    CANCER RESEARCH VOL. 46 MARCH 1986

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    on July 15, 2018. 1986 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

    http://cancerres.aacrjournals.org/

  • 7-OMEN PHARMACOKINETICS AND TOXICITIES

    zIO

    1.000-

    0.7000.500-

    0.300-

    0.100-

    0.070-

    0.050-

    0.030

    0.010-

    0.007-

    0.005-

    0.003-

    0.001

    oB

    !Ml 5(2)

    a 175(1)o 7 (S)

    A3.5(3)

    /O 2 IO 12 14 16 18 20 22 24TIME (hr)

    1.000-

    0.700-

    0.500-

    0.300-

    3. 0.1 00-"~Z 0.070-

    ^ 0.050-

    o,1. 0.030-

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    B

    0 2 4 6 8 10 12 14 16 18 20 22 24

    TIME (hr)Fig. 2. Concentrations of 7-OMEN in plasma of patients treated with varying

    dosages of 7-OMEN. Dosages of 3.5 to 31.5 mg/m2 (A) were infused over 1 h whiledosages of 42 to 56 mg/m2 (B) were infused over 2 h. Concentrations of 7-OMENwere determined by HPLC, as described in "Materials and Methods." Points, mean

    values. The number of courses studied at each dosage are indicated in parenthesesnext to the dosage.

    ent in plasma. Although small HPLC peaks corresponding to themono- and didemethyl metabolites of menogaril were observed,

    the plasma concentrations of these materials were negligible andrepresented

  • 7-OMEN PHARMACOKINETICS AND TOXICITIES

    Table 1Summaryof menogarilplasma pharmacokineticparameters

    Dosage(mg/m2)3.5711.517.531.5425056MeanSDSEDosage(pmd/m2)6.312.9521.27532.37558.27577.791.7103.6No.

    ofstudies23312544(h-)12.087.0611.097.3611.126.323.664.23.694.132.241.971.404.84

    2.527.465.201.06f*

    (h)0.06

    0.220.17+0.080.080.020.090.06

    0.010.200.090.330.190.32

    0.130.190.200.04

    (h-1)0.24

    0.220.1130.060.093

    +0.0160.1210.075

    +0.0040.0570.0060.0570.0160.0490.0120.0710.0440.01f0(h)13.2

    11.611.45.98.0

    1.55.79.3

    0.512.7+1.216.2

    5.217.24.313.227.391.54AUC^M-h)0.158

    0.0840.95...

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