[CANCER RESEARCH 47, 6297-6301, December 1, 1987]

Comparative Pharmacokinetics of Cisplatin and Three Analogues in Mice andHumans1

Maaike B. van Hennik,2 Wim J. F. van der Vijgh, Ina Klein, Frits Elferink, Jan B. Vermorken, Benjamin Winograd,

and Herbert M. PinedoDepartment of Oncology, Free University Hospital, P. O. 7057, 1007 MB Amsterdam, The Netherlands

ABSTRACT

Pharmacokinetics of cisplatin, spiroplatin, ethylenediaminemalonato-platinum(II) (.1X1-40),and carboplatin was studied in BALB/c x DBA/2F, mice receiving 10% lethal doses of 15.S, 6.8, 100, and 165 mg/kg,respectively. Blood samples were collected for up to 5 days after a singlei.v. bolus injection.

Total platinum in plasma and non-protein-bound free platinum inplasma ultrafiltrate were determined by flameless atomic absorptionspectrometry. Parent JM-40 and carboplatin were determined by highperformance liquid chromatography. Calculated pharmacokinetic parameters (peak concentrations, half-lives, areas under the curve) were compared with the corresponding values in patients at the maximal tolerateddose. Peak plasma concentrations were 2.4- to 20-fold higher in micethan in humans. Initial and terminal half-lives in mice were up to 6 timesshorter than in patients. However, the areas under the plasma concentration versus time curves (AUCs) were found to agree. The ratios of theAUCs of free platinum in patients (AUC,) and mice (AUG.) measuredover the first part of the plasma concentration versus time curve were1.2, 0.3, 1.1, and 0.9 for cisplatin, spiroplatin, JM-40, and carboplatin,respectively. These values changed to 1J, 03, 2.5, and 1.0 when the timeinterval was extended to free platinum levels just above the detectionlimit. Ratios of the AUCs of total platinum in patients and mice measuredover 5 days were 2.7, 2.6, 4.2, and 1.8, respectively. Using a ratio of 1for free platinum originating from JM-40, the retrospectively calculatedmaximal tolerated dose from AUCP at low dosages was 1021 mg/m2 (n= 7; range, 836-1282), compared to 1200 mg/m2 as found in the phase I

trial. This suggests that the AI ( P/M ( mratio of free platinum over thefirst part of the concentration venus time curve can possibly be used topredict the maximal tolerated dose of platinum analogues in humans,during the early stage of phase I studies.

INTRODUCTION

The principal objective of phase I studies is to determine theMTD3 and to establish the dose to study the efficacy of ananticancer drug in phase II studies (1-3). It is important for theindividual patient and for the development of anticancer drugsin general to proceed as fast as possible and yet safely with thedose escalation procedure.

Presently, only the entry dose in phase I trials is based onpreclinical toxicology data. In most protocols one tenth of themouse equivalent LDi0 or less is used (4). The subsequentprocedure to reach the MTD is empirical and often leads to alarge number of dose escalation steps, in particular when theMTD is far removed from the starting dose.

Preclinical pharmacokinetic studies may be of help in decreasing the number of dose escalations in phase I studies andmay give this procedure a more rational basis. Several investigators suggested that the AUC (or C x t) might be a good

Received 5/11/87; accepted 8/17/87.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.

1The investigations were supported by the Koningin Wilhelmina Fonds (Netherlands Cancer Foundation) by Grants AUKC 82-6 and 86-3.

' To whom requests for reprints should be addressed.3The abbreviations used are: MTD, maximal tolerated dose; LDio, 10% lethal

dose; AUC, area under the plasma concentration versus time curve; JM-40,ethylenediaminemalonatoplatinum(II).

parameter for transcription of preclinical toxicology data intoclinical predictions (3, 5-7). It has been suggested that the C xt at the LDio in mice and at the human MTD might be similar.Retrospective studies showed that for a number of anticancerdrugs this hypothesis proved to be valid (7).

The objective of the present study was to compare the phar-macokinetics of cisplatin and three analogues (spiroplatin, JM-40, and carboplatin) in mice with data previously obtained inpatients, giving special attention to the C x t concept.

