Pharmacokinetic and Toxicity Scaling of the Antitumor Agents Amsacrine and CI-921, a New Analogue, in Mice, Rats, Rabbits, Dogs, and Humans'

Home , Amsacrine

[CANCER RESEARCH 50. 2692-2697, May I, 1990] Pharmacokinetic and Toxicity Scaling of the Antitumor Agents Amsacrine and CI-921, a New Analogue, in Mice, Rats, Rabbits, Dogs, and Humans'

James VV.Paxton,2 Sang N. Kim, and Lloyd R. Whitfield

Department of Pharmacology and Clinical Pharmacology [J. W. P.], University of Auckland School of Medicine, Private Bag, Auckland, New Zealand; and Parke-Daris Pharmaceutical Research Division, Warner-Lambert Company /S. N. K., L. R. W.], Ann Arbor, Michigan 48105

ABSTRACT (CI-921) are novel antitumor agents with similar structures (Fig. 1). Amsacrine has an established role in the treatment of The aim was to investigate interspecies relationships between body leukemia (1). An analogue of amsacrine, CI-921, was synthe weight (W) (kg) and various pharmacokinetic parameters for the antitumor agents amsacrine and its 4-methyl-5-(/V-methylcarboxamide) an sized in the Auckland Cancer Research Laboratory in an at tempt to develop an agent with greater solid tumor activity. CI- alogue, CI-921, and examine which pharmacokinetic parameter, if any, might be used to predict the toxicity of these agents. Pharmacokinetic, 921 showed significantly greater activity in both in vitro and in plasma protein binding, and toxicity data were available for CI-921 in vivo solid tumor test systems (2) and has recently completed mice, rats, rabbits, dogs, and humans. For amsacrine, similar interspecies Phase I clinical trials with encouraging results (3). Phase II pharmacokinetic data were available but toxicity and protein-binding trials in patients with specific tumors are now under way. Both data were available for only 3 species. Significant linear relationships agents appear to act by inducing the formation of covalent links were obtained for CI-921 between log W and log Vâ€ž(liters)(r = 0.971, between DNA and the enzyme topoisomerase II (4). P = 0.006), and log W and log Cl (liters/h) (r = 0.911, P = 0.031) resulting in the allometric equations F,, = \.22W*M and Cl = 0.91 W051. It is important in cancer chemotherapy to be able to deter For amsacrine these corresponding equations were fâ€ž= 3.37W701"(r = mine from preclinical pharmacological studies an appropriate 0.996, P < 0.001), and Cl = 2.28WÂ«M(r = 0.952, P = 0.012). When safe starting dose for humans which also maximizes the chance that the dose an individual receives has therapeutic potential. interspecies differences in plasma protein binding were taken into ac count, the allometric relationships improved and the exponents of the This is of particular importance with anticancer drugs which power equations increased. For CI-921 the allometric equations for the usually exhibit an extremely narrow therapeutic index. Typi kinetic parameters calculated from plasma "free" concentrations were: cally with antineoplastic agents, a biologically inactive dose y,^ (liters) = 24TWÂ°-n(r = 0.984, P = 0.002) and Clu (liters/h) = may be within 1 log of a lethal dose. The aim of this retrospec 186 W"' (r = 0.961, P = 0.009). The dog was a noticeable outlier in the tive study was to investigate interspecies relationships between relationship between the log maximum tolerated dose (MID) (mg/kg) of the various pharmacokinetic parameters and body weight, and CI-921 and log II. Omission of the latter resulted in a highly significant allometric relationship, MTD = 23.6 ff"""1 (r = -0.988, P = 0.012). For examine which pharmacokinetic parameter, if any, might be used to predict the toxicity of these agents. amsacrine there was no significant allometric relationship between MTD and W. CI-921S