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© 2001 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of LU79553, a DNA Intercalating Bisnaphthalimide, in Patients With Solid MalignanciesFrom the Institute for Drug Development, Cancer Therapy and Research Center, and University of Texas Health Science Center at San Antonio, San Antonio, TX; Dana-Farber Partners in Cancer Care, Boston, MA; Cancer Institute of New Jersey, New Brunswick; Knoll Pharmaceutical Company, Mount Olive, NJ. Address reprint requests to Miguel A. Villalona-Calero, MD, Arthur G. James Cancer Hospital, Ohio State University, B406 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210-1240; email: villalona-1{at}medctr.osu.edu
PURPOSE: To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course. RESULTS: Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m2/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m2/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m2/d dose level. At the 18-mg/m2/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane-resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment. CONCLUSION: Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m2/d, which is the recommended dose for subsequent disease-directed evaluations. The preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent.
THE NAPHTHALIMIDE DNA intercalating agents were designed to incorporate the essential structural components of several well-recognized antitumor moieties, including aristolochic acid, tilorone, CG-603, and cycloheximide into a single molecule.1 The naphthalimides inhibit both RNA and DNA synthesis, and the relegation step of topoisomerase II action.1-3 Early clinical evaluations of the mono-naphthalimides, amonafide and mitonafide, were performed in the 1980s.4,5 Although objective antitumor activity against patients with advanced leukemia and solid neoplasms were documented,6-9 CNS toxicity precluded further development of mitonafide, and unpredictable toxicity resulting from substantial inter-individual pharmacogenetic variability in N-acetylation profiles has been a significant hindrance to the development of amonafide.10-11 Because the bisintercalating agents generally have greater affinity for DNA than mono-intercalating agents,12 bisintercalating naphthalimides, referred to as the bisnaphthalimides, were synthesized.13-15 Although the precise DNA binding site and mechanism of cytotoxic action of the bisnaphthalimides have not been determined, several lines of evidence indicate that they intercalate into the major groove of the DNA double helix.15-17 The bisnaphthalimides have indeed demonstrated greater DNA binding affinity and cytotoxic potency than the mono-naphthalimides both in vitro and in vivo.15,17 The prototypical bisnaphthalimide, LU79553, (Elinafide; N,N-bis[2-(1,8-naphthalimido)ethyl]-1,3-diaminopropane bismethane sulfonate; Knoll AG, Ludwigshafen, Germany; Fig 1) was designed so that two naphthalimide moieties are bound together by an alkylamino linker.18 In addition to experimental evidence indicating that LU79553 induces cytotoxicity by DNA intercalation, leading to the disruption of DNA synthesis, transcription, and chromosome segregation, the agent inhibits the catalytic activity of human topoisomerase II by a unique mechanism. In contrast to doxorubicin, VP-16, and m-AMSA, LU79553 does not stabilize the DNA-topoisomerase II cleavable complex, but instead interferes with the catalytic activity of topoisomerase II by a distinct, as of yet, unidentified mechanism.17 Additionally, because there are no amino substitutions on the naphthalimide groups of LU79553, it is not metabolized by N-acetylation, and in contrast to amonafide, pharmacogenetic differences in acetylator phenotype would not be expected to result in substantial inter-individual differences in metabolism, which can cause unpredictable toxicity and antitumor activity.