MATERIALS AND METHODS

Drugs. Cisplatin solution [m-diamminedichloroplatinum(II)] wasprepared from standard vials of Platino! [Bristol Myers Company,Weesp, The Netherlands] by reconstitution with sterile water to aconcentration of 2 mg/ml for the LD,0 studies and to 1.92 and 2.14mg/ml for the pharmacokinetic studies. Spiroplatin (TNO-6; aquated[l,l-bis(aminomethyl)cyclohexane]sulfatoplatinum(II) was supplied byBristol Myers (Brussels, Belgium). Solutions of 1 mg/ml were preparedin 5% glucose. JM-40 was supplied by Johnson Matthey ResearchCentre (Reading, Berkshire, United Kingdom) and formulated by T. J.Schoemaker, pharmacist at the Netherlands Cancer Institute, Amsterdam, The Netherlands. The drug was dissolved in sterile water toconcentrations of 8.19 mg/ml for LDio studies and 7.08 mg/ml forpharmacokinetic studies. Carboplatin [diammine( 1,1-cyclobutanedicar-boxy-lato)platinum(II)] was supplied by Bristol Myers (Brussels, Belgium). From the formulation of ISO mg/vial, solutions were made insterile water to concentrations of 15.2 and 16.5 mg/ml for 1.1),„studiesand 15.3 and 17.3 mg/ml for pharmacokinetic studies.

Animals. Male BALB/c x DBA/2 F, (hereafter called CD2F,) micewere supplied by the NIH (Animal Production Section, Division ofCancer Treatment, Frederick Cancer Research Centre, Frederick, MD).Six- to 12-week-old mice, weighing 20 to 28 g, were used for the LD,ostudies. For the pharmacokinetic studies, mice at least 10 weeks oldwere used.

Analytical Methods. Total platinum in plasma and plasma ultrafil-trate (free platinum) was analyzed by flameless atomic absorptionspectrometry as described previously (8). Concentrations of intact JM-40 and carboplatin were determined in plasma ultrafiltrate by highperformance liquid chromatography with UV and electrochemical detection, respectively (9, 10).

LDio Studies. LDIO values of the four platinum analogues in micewere determined after single i.v. bolus injections. For each dose levelgroups of 10 mice were used.

Each drug was tested over a range of four doses or more. Indicationsfor the dose ranges were first obtained in a pilot study with groups ofthree mice. The dose ranges were: 14.0, 14.5, 15.0, 15.5, and 16.0 mg/kg for cisplatin; 6.5, 6.75, 7.0, and 7.5 mg/kg for spiroplatin; 80, 90,100, and 120 mg/kg for JM-40; and 150, 160, 175, 190, and 200 mg/kg for carboplatin. The mice were observed for 21 days or until completerecovery with measuring body weight during the first 14 days. The totalobservation time of the surviving mice was 4 weeks. The I .I),,, wascalculated from dose mortality curves according to established methods(11).

Pharmacokinetic Studies in Mice. The drugs were administered atthe LD,o level as a single bolus injection in the tail vein. Blood sampleswere taken by intracardial puncture under anesthesia with ethyl etherat 0, 15, 30, 60, and 90 min as well as 2, 4, 6, and 24 h and 2, 3, 4. and5 days after drug administration. At each time point the blood of three

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mice was collected. Each sample was processed separately. All bloodsamples were centrifuged immediately and plasma was removed.Plasma (200 til) was ultrafiltered through a YMT membrane (batch40420) in a Micropartition System (Amicon, Oosterhout, The Netherlands). The ultrafiltrate was used for the determination of free platinum and in the case of JM-40 and carboplatin also for high performanceliquid Chromatographie analysis of the parent drug. Plasma and ultra-filtrate were either processed immediately or stored at -20°C until

analysis.AUC Calculations. The trapezoidal rule was used to calculate the

AUCs. In mice AUCs of each compound were calculated from themean concentration versus time curve at the LDI0.