prolonged r,, in the dog and the dog's increased suscep tibility to CI-921 toxicity suggested a relationship between MTD and f.,, MATERIALS AND METHODS (h). A significant linear relationship was observed between In MTD and t* (r = -0.994, P < 0.001), from which the following equation was Toxicity Data. Toxicity data were obtained in animals after a single developed i.v. dose of amsacrine (5) or CI-921.3-4 The biological end point was MTD = 47.5e-Â«-5"Â» the lethal dose in 10% of mice and the highest nonlethal dose (i.e., the MTD) in rats, rabbits, and dogs. The MTD in humans was obtained from Phase I trials using a single i.v. dose treatment schedule (6, 7). Combining the amsacrine toxicity data in the latter relationship yielded Pharmacokinetic Data. Pharmacokinetic data were available for am a similar equation sacrine in patients (8), dogs,4 rabbits (9), rats (10), and mice (11); and MTD = 44.7e-05"" for CI-921 in patients (12), dogs,4 rabbits (13), rats," and mice (11). Plasma concentrations of amsacrine and CI-921 were measured by (r = -0.933, P < 0.0001). It was concluded that allometric equations high-performance liquid chromatography methods using UV absorb- may be developed for CI-921 and amsacrine from animal pharmacokinetic ance or electrochemical detection (11. 14-16). Determination of am data Â»hii-liallow a reasonable prediction of Cl and yâ€žinpatients, despite sacrine in the rat was by extraction of unchanged ['4C]amsacrine (10). these agents being eliminated mainly by biotransformation. However, The pharmacokinetic parameters, plasma clearance (Cl), and volume similar relationships between toxicity and body weight were susceptible of distribution at steady state (Kss)were estimated by noncompartmental methods based on statistical moment theory (17). The elimination half- to variation between individual species. Species differences in the toxicity of these agents were predictable from the r.,. This study emphasized the life (/i/,)was calculated from In 2 divided by the slope of the terminal linear portion of the log concentration-time profile, estimated by un importance of pharmacokinetic data in preclinical toxicity and efficacy weighted least squares regression. The plasma unbound fraction (fu) testing of antitumor agents. was determined by equilibrium dialysis using [I4C]CI-921 (18) or [I4C]- amsacrine (19, 20). Plasma protein binding data for amsacrine were INTRODUCTION not available for rat or dog. Clearance (Clu) and the volume of distri bution of the unbound CI-921 (F5S/)were calculated from Cl, Vss,and jV-[4-(9-Acridinylamino)-3-methoxyphenyl]methanesulfon- /Â«- amide (amsacrine) and 9-||2-methoxy-4-[(methylsulfonyl) The power equation (or equation of simple allometry) amino]phenyl|amino|-N,5-dimethyl-4-acridinecarboxamide Y= Received 10/3/89; revised 12/27/89. The costs of publication of this article were defrayed in part by the payment 'The abbreviations used are: CI-921, 9-| |2-methoxy-4-[(methyl-sulfonyl) of page charges. This article must therefore be hereby marked advertisement in amino]phenyl|amino||-A'-5-dimethyl-4-acridinecarboxamide; MTD, maximum accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tolerated dose (mg/kg). 1Supported by the Medical Research Council of New Zealand and the Parke- 4 Unpublished data on file at Parke-Davis Pharmaceutical Research Division, Davis Pharmaceutical Research Division. Warner-Lambert Company. Ann Ar Warner-Lambert Company. Ann Arbor, MI 48105 (mice, rats, and dogs) and at bor, MI. Department of Pharmacology and Clinical Pharmacology, University of Auckland 1To whom requests for reprints should be addressed. School of Medicine, Auckland, New Zealand (rabbits). 2692

NHSO-CH.,

Fig. 1. Structures of amsacrine and Cl-921.