LU79553 demonstrated impressive cytotoxic activity against human tumor cell lines and xenografts, which was superior to those of amonafide and mitonafide.15,17 IC50 values ranged from 0.5 to 20 nmol/L against a series of human tumor cell lines, including HT-29 colon and MX-1 breast carcinomas, 8,226 myeloma, and CEM leukemia.17 Higher drug concentrations were generally required to induce equivalent cytotoxicity in multidrug resistant tumors conferred by P-glycoprotein overexpression and altered topoisomerase II. Nonetheless, the IC50 values of LU79553 in these multidrug resistant neoplasms were still relatively low (1 to 10 nmol/L). The agent also produced notable activity against human MX-1 breast, LX-1 lung, OVCAR-3 ovarian, CX-1 colon, and DLD colon carcinomas, and LOX melanoma, with cures noted in both early and well-established xenografts.17 Frequent or divided administration schedules generally resulted in superior therapeutic indices compared with less frequent dosing schedules. For example, LU79553 was more effective against MX-1, LX-1, and LOX tumors when administered either daily for 5 days, twice weekly, or weekly than as a single treatment.17 In the human tumor colony-forming assay, in which the fresh tumor cells from patients were treated with LU79553 concentrations ranging from 0.01 to 1 µmol/L for 1 hour and 14 days, growth inhibition was impressive.19 The growth of approximately 75% of the fresh tumor explants was profoundly inhibited after treatment with the lowest concentration of LU79553, with fresh human breast, non–small-cell lung, ovarian carcinoma, and melanoma demonstrating extraordinary sensitivity. Interestingly, growth inhibition was similar after brief (1-hour) and protracted (14-day) treatment. Preclinical toxicity studies in mice, rats, and dogs demonstrated that LU79553 reversibly affects rapidly proliferative tissues such as hematopoietic, lymphoid, and gastrointestinal organs.20 Myodegeneration of both skeletal and cardiac muscle was also observed at necropsy of rodents and dogs treated at lethal or near lethal doses. Other relevant drug-related effects included inflammation at the site of injection and inflammatory changes throughout the nephron and interstitium of the kidney, which was not completely reversible at the higher doses. The impetus to develop LU79553 was based on its novel cytotoxic mechanism, high potency, broad antitumor spectra, prominent activity in well-established xenografts, and potential metabolic advantages over amonafide. The principal objectives of this phase I and pharmacologic study of LU79553 administered as a 30-minute intravenous (IV) infusion daily for 5 days every 3 weeks in patients with advanced solid malignancies were to accomplish the following: (1) characterize the principal toxicities of LU79553 on this schedule; (2) determine the maximum-tolerated dose (MTD) and recommend a safe starting dose for phase II studies; (3) characterize the pharmacokinetic behavior of LU79553; and (4) seek preliminary evidence of antitumor activity.
Eligibility Patients with histologically confirmed solid malignancies refractory to conventional therapy or for whom no effective therapy existed were candidates for this study. Eligibility criteria also included the following: (1) age  18 years; (2) Eastern Cooperative Oncology Group performance status  2 (ambulatory and capable of self-care); (3) a life-expectancy 12 weeks; (4) no major surgery, radiation therapy, or chemotherapy within 28 days (42 days for mitomycin C or nitrosureas); (5) adequate hematopoietic (WBC count 3,500/µL, absolute neutrophil count [ANC] 2,000/µL, platelet count 100,000/µL, and hemoglobin 9.0 g/dL), hepatic (total bilirubin level < 2 mg/dL; AST, ALT, and alkaline phosphatase two times the upper limit of normal, unless the elevation was a result of hepatic metastases, in which case elevations five times the upper normal limits were permitted), and renal (serum creatinine 1.5 mg/dL or a measured creatinine clearance 60 mL/min) functions and normal serum electrolytes; (6) no significant cardiac disease (eg, congestive heart failure, angina pectoris, or myocardial infarction) within 12 months; (7) no active neoplastic involvement of the CNS; (8) no prior history of high-dose myeloablative chemotherapy requiring hematopoietic stem-cell support; and (9) no coexisting medical problems of sufficient severity to prevent full compliance with the study. All patients gave informed written consent before treatment.
Dosage and Dose Escalation
Drug Administration LU79553 was supplied by Knoll Pharmaceutical Company (Mount Olive, NJ) in 5- and 20-mL ampules that contained 50 and 200 mg of LU79553 (10 mg/mL) in liquid form. Initially, LU79553 was diluted in 100 mL of normal saline and infused IV over 30 minutes using a Harvard pump (Harvard Apparatus, Inc, South Natick, MA) through a peripheral vein. However, a high incidence of inflammation along the course of the injected vein led to several modifications. First, LU79553 was progressively diluted in 250 to 500 mL of normal saline and administered over 3 hours through a peripheral vein. Because this maneuver was not effective, LU79553 was then diluted in 250 mL of normal saline and infused over 3 hours through a central venous catheter. This maneuver was successful and used thereafter.