AUCs in patients were calculated from concentration-time curvesafter short term infusions only. The pharmacokinetic data in patientswere collected from our own previous studies (8, 12-14). In thosestudies the applied doses were: cisplatin, 60 mg/m2 (n = 1), 75 mg/m2(n= I), 100 mg/m2 (n = 3); for spiroplatin, 25 mg/m2 (n = 4), 30 mg/nr (n = 1); for JM-40, 800 mg/m2 (n = 1), 900 mg/m2 (n = 3), 1000mg/m2 (n = 3), and 1200 mg/m2 (n = 1); for carboplatin, 280 mg/m2(n = 1), 350 mg/m2 (n = 4), and 400 mg/m2 (n = 1).

Pharmacokinetics of platinum compounds have proved to be linear(15, 16) and certainly over the selected small dose ranges. Therefore,individual AUCs of patients not having received the MTD could beextrapolated to the MTD by

AUC*MTD

individual dosex AUC„,

The mean values of these extrapolated AUCs were used for comparisonwith the AUCs at the LDio in mice.

RESULTS

LDIO Studies. I.I >,„values ¡nmice obtained after a single i.v.bolus injection were 15.5 mg/kg for cisplatin, 6.75 mg/kg forspiroplatin, 100 mg/kg for JM-40, and 165 mg/kg for carboplatin. Using a conversion factor of 3 (5), the equivalents inmg/m2 are calculated, as mentioned in Table 1.

Pharmacokinetics. For each of the analogues semilogarithmicplots of total platinum, free platinum, and concentrations offree parent drug in plasma or plasma ultrafiltrate are shown inFig. 1. At each time point the mean concentration in three mice±SD is indicated. Peak concentrations of total platinum inmice and in patients are summarized in Table 2. The peakconcentrations in patients were corrected for the time of infusion and extrapolated to the MTD for the respective platinumcompounds. Peak values in mice were much higher than thosein patients. No relationship could be found between thesevalues.

Total platinum was detectable for 5 days after administrationof each drug. The curves showed consistently three phases.

Free platinum could be detected for 2 h after cisplatin andspiroplatin administration, for 6 h after carboplatin, and for 5days after JM-40. AH free platinum curves showed a secondphase. Only the curve originating from JM-40 showed a thirdphase.

Nonmetabolized JM-40 and carboplatin could be detectedfor 90 and 120 min, respectively. Concentrations of these drugsdropped rapidly in two phases.

Table 1 Comparison of the MTD in patients and the LDW in mice of fourplatinum compounds

CompoundCisplatin

SpiroplatinJM-40

CarboplatinMouse

ID,,,(mg/m2)46.5

20.3300495MTD(mg/m2)100

351200550Refs.17,

18121920Ratio

MTD/LD.o2.2

1.74.01.1

Half-lives of total platinum, non-protein bound (free) platinum, and parent drug are summarized in Table 3. Half-lives ofsecond and third phases of free platinum and parent drug arenot mentioned in Table 3, because time intervals over whichthese parameters could be measured varied in a wide range andtv,ßis dependent on the time interval over which it is determined. For this reason, these values could not be used for areliable comparison between the compounds. Initial and terminal half-lives in mice were shorter than corresponding valuesin patients. In mice and patients initial half-lives increased inthe order cisplatin, JM-40, and carboplatin. Spiroplatin showedthe lowest value for all half-lives in patients. In mice, its rankvaried over the type of half-lives.

The AUCs in mice at the LDi0 and in patients at the MTD,including their ratios, are shown in Tables 4 and 5 for totalplatinum, free platinum, and parent drug. The AUCs werecalculated over 5 days, or a shorter time when the detectionlimit was reached earlier (Table 4). Additionally, AUCs weredetermined over limited time intervals (Table 5), i.e., the timeover which free platinum or parent drug could be measured inboth species. For JM-40, however, this limited time intervalwas chosen up to the time point at which the curves of freeplatinum and parent drug deviated.

For all analogues the AUC of total platinum over a period of5 days in patients was several times higher than in mice. Thedifference between patients and mice decreased when the AUCsof total platinum were compared during the time that freeplatinum was detectable in the mice (Table 5). Except forspiroplatin, these ratios were close to 1 (range, 0.9 to 1.3).