CONHCH, was applied to the relationships between MTD (mg/kg) and mean body weight (WOand between various pharmacokinetic parameters and W. 100 This equation may also be written in the form

log Y = log a + b log W HUMAN where Y is the MTD (or pharmcokinetic variable), log a is the Y- intercept, and b is the slope of the log Y versus log H7relationship. The 01 1.0 power equation was fitted to data by least squares linear regression, and Student's t test was used to determine if the slope (b) of the log Y versus log W linear relationship was significantly different from zero (i.e., P < 0.05). The same methods were used to fit the exponential equations and test their significance. 0.01 0.01 0.1 RESULTS r = 0.91 1 Kinetic Data. Table 1 summarizes the mean CI-921 pharma p = 0.031 0.51 cokinetic parameters normalized to body weight and mean body CI=0.91W HUMAN weight of the five species studied. When normalized to weight, 10 humans, and rabbits had similar small values for Vssof CI-92 1. Overall there was a 14-fold range in Fss, from 0.3 liter/kg (rabbit and human) to 4.3 liters/kg in the mouse. When the Cl RABBIT of CI-921 was normalized to body weight, there was a 28-fold range across species. Humans, rabbit, and dog all had similar 'MOUSE low values, i.e., 0.16, 0.19, and 0.22 liter/h/kg, respectively. The greatest Cl value was observed in the mouse, 4.46 liters/h/ kg. An 11-fold range (0.6-6.7 h) was observed for i./, of CI-921 0.01 1.0 100 with the dog having the longest />/,.There were significant linear WEIGHT (kg) relationships between the log W (kg) and log Kss(liters), and Fig. 2. Log-log plot for CI-921 of (A) Vâ€žversusspecies body weight, and (B) log Cl (liters/h) (Fig. 2), but not between log W and log tv, (h). Cl versus body weight. . least squares linear regression line. The allometric equations for these relationships were kinetic parameters based on the plasma free concentration (Fig. = 1.22 (A) 3). The allometric equations for the latter were

(r = 0.97 \,P = 0.006), and y^ = 247 W0" (C) Cl = 0.91 W051 (B) (r = 0.984, P = 0.002), and (r = 0.911, P = 0.031). CI-921 is highly protein bound in CIu = 186W076 plasma. The 10-fold range (0.001-0.011) in the plasma free (D) fraction of CI-921 across species may affect the relationships (r= 0.961, P = 0.009). between body weight and Cl, and Vx, which are based on total The mean amsacrine pharmokinetic parameters normalized plasma concentrations (i.e., bound plus free). Improved allo to body weight and mean body weights are reported in Table 2. metric relationships were obtained between body weight and Amsacrine Kssvalues normalized to body weight were greater than those for CI-921. However, the rank order of Fss values Table 1 Mean CI-921 pharmacokinetic parameters, free plasma fractions, and body weights for various mammalian species across species was the same, with the largest Fssvalue observed Body wt Dose0 Cl fÂ» in the mouse (7.4 liters/kg) and the smallest in the rabbit (1.7 Species (kg) (mg/kg) (liters/kg) (liters/h/kg) (h) liters/kg) and human (1.6 liters/kg). The overall range of Fss MouseRatRabbitDogHuman0.0210.434.610.570.56.70.1-3.03.00.1-3.00.3-6.54.311.980.321.000.324.463.950.190.220.160.60.61.76.72.60.00900.01070.00320.00380.001values across species was less for amsacrine (5-fold) than for CI-921. In contrast, the overall range of Cl values normalized to body weight was considerably larger (83-fold) for amsacrine, 1 with humans having the lowest (0.26 liter/h/kg) and mouse â€¢Freebase. (21.6 liters/h/kg) the highest clearance. There was a 32-fold 2693

relationship. Omission of the dog datum resulted in an excellent linear relationship (r = -0.988, P = 0.012) between log MTD (mg/kg) and log H7(kg) for CI-921. The allometric equation for this relationship was MTD = 23.6 ff-014 (H)

Toxicity data for amsacrine after a single i.v. dose were available only for mice, dogs, and humans (Fig. 6). A significant allo metric relationship for the MTD of amsacrine was not observed. The prolonged tv, for CI-921 in the dog and the dog's appar ently increased susceptibility to CI-921 toxicity suggested that there may be a relationship between MTD (mg/kg) and tv, (h).