Pretreatment Assessment and Follow-Up Studies
Sampling and Assay Plasma and urine samples were analyzed using reverse phase high-performance liquid chromatography (HPLC) with fluorescence detection and LU66315 (N,N-bis[3-(1,8-naphthalimido) propyl]-1,3-diaminopropane) as an internal standard. LU79553 and the internal standard were separated from the biologic samples using solid phase (cation exchange) extraction. After rinsing the sample with a mixture of 6% sodium chloride and ethanol-water (1/1, v/v), extraction of the solid phase was performed with 2.6 mL of a mixture containing acetonitrile (26%) and water (74%), to which diethanolamine (20 g/L) was added. Acidity of the solution was adjusted to a pH of 2.5 with H3PO4. HPLC was performed using a Beckmann Ultrasphere Octyl, YMC-Pack ODS (YMC, Kyoto, Japan) with a 4.6 mm x 15 cm steel column and a flow rate of 0.8 mL/min. Detection and excitation were at 385 and 335 nm, respectively. The retention times for LU79553 and LU66315 were 4.5 and 7.5 minutes, respectively. LU79553 concentrations were calculated using a calibration curve prepared from spiked plasma and urine samples. The calibration range was 0.5 to 50 ng/mL for plasma and 0.5 to 200 ng/mL for urine. The accuracy of the assay was estimated to be 93.8% to 111% for plasma and 96.2% to 109.4% for urine, and the lower limits of detection for plasma and urine were 0.20 and 0.22 ng/mL, respectively.
Pharmacokinetic and Pharmacodynamic Analyses The Wilcoxon matched-pairs signed-rank test was used to compare pharmacokinetic parameters on days 1 and 5. Univariate correlation analysis was performed to examine the relationship between parameters of exposure and indices of both renal (serum creatinine clearance) and hepatic (transaminases, total bilirubin, alkaline phosphatase) functions. Statistical analysis was performed using the statistical software program Stat View, Version 5.0 (SAS Institute, Cary, NC). The relationships between LU79553 systemic exposure and toxicity were explored. Dose, Cmax,and AUC0-24 on days 1 and 5 were related to the percentage decrements in the ANC and platelet counts and to categorical grades of toxicities. The percentage decrement in the blood cell count was calculated as follows: % decrement in blood cell count = 100 x (pretreatment count - nadir count) pretreatment count Both simple linear and sigmoidal maximum effect (Emax) models of drug effect were fit to data sets using nonlinear least-squares regression. Discrimination between pharmacodynamic models was guided by minimization of the weighted sum of squares and standard errors for the pharmacokinetic parameters, examination of the dispersion of the residuals, and use of the coefficient of determination (R2). The Wilcoxon rank sum test was used to compare values of systemic exposure in patients with different degrees of toxicity.
General Thirty assessable patients received 105 total courses of LU79553 at doses ranging from 2 to 24 mg/m2/d. One additional patient, who died of rapidly progressive disease 1 week after receiving a first course of LU79553 at the initial dose level, was considered not assessable for toxicity. The numbers of patients, courses, and rates of DLT as a function of dose level are depicted in Table 1. The pertinent demographic characteristics of the patients are listed in Table 2. All patients received prior chemotherapy, and 11 subjects were previously treated with both chemotherapy and radiation therapy. Although bilirubin levels as high as 1.9 mg/dL were allowed in the eligibility criteria for this trial, only two patients (1.2 and 1.1 mg/dL, respectively) had bilirubin levels higher than 1 mg/dL at study entry.