Ratios of the AUCs of free platinum calculated down to thedetection limits ranged from 0.3 to 2.5. The ratios of the AUCsof free platinum calculated over limited time intervals wereclose to 1, except for spiroplatin (Table 5). Comparable valuesof about 1 were obtained from the ratios of the AUCs of intactJM-40 and carboplatin.

To predict retrospectively the MTD for JM-40 based on theinitial doses of the drug during the phase I study, we used thisratio of 1. AUCs of free platinum over the first 90 min werecalculated (Table 6) and from these values and the AUC at theLDio in mice the MTD was predicted by means of the formula

MTD = AUCLD|CAUCDp„

x DD,

The MTDs calculated by this formula were quite close to theMTD established at the end of the phase I study (19).

DISCUSSION

Possible explanations of variations in toxicity between different species are in: differences in drug metabolism, elimination,and binding properties; schedule dependency due to exposuretime differences; and target cell sensitivity (7, 21, 22).

The approach of Collins et al. (7) is to apply preclinicalpharmacokinetic data in the design of phase I trials. As theyemphasized, predictions from preclinical Pharmacokinetics arequestionable for drugs for which the degree of activity dependson the duration of exposure above a threshold level (e.g.,antimetabolites). In addition it is obvious that this hypothesisis not applicable for drugs with an interspecies difference oftarget cell sensitivity. For all other drugs major interspeciesdifferences in toxicity arise from processes preceding drug-target site interactions (23, 24). These biological processesfinally determine the magnitude of the AUC.

The central concept of the proposed modifications in the6298

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PRECLINICAL PHARMACOKINETICS AND PHASE I OF PLATINUM COMPOUNDS

200

100

l lot« PI; Irte Pt

jjmol/,

WO

total Ptfree Pt

° 1530 60 0 1530 60 45day

2000

rooointact drugtotal Pt»reePt

2000

1OOO

O 15 30 60 90 120

Carbopiatin165mg,kg

intact drugtotal PtfreePt

•ftday O 15 30 60 90 120 360™ 234 5d»y

Fig. 1. Concentration versm time curves of total platinum, free platinum, and parent drug in CD2F, mice following administration of LD,0 doses of cisplatin,spiroplatin, JM-40, and carboplatin.

Table 2 Peak concenlrations of total platinum after administration of four platinum compounds in mice (n = 3) at the LD,0 and in patients at the MTD

CompoundCisplatin

SpiroplatinJM-40CarboplatinDose(mg/m2)46.5

20.3300495MicePeak

concentration (±SD)(fimol/liter)119.9(11.1)

63.4 (9.5)178 (68)

1705 (424)PatientsDose"(mg/m2)100

351200550n4

586Peak

concentration (±SD)"1*

(ftmol/liter)49.8(13.3)

16.9 (5.9)88.0(16.9)

250.7(41.0)* Normalized to MTD values.* Corrected for infusion time, according to the formula

/, = /,*•*,. 77( 1 -«T*")

in which /, is intercept of phase i, I* is the measured intercept, K¡is the slope, and T is infusion time.

Peak concentration = £/,

strategy for dose escalations during phase I studies with cyto-statics is that the AUC is a more accurate measure of drugexposure than dose. Thus the ratio of the absolute AUC values(in units of concentration x time) at the human MTD andmouse LD,o should be closer to unity than the ratio of the dosesexpressed in mg/m2.

This hypothesis was proved to be valid for a number of drugsin retrospective investigations (7). Confirmation of this observation for a larger number of drugs will stimulate clinicians touse this approach in a prospective manner and perform phaseI studies much faster. In order to investigate whether this

strategy would have been useful and safe for platinum analogues, we performed pharmacokinetic studies of cisplatin,spiroplatin, JM-40, and carboplatin in CD2Fi-mice.

Initial half-lives of all platinum-species in mice were shorterthan in patients, except tv.a (0-30 min) of free platinum,originating from spiroplatin (6.9 min). This can be explainedby the relatively long time interval over which tv,a values weredetermined in the mice (when measured over 0-15 min, tv,awas 5.7 min). However, more measuring points would havebeen required to establish all initial half-lives over a shortertime interval.