0.0 Â¡ 0.1 1 10 An arithmetic plot of MTD versus f./, suggested that an expo nential relationship may be appropriate. Transforming MTD WEIGHT (kg) to In values gave a significant linear relationship with tv, values for CI-921 (r = -0.994, P = 0.0006). From this log-linear 100000 r = 0.961 relationship the CI-921 MTD could be expressed as MTD = 47.5e>-Â°-5"Â» p = 0.009 (I) 10000 O HUMAN Clu = 186W ÃŽ r = 0.996 3 1000 1OOO â€¢DOG p < 0.001 RABBIT 0 Vss = 3.37W 0 10Â° 100

0.01 0.1 100 WEIGHT (kg) 1.0 Fig. 3. Log-log plot for CI-921 of (A) V^ versus species body weight, and (B) Clu versus species body weight. , least squares linear regression line. 0.1 0.01 0.1 1.0 10 Table 2 Mean amsacrine pharmacokinetic parameters, free plasma fractions, and body weights for various mammalian species r =0.952 wt p^ 0.01 2 C SpeciesMouse(kg)0.020 CI = 2.28W NAC Rat* 0.28 10.0 4.5 5.00 0.5 Rabbit 4.2 2.5 1.70 0.46 2.6 0.0278 Dog 10.5 3.0 2.80 0.97 6.54.7/Â«0.0672NA HumanBody81.3Dose"(mg/kg)4.53.8-5.6YÂ»(liters/kg)7.421.56a(liters/h/kg)21.590.26fe(h)0.2 0.0298 " Free base. * RABBIT * Calculated from the graph in Ref. 10. 1.0 ' NA. not available. MOUSE range in amsacrine /./, values across species. The log-log plots 0.1 of the pharmacokinetic parameters of the amsacrine versus body 0.01 0.1 1.0 10 100 weight are shown in Figs. 4 and 5. Significant linear relation WEIGHT (kg) ships were obtained between log W (kg) and log F55(liters) (r = Fig. 4. Log-log plot for amsacrine of (A) Kâ€žversusspecies body weight, and 0.996, P = 0.0003), log CI (liters/h) (r = 0.952, P = 0.0124), (A) Cl versus body weight. . least squares linear regression line. and log tv, (h) (r = 0.950, P = 0.0135) and the following allometric equations were established: 10 r = 0.950 DOG YÂ»= 3.37 W08' (E) p = 0.013 0.44 Cl = 2.28 W046 (F) RABBIT tÂ»= 1.15 W" (G)

The plasma free fraction for amsacrine was significantly greater â€” 1.0 than that for CI-921 (7.5-fold for the mouse, 8.7-fold for the rabbit, and 27-fold for humans). Because these data were avail * RAT able for only three species (Table 2), allometric relationships for kinetic parameters based on plasma free concentrations of MOUSE amsacrine were not investigated. 0.1 Toxicity Data. The MTD for CI-921 and amsacrine and mean 0.01 0.1 10 100 body weight for various species are reported in Table 3. The WEIGHT(kg) relationship between log MTD for CI-921 and log W K shown Fig. 5. Log-log plot for amsacrine of tv,versus species body weight. , least in Fig. 6. The dog datum was a noticeable outlier in this squares linear regression line. 2694