Six assessable patients were treated at the first dose level because of the death of one subject 4 weeks after the first course of LU79553. A postmortem examination established that the cause of death was bacterial pneumonia and not drug-related. Although DLT did not occur during the first course of LU79553 at any dose level, a male patient developed severe proximal myopathy and erectile dysfunction along with brief grade 4 neutropenia after his third course of LU79553 at the 24 mg/m2/d dose level, and a second male subject developed severe erectile dysfunction, a moderate proximal myopathy, and brief grade 4 neutropenia after his third course at the same dose level. Because of the atypical and cumulative nature of these toxicities, these patients received no further treatment, and 24 mg/m2/d was considered an intolerable dose. Instead, the 18 mg/m2/d dose level, which was associated with DLT, consisting of severe (grade 4) neutropenia, fever, and grade 2 proximal myopathy in one of six patients, was considered the MTD and the dose recommended for phase II evaluations. Three of six patients at this dose level received three courses of LU79553.
Myopathic Effects
Other pertinent studies in the two aforementioned patients included ECGs and MUGA scans, which were unremarkable. However, electromyography was clearly abnormal. Electromyography revealed increased insertional and spontaneous activity, small myopathic motor unit potentials, and early recruitment, indicating a primary myopathic process. Further support for a primary myopathic process was from nerve conduction and repetitive nerve stimulation studies, which were normal. Histopathologic examination of muscle biopsies from the biceps musculature of both individuals revealed mild variability in fiber size, few scattered necrotic fibers, and amorphous deposits of fine blue green granular material, as well as pleomorphic or spherical cytoplasmic inclusions, better seen on Gomori trichrome staining. Ultrastructural studies demonstrated severe myofibrillarly disruption and electron-dense granulofibrillar masses surrounded by a clear zone characteristic of cytoplasmic bodies, resembling myofibrillarly myopathy ( Fig 2). Both individuals also developed severe myelosuppression, with respective ANC nadirs of 100/µL and 410/µL on day 18, respective platelet count nadirs of 54,000/µL and 68,000/µL on day 10, and respective nadir hemoglobin values of 7.4 g/dL and 9.4 g/dL on day 18.
Three other patients developed a proximal myopathy. Two individuals developed moderate (grade 2) weakness of their proximal lower extremity muscles after three courses of LU79553 at the 18 mg/m2/d dose level. In addition, both individuals could achieve, but had difficulty maintaining, erections (grade 2 erectile dysfunction) during all three courses of LU79553, and one of these subjects developed grade 4 neutropenia associated with fever (course 3) and grade 3 thrombocytopenia (courses 2 and 3). The third subject, a female patient, developed moderate (grade 2) weakness and discomfort of the proximal lower extremities after treatment with five courses of LU79553 at the 14 mg/m2/d dose level. In two of these three patients, serum CPK values were also elevated (peak values, 416 and 417 U/L).
The five patients who developed grade Neither clinical evaluations nor sequential MUGA scanning demonstrated that LU79553, in the cumulative dose range studied, adversely affected cardiac function. Twelve and four patients had MUGA scans performed to assess left ventricular function after treatment with two and four courses, respectively, at cumulative doses ranging from 40 to 240 mg/m2. Two patients also had evaluations performed after treatment with 12 (240 mg/m2) and 20 (1,400 mg/m2) courses. All left ventricular ejection fraction values were within the normal range, and there was no significant differences between pretreatment and posttreatment values (P = .85, Wilcoxon rank sum test). The maximal decrement in left ventricular ejection fraction values in the patients who experienced proximal myopathy was 3%.
Hematologic Toxicity
Miscellaneous Toxicity Nine patients complained of discomfort and inflammation along the course of the peripheral vein used for drug administration (14 courses). Phlebitis occurred in four patients treated with 30-minute infusions of LU79553 (2 mg/m2/d), and five patients in whom progressive dilution and prolongation of infusion time to 3 hours were attempted (4 mg/m2/d [two patients], 10 mg/m2/d [one patient], and 14 mg/m2/d [two patients]). Thereafter, LU79553 was successfully administered through a central venous catheter over 3 hours. LU79553 was mildly emetogenic, with nine (29%) and two patients (6.4%) developing grades 1 and 2 nausea/vomiting, respectively. Mucositis was uncommon, with five patients (16.1%) developing grade 1 toxicity. Other mild to modest nonhematologic toxicities, which were not dose-related, included peripheral edema (grade 1 [three patients] and grade 2 [two patients]), diarrhea (grade 1 [six patients] and grade 2 [three patients]) and transient grade 2 hyperbilirubinemia (peak range, 1.1 to 1.7 mg/dL) in four patients. These toxicities resolved spontaneously and were never responsible for treatment delay.