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Table 3 Half-lives of four platinum compounds in mice and patients

TotalplatinumCompoundMice

(n =3)CisplatinSpiroplatinJM-40CarboplatinPatients

(n =5-8)CisplatinSpiroplatinJM-40Carboplatinty,a'

t»y(1-5 days)

(min)(day)7.410.67.69.714.111.234.545.81.91.73.61.85.53.84.55.2Freeplatinum

t*of(min)6.16.97.89.015.06.835.548.1Parentdrug

tv,a"(min)ND*ND7.18.5NDND30.847.0

•A/ = 0-30 min in mice and 0-20 min in patients, fv.«values of total platinumwere calculated after subtraction of the extrapolated .phase.

* ND, not determined.

More rapid distribution of the platinum compounds to tissuesand/or a faster clearance from the plasma are probably reasonsfor the shorter initial half-lives in mice than in humans. Also,the terminal half-lives of total platinum were shorter in micethan in patients. Vermorken et al. (16) discussed the possibilitythat the elimination rate of total platinum from plasma couldbe related to the turnover rate of the plasma proteins, inparticular albumin and IgG. Because composition and amountsof plasma proteins differ in mice and humans, we suggest thatthe shorter terminal half-lives in mice may be caused by a fasterturnover of platinum binding proteins in mice.

As might be expected initial half-lives of total platinum werelonger (except for JM-40) than those for free platinum whichin turn were longer than half-lives of parent drugs (25). Theexception observed for JM-40 in this sequence is probably dueto small variations in the concentration-time curves during theinterval (0-30 min) over which half-lives were measured. Themain pharmacokinetic parameters determining the AUC arepeak levels and half-lives. In mice the peak concentrations weremuch higher than the extrapolated concentrations in patients,whereas half-lives were shorter. Thus the plasma concentrationcurves in mice and humans do not run parallel, implying thatthe time interval over which the AUCs are being compared ismost critical. Therefore, it is obvious that the AUCp/AUCmratios increase with the duration of these time intervals.

Several authors have shown platinum complexes to lose theirbiological activity (26-30) by binding to proteins, which indicates that AUCs of total platinum are of questionable value forstudies aiming at the relation of drug concentrations and tox-icity (26). A better correlation is expected between concentrations of free platinum or parent drug, which are the platinumspecies thought to be responsible for therapeutic and toxiceffects. For these reasons AUCs over limited time intervals areof more relevance to studies investigating toxicology of plati

num analogues, inasmuch as total platinum mainly representsfree platinum and parent drug over those intervals. In thisrespect, it is of interest that we observed a good correlation ofAUC values over limited time intervals of the platinum speciesat the MTD in patients and at the LD10 in mice for cisplatin,JM-40, and Carboplatin. This is in agreement with the hypothesis that the AUC ratio of humans to mice is about 1at equitoxicdose levels (7).

In contrast, very low AUC ratios were found for spiroplatin,which may be related to the composition of spiroplatin infusionfluids, as reported by Elferink et al. (31). These solutionscontain several aquated complexes in mutual equilibrium. Theequilibrium shifts after dilution of the infusion fluids used inadministration to patients, which means that the solutions ofspiroplatin administered to mice contain a different composition of platinum complexes than the solutions given to patients.The stability of platinum compounds seems to be an importantfactor in the relation between AUCs and MTD. The influenceof this relation on the predictability of the MTD has to beevaluated in future studies of this type.

In order to evaluate whether the MTD of JM-40 could havebeen predicted from pharmacokinetic data obtained during theinitial courses in the phase I study, we calculated the MTDbased upon the AUC of free platinum at the lower dose levels.For this purpose free platinum concentrations were used. Dataof the parent drug would have been more desirable; intact JM-40, however, could not be determined, due to technical problems, during the first part of the phase I study. Seven AUCvalues, derived from doses ranging from 20 to 120 mg/m2,

provided (calculated) MTD values which were close to theactual MTD of 1200 mg/m2. There was only one AUC which

would have resulted in an overprediction of the MTD (1282mg/m2). However, such a difference would not have led to

problems, because the objective of this approach is not toproceed immediately to the MTD but to perform the escalationprocedure faster, in particular at the lower dose levels. Themerits of the faster escalation procedure provided by either the"square root" method or the "extended factor 2" method (7)

would have been the use of about 7 escalation steps instead of13 as used in the phase I study of JM-40 (19).