There were no significant linear relationships between MTD as basal oxygen consumption, liver weight, and creatinine clear and KÂ«,orCl on either rectilinear or log scales. Similar results ance) can be scaled as an exponential function of body weight were observed for amsacrine with a significant linear relation (21). Pharmacokinetic parameters are a reflection of the com ship (r = -0.998, P = 0.041) only between In MTD and i*, plex relationships between anatomical, biochemical, and phys represented by iological variables that govern drug disposition. Similarly, phar- MTD = 37.0iT0-501Â» macokinetic parameters may also be scaled from species to (J) species. One example of a particularly successful scale-up of The similarity of the latter equations suggested combining the animal data to humans has been methotrexate (22). data for CI-921 and amsacrine (Fig. 7). The resulting equation Of the pharmacokinetic parameters studied, the most statis from the combined data was tically significant allometric relationships reported in the liter MTD = 44.7e>-Â°-5"* (K) ature have been for the volume of distribution. The exponents of the allometric equations for most drugs (e.g., methotrexate, (r =-0.933, P < 0.0001). cyclophosphamide, phencyclidine, and antipyrine) were >0.9, indicating that volume of distribution was almost directly pro DISCUSSION portional to body weight (i.e., exponents approaching unity) (23-25). For amsacrine and CI-921, the exponents were lower There are many similarities in the anatomy and physiology of mammalian species, and many physiological processes (such (0.81 and 0.68, respectively) indicating that the volume of distribution did not increase across species in direct proportion Table 3 Toxic dose (mg/kg) and body weight (kg) for CI-921 and amsacrine to weight. Thus, the larger animal, such as humans, had a across species smaller than expected volume of distribution. This is, at least Species in part, due to species differences in plasma protein binding as DrugCI-921AmsacrineParameterWt judged by the relationship between body weight and volume of (kg) distribution calculated from the free CI-921 concentration in Toxic dose(mg/kg)Wt 420.022 30NAÂ° 17.7NANADog9.51.610.5 1466 plasma, which gave an allometric equation with an exponent of 0.93. Thus the volume of distribution calculated from unbound (kg) Toxic dose (mg/kg)Mouse0.02034.6Rat0.22NARabbit4.25 1.6"Human62.33.1 drug (i.e., independent of plasma protein binding) is almost Â°NA, not available. directly proportional to body weight. With clearance, the scal * Lowest dose which produces drug-induced pathological alterations in hema- ing from animals to humans appears to be relatively successful tological, chemical, clinical, or morphological parameters (5). for renally excreted compounds (26-29). Interspecies scaling is less successful when biotransformation is the primary mecha -0.14 r =0.988 MTD=23.6W nism for drug elimination. Different metabolites and different p = 0.012 rates and extent of metabolism may occur in different species 100 (30). Evidence indicates that both CI-921 and amsacrine are MOUSE eliminated primarily by metabolism in the liver and excretion in the bile in most species (8, 10-12, 31). Interspecies scaling of drugs that are eliminated by biliary excretion may not be O) RABBIT 5 10 successful because biliary excretion of xenobiotics may be vari able across species (32, 33). The allometric relationship for clearance may also have been complicated by the dose-depend

0 HUMAN ent kinetics exhibited by CI-921 (11, 13)4 and amsacrine (9- 11). To minimize this, CI-921 and amsacrine kinetic data were Â«ODOG utilized from the lowest dose. Another potential complicating

0.01 0.1 1.0 10 100 factor in the scale-up of antitumor agent data from animals to humans is that the kinetics and toxicity studies were undertaken WEIGHT (kg) in normal healthy animals, whereas the human studies were in Fig. 6. Log-log plot of MTD versus species body weight for CI-921 (*) and amsacrine (O). , least squares linear regression line for the CI-921 data patients with cancer. There are a number of reports of impaired (excluding the dog datum point). hepatic drug metabolism in tumor-bearing animals (34-37) and altered pharmacokinetics in cancer patients (38-41); however, ,,-0.993 we observed no significant difference in the plasma kinetics of p < O.OO01 either CI-921 or amsacrine in normal mice compared to mice 1OO -0.51tj MTD 44.7e with a s.c. Lewis lung tumor (11). Despite these complicating factors, there were significant linear relationships between log Cl and log W, resulting in RAT power equations with exponents of 0.51 and 0.46 for CI-921 at HUMAN E and amsacrine, respectively. These exponents are lower than reported for other drugs, which ranged from 0.57 to 1.37 with most clustered between 0.6 and 0.8 (21-24). Low allometric exponents (0.54 and 0.41) have been reported for the clearance DOG of 0-lactam antibiotics, cefotetan and cefpiramide, and it was 1.0 suggested that a low exponent might be characteristic of biliary 1.5 excretion (42). However, as with volume of distribution, the linear relationship improved and the exponent of the power Fig. 7. Log-linear plot of MTD versus rw for CI-921 (*) and amsacrine (O). equation rose to 0.76 when plasma clearance of unbound drug â€”,least squares linear regression line. was substituted for total plasma clearance of CI-921. 2695