Antitumor Activity
Pharmacokinetics
LU79553 plasma concentration data were also analyzed using model-dependent methods. After inspection of plasma concentration-versus-time curves, all plasma concentration data encompassing days 1 to 5 were fitted as a single data set using nonlinear least-squares regression. Paired plasma concentration data from days 1 and 5 were available in 18 of 25 patients treated with LU79553 as a 3-hour infusion. Plasma sampling on the terminal disappearance phase of the day 5 plasma profile was insufficient in the remaining seven subjects. Table 5.A three-compartment model was systematically superior than other models in describing plasma concentration-time data sets for 14 of the 18 patients. A representative plasma concentration data set fit to this population model is shown in Fig 4. Pertinent pharmacokinetic parameters for LU79553 derived from this model, which are listed in Table 6, were similar to those derived using noncompartmental methods. The mean Vss, 486.2 ± 252.4 L/m2, was approximately 100-fold greater than that for Vc (mean, 4.1 ± 4.2 L/m2). T1/2  , t1/2ß,and t1/2 values averaged 4.4 ± 5.2 minutes, 1.92 ± 0.48 hours, and 52.6 ± 12.2 hours, respectively. LU79553 exposure during the terminal phase (AUC0-) accounted for approximately 42% of the total AUC. Although study participation was limited to patients with relatively normal hepatic and renal functions, no relationships were evident between Cls and the pretreatment magnitude of elevations in serum transaminases, alkaline phosphatase, and bilirubin levels (R2 = 0.003, 0.018, 0.211, and 0.006, respectively), or pretreatment decreases in creatinine clearance (R2 = 0.089). Similarly, no relationship was observed between body-surface area and Cls (R2 = 0.049).
Seventeen patients had urine collected continuously for 24 hours after treatment on days 1 and 2 and for 48 hours in two consecutive 24-hour collections after treatment on day 5. The fractional urinary excretion of LU79553 was low and dose-independent, averaging 1.5% ± 0.6% and 3.2% ± 3.6% over 24 hours after treatment on days 1 and 2, respectively, whereas 3.0% ± 1.2% and 1.4% ± 0.6% of the total dose of LU79553 were excreted in urine collected from 0 to 24 hours and 24 to 48 hours, respectively, after treatment on day 5.
Pharmacodynamic Studies
Despite many of the unique characteristics of the naphthalimides, evaluations of their potential therapeutic value have been precluded by CNS toxicity (mitonafide) and substantial inter-individual variability in drug metabolism (amonafide). Because bisintercalating compounds generally have greater affinity for DNA and higher potency than mono-intercalating agents,12 the bisnaphthalimides were synthesized and LU79553 was selected for clinical development. The rationale for the development of LU79553 include its unique DNA intercalating properties and mode of topoisomerase II inhibition, high potency, broad antitumor spectrum, and activity against multidrug resistant malignancies.15,17 In contrast to amonafide, many of the physicochemical features of LU79553, particularly the absence of amino group substitution on its naphthalimide ring systems, indicate that the agent would not be a substrate for N-acetylation. Based on the schedule-dependency of LU79553 in well-established human tumor xenografts, with more frequent and divided dosing schedules consistently demonstrating superiority over less frequent dosing schedules, the feasibility of administering LU79553 as a 30-minute IV infusion daily for 5 days every 3 weeks was evaluated in the present study. Although dose-limiting events were not noted in the first two courses of LU79553 in the dosing range evaluated in the study, cumulative neuromuscular toxicity associated with erectile dysfunction was the principal toxicity that precluded repetitive treatment with LU79553 at doses above 18 mg/m2/d. Although higher doses seem to be tolerated for up to two courses, the present study demonstrated that clinically significant neuromuscular effects are likely to occur after additional therapy at LU79553 doses exceeding 18 mg/m2/d. Therefore, based on the results of this study, the recommended dose of LU79553 for subsequent phase II studies is 18 mg/m2/d for 5 days every 3 weeks. However, the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated with multiple courses, mandate that rigorous and long-term toxicologic monitoring of patients be performed in subsequent evaluations. In addition, because of an unacceptably high rate of local venous toxicity that was not ameliorated with standard measures such as dilution of the infusate and prolongation