A general problem which will be encountered with applyingthis method of dose escalation is the lack of availability ofsensitive detection methods for new agents. Often, assay procedures will not be optimally developed at the time phase Istudies are being initiated. Thus, a prerequisite for the use ofthe proposed escalation procedure is that increased attentionwill have to be paid to sensitive assays of potential anticancerdrugs during proci in¡caistudies.

A problem of general importance with which we were confronted in this study is the relative value of the actual MTD.

Table 4 AUCs (as measured up to the detection limit) of four platinum compounds, in mice at the LDia and in patients at the MTD

TotalplatinumCisplatinSpiroplatinJM-40CarboplatinUltrafiltrable

platinumCisplatinSpiroplatinJM-40CarboplatinIntact

drugJM-40CarboplatinTime

interval(days)S555(min)190607,2001,4402401,440AUC

patients(min-fimol/liter)54,45638,261441,63383,0921,72810455,11530,35320,64927,382Time

interval(days)5555(min)120607.20036090120AUC

in mice(min jjmol/liter)20,42814,812104,96746,7841,34835121,84529,27715,75826,550AUCratio02.72.64.21.81.30.32.51.01.31.0•

AUC..WAUC.,«,.

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PRECLINICAL PHARMACOKINETICS AND PHASE I OF PLATINUM COMPOUNDS

Table 5 AUCs of four platinum compounds over limited time intervals in mice atthe /.Dio and in patients at the MTD

CompoundTotal

platinum('¡spiatiliSpiroplatinJM-40CarboplatinUltrafiltrable

platinumCisplatinSpiroplatinJM-40CarboplatinIntact

drugJM-40CarboplatinTime

interval(min)1206090360120609036090120AUC

for patients(min-¿mini

MUT)2,64267626,62626,2941,64010421,48826,02919,06215,554AUCfor mice

(min fimol/liter)2,1081,19624,04228,7831,34835118,89329,27715,75826,550AUCratio"1.30.61.10.91.20.31.10.91.20.6

Table 6 Prediction of the maximal tolerated dose of JM-40 in patients fromAUC, at low dosages

Patient"laIb

2>2b

34

5Dose

(mg/m2)20

4080

120120120120AUC

of freeplatinum(min-

fimi>l/liliT)352

90416502276176822942254Calculated

MTD*(mg/mj)1074

836916996

1282988

1055* a, first course; b, second course.* According to the formula

MTD =AUC,

x D.Op.lic.il

The observed MTD in patients was 1200 mg/m2.

For instance, the MTD of single dose cisplatin was reported tobe 100 mg/m2 (17, 18), but after repeated doses this would havebeen too toxic unless combined with pre- and posthydration.However, with adequate hydration procedures, the MTD canbe considered higher than 100 mg/m2. Another example of

controversial reports on the MTD of a drug is Carboplatin, forwhich the MTD of a single dose was first determined at 550mg/m2 (20). Recently, high dose studies have been started andthere are indications that doses up to 1.6 g/m2 or even higher

are feasible (32).

ACKNOWLEDGMENTS

The authors are grateful to Dr. J. M. Collins for his helpful discussions. We also like to thank Dr. C. Reeder for providing CD2F, mice;Dr. H. Brouwer and his staff for taking care of the animals; and R.Schoemaker-Voogdt, C. Vanderlans, and H. Kempes for their assistance in preparing the manuscript.

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1987;47:6297-6301. Cancer Res   Maaike B. van Hennik, Wim J. F. van der Vijgh, Ina Klein, et al.   Analogues in Mice and HumansComparative Pharmacokinetics of Cisplatin and Three

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