Hardy. J. R.. Harvey, V. J.. Paxton. J. W., Evans. P. C.. Smith. S.. Grove. With regard to the hybrid kinetic parameter, f,,, a significant \V.. Grillo-Lopez, A. J.. and Baguley. B. C. A phase 1 trial of the amsacrine allometric relationship was observed for amsacrine and not for analog 9-[|2-methoxy-4-|(methylsulfonyl)amino]phenyl]amino]-.V,5-di- CI-921. Particularly noticeable for CI-921 was the long f./; in methyl-4-acridine carboxamide (CI-921 ). Cancer Res.. 48:6593-6596. 1988. the dog which, along with the dog's intolerance to CI-921, Covey. J. M., Kohn. K. W., Kerrigan, D., Tilchen, E. J.. and Pommier. V. Topoisomerase Il-mediated DNA damage produced by 4'-(9-acridinylam- suggesting a relationship between toxicity and t.,. An excellent ino)methancsulfon-m-anisidide and related acridines in LI210 cells and allometric relationship was observed for the MTD for CI-921 isolated nuclei: relation to cytotoxicity. Cancer Res.. 48: 860-865. 1988. Henry. M. C.. Port, C. D.. and Levine. B. S. Preclinical toxicologie evaluation between mouse, rat, rabbit, and humans; however, the dog was of 4'-(9-acridinylamino)methanesulfon-/Â«-anisidide (AMSA) in mice, dogs strikingly different, emphasizing the hazards of attempting and monkey. Cancer Treat. Rep., 64: 855-860. 1980. direct allometric extrapolation of toxicity across species without Von Hoff. P. D.. Howsa, D., Gormley, P.. Bender, R. A., Glaubiger. D.. Levine, A. S.. and Young, R. C. Phase I study of methanesulfonamide, N- regard to other factors such as pharmacokinetics. A more |4-(9-acridinylamino)-3-methoxyphenyl]-(m-AMSA) using a single-dose predictive, yet empirical relationship (incorporating data from schedule. Cancer Treat. Rep.. 62: 1421-1426, 1978. Robert. F.. Mignucci, M., Grove, W., Javier. J.. Asmar, S., and Grillo-Lopez. all species investigated) was obtained between the In MTD (mg/ A. Phase I study of CI-921: single dose schedule. Proc. Am. Soc. Clin. kg) and /., (h), allowing the development of a simple exponential Oncol.. 6: 26. 1987. equation in which the MTD for CI-921 was expressed as a .Ini Â¡ni.iJ. L.. Varcoe, A. R.. and Paxton. J. W. Pharmacokinetics of amsa crine in patients receiving combined chemotherapy for treatment of acute function of e (the base of natural logarithms) raised to a constant myelogenous leukemia. Cancer Chemother. Pharmacol.. 14: 21-25, 1985. x /,/,. Paxton. J. W.. and Jurlina. J. R. Elimination kinetics of amsacrine in the rabbit: evidence of non-linearity. Pharmacology.31: 50-56. 1985. MTD = 47.5-05"Â» 13. kinetics of ,V-5-dimethyl-9-|(2-methoxy-4-methylsulphonylamino)phcnyl- amino]-4-acridinecarboxamide (CI-921 ) in rabbits. Cancer Chemother. Phar After omitting the human data from this relationship, the macol.. 20: 13-16, 1987. 14. Jurlina. J. I... and Paxton, J. W. High-performance liquid Chromatographie equation was recalculated as method for the determination of 4'(9-acridinylamino)methanesulphon-m- MTD = 43.4Ã•-0-5"* anisidide in plasma. J. Chromatogr.. 276: 367-374, 1983. (L) 15. Jurlina. J. L., and Paxton. J. W. A high-performance liquid Chromatographie assay for plasma concentrations of A'-5-dimethyl-9-[(2-methoxy-4-methyl- Using the latter equation to estimate the MTD for CI-921 in sulfonylamino)phenylamino]-4-acridineearboxamide. J. Chromatogr.. 342: patients, we obtained a value of 11.5 mg/kg (approximately 431-435. 1985. 16. \\hitfield. L. R.. Tucker. E., Ferry. J.. Chang. T.. Showalter. H., and 470 mg/irr), which is of magnitude similar to the MTD ob Malspeis, L. Development of an HPLC assay with electrochemical detection served (648 mg/nr) after a single dose in patients (7). of CI-921 in human plasma. Proc. Am. Assoc. Cancer Res., 28: 195. 1987. 