of the infusion duration, central venous access is required for the administration of LU79553, particularly on frequent dosing schedules. The principal dose-limiting effect of LU79553, proximal myopathy, was evident in patients who were treated with more than two courses at doses exceeding 18 mg/m2/d. The clinical, laboratory, and electrophysiologic findings strongly suggested that LU79553 induces a primary myopathic process. Furthermore, the results of ultrastructural studies of muscle biopsies from affected patients, which revealed severe myofibrillarly disruption and pleomorphic cytoplasmic inclusions, support this hypothesis. The myopathy developed after treatment with cumulative LU79553 doses of at least 270 mg/m2 and resolved within 2 to 6 weeks after discontinuation of treatment. Most individuals who developed clinically significant proximal myopathy also experienced erectile dysfunction and moderate to severe myelosuppression, which were readily reversible. Interestingly, the results of serial clinical evaluations, ECGs, and MUGA scans suggested that LU79553, in the dosing range evaluated in the present study, does not significantly depress myocardial function. Proximal myopathy was also reported to be the principal toxicity of LU79553 administered on two other schedules—a single IV infusion every 3 weeks and weekly for 3 weeks every 4 weeks, precluding dose escalation above 100 and 35 mg/m2, respectively.23,24 Interestingly, both myelosuppression and erectile dysfunction were also noted in these phase I studies of alternate dose-schedules. In contrast to the results of the present study, early cardiac toxicity, as manifested by asymptomatic decrements in the left ventricular ejection fraction and/or symptomatic dilated cardiomyopathy, which histologically resembled anthracycline toxicity, occurred in one subject each in these two other studies. Although severe CNS toxicity, characterized by memory loss, disorientation, and cognitive impairment, thwarted the development of the naphthalimide mitonafide,5,27 myopathic effects have not been noted with the naphthalimides.5,6,7,28 On the other hand, the anthracyclines, which also intercalate into DNA and inhibit topoisomerase II, albeit by different mechanisms than LU79553, are well known to induce cardiomyopathy, but are not known to affect skeletal muscles.29 Characteristic histopathologic and ultrastructural findings of the cardiomyopathy include myocyte fragmentation, intracellular inclusion bodies, and mitochondrial swelling.30 Pathophysiologically, several mechanisms for anthracycline-induced cardiomyocyte damage have been demonstrated experimentally such as injury caused by oxidative stress resulting from free radical generation and reduction of endogenous antioxidants that normally scavenge highly reactive chemical intermediates.31-33 One can speculate about the mechanism for the myopathy induced by LU79553. Perhaps one of the most important clues regarding the etiology of this process is that a similar proximal myopathy has been reported in individuals who have ingested large quantities of a structurally-related compound, emetine hydrochloride, an alkaloid derived from the plant Radix ipecacuanhae.34-38 This proximal myopathy has generally been reported in patients who have undergone long-term treatment with emetine hydrochloride for chronic Entamoeba histolytica infections and in individuals with severe eating disorders who have ingested large amounts of ipecac syrup, whose main ingredient is emetine hydrochloride, to intentionally induce emesis.35-38 Afflicted individuals typically complain of weakness and discomfort in their proximal muscles, which usually resolves several weeks after treatment is discontinued.35-38 In most cases, serum concentrations of aminotransferase, CPK, and aldolase are modestly elevated, indicating myocyte damage. Like LU79553 in the present study, electromyographic studies characteristically reveal increased insertional activity, fibrillations, and myopathic motor-unit potentials in the affected proximal musculature, but motor and sensory nerve conduction velocities and repetitive stimulation studies are unremarkable.36 A predominance of type 1 muscle fibers with amorphous eosinophilic intracytoplasmatic rod-like inclusions are usually noted on histopathologic examination of biopsies of the affected muscle. Interestingly, a dilated cardiomyopathy associated with congestive heart failure, arrhythmia, and sudden death, has also been described in patients after emetine ingestion.37,38 Although the precise mechanism of the myopathy induced by emetine is not known, a common finding in the myocardium of rats treated with emetine and the antitumoral agent cycloheximide, which shares the same glutarimide ring as LU79553, and other related glutarimide antibiotics is that the incorporation of leucine into actomyosin and other soluble proteins, which is necessary for muscle contractility, is substantially reduced.39 It has been proposed that the structure-functional basis for the similar inhibitory effects of both emetine and cycloheximide on protein synthesis is a result of the structural similarities of these two agents, particularly with regard to the glutarimide ring system.40 It is of interest that LU79553 glutarimide ring system seems to be responsible for the increased cytotoxic potency of LU79553 as compared with other bisnaphthalimides.1 Hypothetically, drug-induced perturbations of protein synthesis and metabolic processes may be more readily manifested in highly metabolic tissues such as skeletal and cardiac muscles, particularly when agents are widely distributed or preferentially distributed to myofibrillarly elements. Tissue distribution studies in animals treated with14C-labeled LU79553 indicate that LU79553 is widely distributed to peripheral tissues, with high levels of radioactivity in muscles and most other peripheral tissues immediately after treatment that are sustained for 14 days.20 However, there was no preferential distribution or accumulation of LU79553 in muscle. The results of the present study also indicate that LU79553 is extensively distributed to human tissues and has a long terminal half-life. To minimize drug-induced myopathy and other noxious toxicities and to maximize the overall therapeutic index of LU79553, it will be necessary to comprehend the toxicokinetic behavior of the agent, particularly the precise determinants of toxicity. At this juncture, preliminary clinical data indicate that there is a cumulative threshold dose, above which both clinically relevant hematologic and nonhematologic toxicities will likely manifest. In the present evaluation of a daily x5-day administration schedule, moderate to severe myelosuppression and/or myopathy occurred at cumulative LU79553 doses of at least 270 mg/m2. Given the pharmacokinetic profile of LU79553, alternate schedules that are being evaluated, in which the agent is administered as a single injection either every 3 weeks or weekly, were initially anticipated to result in less drug accumulation in peripheral tissues and, consequently, a lower likelihood of developing toxicity in peripheral tissues than a daily x5-day schedule. However, this does not seem to be the case. In the single dosing every 3-week study, grade 3 myopathy was observed in one of two patients receiving cumulative doses exceeding 400 mg/m2, three of five patients receiving cumulative doses of 300 to 400 mg/m2, and one of eight patients treated with cumulative doses below 250 mg/m2.23 With the weekly administration schedule, severe muscle toxicity occurred in patients treated with LU79553 at relatively low cumulative doses (180 mg/m2), albeit relatively high single treatment doses; three patients developed severe myopathy (grade 4 [two patients] and grade 3 [one patient]) after treatment with 60 mg/m2 weekly x3.24 From both therapeutic and toxicologic standpoints, the optimal administration schedule for LU799553 is not known at this time. However, the results of the present and other phase I studies indicate that the magnitude of both the single treatment dose and the total cumulative dose may be important determinants of toxicity. Another potential important toxicologic determinant is dose-intensity, which can be modified by prolonging the dosing interval to facilitate clearance of drug from muscle and peripheral tissues and to decrease drug accumulation in peripheral tissues. The impressive antineoplastic activity observed in a patient with a platinum- and taxane-resistant peritoneal carcinoma who received 20 total courses of LU79553 at 14 mg/m2/d to a cumulative dose of 1,400 mg/m2 without significant toxicity suggests that further studies of determinants of toxicity and activity are necessary to optimize the therapeutic index of this unique agent and the bisnaphthalimides in general.
Supported in part by a grant From Knoll Pharmaceutical Company and National Institutes of Health grant no. MO1 RR01346 to the Frederick C. Bartter Clinical Research Unit of the Audie Murphy Veterans Administration Hospital.
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ABSTRACT
INTRODUCTION
), CLs, Vss,and the volume of distribution for the central compartment (Vc). Values are reported as means ± SD. 