17. Gibaldi. M.. and Perrier, D. Pharmacokinetics. Ed. 2. New York: Marcel In conclusion, this retrospective study has emphasized the Dckkcr. Inc.. 1982. importance of pharmacokinetics in preclinical toxicity and ef 18. Andress. L.. Chang. T.. and \\hitfield. L. Characterization of CI-921, the amsacrine analog, binding to human plasma and plasma proteins. Pharm. ficacy testing of anticancer agents. Even with agents such as Res., 5.-S-2I5. 1988. amsacrine and CI-921 which are highly bound in plasma and 19. Paxton. J. W., Jurlina. J. L.. and Foote. S. E. The binding of amsacrine to which are eliminated mainly by metabolism and biliary excre human plasma proteins. J. Pharm. Pharmacol.. 38: 432-438. 1985. tion, it appeared possible to extrapolate animal pharmacoki- 20. Paxton, J. \V., and Jurlina. J. L. Comparison of the pharmacokineties and protein binding of the antieancer drug, amsacrine and a new analogue. A'-S- netic data to patients using allometry. Prediction of the mag dimethyl-9-|(2-methoxy-4-methylsulfonylamino)phenylamino-4-aeridinecar- nitude of K,sand Cl values in humans would allow estimation boxamide in rabbits. Cancer Chemother. Pharmacol.. 16: 253-256, 1986. 21. Davidson, 1. W. F., Parker. J. C, and Beliles. R. P. Biological basis for of a more appropriate starting dose which might result in extrapolation across mammalian species. Regul. Toxicol. Pharmacol.. 6: potential savings in escalation steps during Phase 1 clinical 211-237. 1986. testing and also would maximize the chance that the dose which Dedrick. R. L.. Bischoff. K. B., and Zaharko, D. S. Inlerspccies correlation of plasma concentration history of methotrexate (NSC-740). Cancer Chem an individual receives had the potential for therapeutic value. other. Rep. Part 1. 54: 95-101. 1970. This study also demonstrated the hazards of allometric extrap 23. Boxenbaum. M. Interspccies pharmacokinetic scaling and the evolutionary- olation of toxicity data from one species to another without comparative paradigm. Drug Metab. Rev.. 15: 1071-1121. 1984. 24. Ritschel. W. A., and Banerjee. P. S. Physiological pharmacokinetic models: regard to other factors such as pharmacokinetics. In addition, principles, applications, limitations and outlook. Methods Find. Exp. Clin. this study suggested that tVlis a reasonable predictor of the Pharmacol.. 8: 603-614. 1986. 25. Owens, S. M.. Hardwick. VV.C.. and Blackall. D. Phencyclidine pharmaco toxicity of amsacrine analogues in different species. kinetic scaling among species. J. Pharmacol. Exp. Thcr., 242: 96-101. 1987. 26. Duthu. G. S. Interspecies correlation of the pharmacokinctics of erythromy- cin. oleandomycin, and tylosin. J. Pharm. Sci., 74: 943-946. 1985. ACKNOWLEDGMENTS 27. Mordenti, J. Dosage regimen design for pharmaceutical studies conducted in animals. J. Pharm. Sci.. 75: 852-856, 1986. Thanks are extended to Dorothy Vance for typing the manuscript. Boxenbauni. N. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinelics. J. Pharmacokinet. Biopharm.. 10: 201- 227, 1982. REEERENCES 29. Mordenti. J. Pharmacokinctic scale-up: accurate prediction of human phar macokinetic profiles from animal data. J. Pharm. Sci.. 74: 1097-1099, 1985. 1. Arlin. Z. A. Current status of amsacrine combination chemotherapy pro 30. Dedrick. R. L.. and Bischoff. K. B. Species similarities in pharmacokinetics. grams in acute leukemia. Cancer Treat. Rep.. 67: 967-970. 1983. Fed. Proc.. 39: 54-59. 1980. 2. Baguley. B. C.. Denny. \V. A., and Alwell, G. H. Synthesis, antitumour 31. Robertson. I. G. C.. Kestell. P.. Dormer. R. A., and Paxton. J. W. Involve activity, and DNA binding properties of a new derivative of amsacrinc. iV-5- ment of glutathione in the metabolism of the anilinoacridine antitumor agents dimethyl-9-[(2-methoxy-4-mcthylsulfonylamino)phenylamino]-4-acridine CI-921 and amsacrine. Drug Metab. Drug Interact., 6: 371-381, 1988. carboxamide. Cancer Res.. 44: 3245-3251. 1984. 32. Klaassen. C. D.. and Watkins. J. B. Mechanisms of bile formation, hepatic 2696

uptake, and biliary excretion. Pharmacol. Rev.. 36: 1-69. 1984. 38. Higuchi. Z., Nakamura. T., and Uchino. H. Amipyrine metabolism in cancer 33. Mizen, L., and Woodnutt. G. A critique of animal pharmacokinetics. J. patients. Cancer (Phila.), 45: 541-544, 1980. Antimicrob. Chemother., 21: 273-280. 1988. 39. Teunissen. M. W. E.. Willemse, P. H. B.. Sleijfer. D. T., Sluiter. W. J., and 34. Sladek. N. E.. Domeyer. B. E.. Merriman. R. L.. and Brophy, G. T. Differ- Breimer. D. D. Antipyrine metabolism in patients with disseminated testic- ential effects of Walker 256 carcinosarcoma cells growing subcutaneously. ular cancer and the influence of cystostatic treatment. Cancer Chemother. intra-muscularly. or intraperitoneally on hepatic microsomal mixed-function Pharmacol.. 13: 181-185, 1984. oxygenase activity. Drug Metab. Dispos.. 6:412-417. 1978. 40. Bryson, S. M.. McGovern, E. M., Kelman. A. W., White, K., Addis, G. J., 35. Donelli, M. G., D'Incaici, M., and Garattini, S. Pharmacokinetic studies of and Whiting. B. The pharmacokinetics of high dose metoclopramide in anticancer drugs in tumor-bearing animals. Cancer Treat. Rep., 68:381-400. patients with neoplastic disease. Br. J. Clin. Pharmacol., 19: 757-766, 1985. 1984. 41. Relling. M. V.. Crom, W. R., Pieper. J. A., Cupit. G. C, Rivera. G. K.. and 36. Dogra, S. C., Khanduja, K. L., and Sharma, R. R. Hepatic drug-metabolising Evans, W. E. Hepatic drug clearance in children with leukemia: changes in enzymes in lung tumor-bearing rats. Biochem. Pharmacol., 34: 3190-3193, clearance of model substrates during remission-induction therapy. Clin. 1985. Pharmacol. Ther., 4/: 651-660, 1987. 37. Powis. G.. Harris, R. N., Basseches, P. J., and Santone. K. S. Effects of 42. Sawada. Y., Hanano. M., Sugiyama, V'., and Iga. T. Prediction of the advanced leukemia on hepatic drug-metabolizing activity in the mouse. disposition of/^-lactam antibiotics in humans from pharmacokinetic param- Cancer Chemother. Pharmacol., 16: 43-49. 1986. eters in animals. J. Pharmacokinet. Biopharm.. 12: 241-261, 1984.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1990 American Association for Cancer Research. Pharmacokinetic and Toxicity Scaling of the Antitumor Agents Amsacrine and CI-921, a New Analogue, in Mice, Rats, Rabbits, Dogs, and Humans

James W. Paxton, Sang N. Kim and Lloyd R. Whitfield

Cancer Res 1990;50:2692-2697.

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