(CANCER RESEARCH 49, 753-757. February 1, 1989)

Comparative Pharmacokinetics and Alkylating Activity of Fractionated Intravenous

and Oral Ifosfamide in Patients with Bronchogenic CarcinomaM. J. Lind,1 J. M. Margison, T. Cerny, N. Thatcher, and P. M. Wilkinson

CRC Department of Medical Oncology [M. J. L., T. C.. N. T.], Department of Clinical Pharmacology ¡J.M. M., P. M. W.], Christie Hospital and Holt Radium Institute,Manchester, M20 9BX, United Kingdom

ABSTRACT

20 patients with advanced non-small cell lung cancer were treated withifosfamide and mesna 1.5 jj/nr daily for 5 days; 10 received the drug bymouth and 10 i.v. Both schedules resulted in a reduction in the eliminationhalf-life with an increased total and nonrenal clearance of ifosfamide overthe 5-day period. Oral administration resulted in an unacceptably highincidence of encephalopathy(5/10) which was not seen in the i.v. group.In two patients this encephalopathy manifested itself as coma whichlasted for 24 to 48 h but was fully reversible and in the other three casesas somnolence occurring for more than 50% of the patients' waking

hours. Nadir blood counts and response rates were similar in both arms.The encephalopathy suggests that there are metabolic differences between the i.v. and oral routes and that a metabolite rather than the parentdrug is responsible for this syndrome. In addition it was shown that thetotal and nonrenal clearance of the drug was significantly less when thedrug was administered orally.

None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creati-nine clearance and ifosfamide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot begiven orally at the conventionally employed i.v. doses.

INTRODUCTION

Ifosfamide (I) (3-(2-chlorethyl)-2-(2-chlorethylamino)tetra-hydro-2H-1,2,3 oxazaphosphorine oxidej (Mitoxana) is a structural isomer of the oxazaphosphorine cyclophosphamide, awidely used alkylating agent. It is a "prodrug" that requires

biotransformation in order to become cytotoxic. This occursmainly in the liver (1) by the action of a mixed function oxidaseproducing the active metabolites 4-hydroxyifosfamide (2) andisophosphoramide mustard (3). Ifosfamide is less myelosup-pressive than cyclophosphamide (4) but is more urotoxic thanthe latter drug (5). However, with the introduction of theuroprotector mesna (uromitexan) in 1982 (6), this toxicity isnow largely avoidable. This has resulted in réévaluationofifosfamide in many malignancies (7-15). In the majority ofthese studies Ifosfamide has been administered intravenouslywith mesna either as a 24-h infusion or fractionated over 3-5days. Cerny et al. (16) and Wagner et al. (17) have both shownthe bioavailability of orally administered ifosfamide to be closeto 100%. However both authors found an unacceptably highlevel of central nervous system toxicity at conventionally employed doses. A study of patients with non-small cell lung cancercomparing fractionated doses of ifosfamide given either orallyor i.v. over 5 days was planned to determine whether encephalopathy could be avoided by dividing the oral dose over severaldays. In addition a pharmacokinetic study was undertaken toascertain if any pharmacokinetic parameter correlated withdrug toxicity and to determine any differences in pharmacokinetic handling between the two routes of administration.

Received 4/20/88; revised 10/3/88; accepted 10/26/88.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.

1To whom requests for reprints should be addressed, at Department of MedicalOncology, University of Manchester, Christie Hospital, Wilmslow Road, M209BX, England.

PATIENTS, MATERIALS, AND METHODS

Patients

20 patients with advanced histologically proven non-small cell lungcancer were treated with ifosfamide. Their median age was 59.5 years(range, 44-71 years) and all had pretreatment Karnofsky scores >50and creatinine clearances of >50 ml/min.

The two regimens employed were as follows: (a) 10 patients receivedi.v. ifosfamide (Boehringer Ingelheim, Mitoxana) at a dose of 1.5 g/m2/day for 5 days. The dose was rounded down to the nearest 500 mg.Ifosfamide was given as a 30-min infusion in 250 ml normal saline.The uroprotector 2-mercaptoethane sodium (mesna) was given at adose of 1.5 g/m2/day in 2 liters of normal saline as a 24-h infusion for5 days. (¿>)10 patients received oral ifosfamide (only available as 500-mg capsules) at a dose of 1.5 g/m2/day for 5 days 30-60 min before

breakfast. The dosage was rounded up or down as outlined in a. Mesnawas administered in a similar manner as outlined in a with a further500 mg of oral mesna given every 6 h for four doses after the last i.v.mesna dose on Day 5.

Serial blood samples were collected at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3,6, 9, and 24 h postifosfamide administration on each of the 5 days inaddition to 24-h urine samples. Blood samples were centrifuged immediately; the serum was separated off and stored at —¿�20'C. Urinesamples were also stored at —¿�20°C.

Analytical Methods

Plasma, Urinary Ifosfamide and Urinary 4Keto Ifosfamide Assay.These were determined using the high-performance liquid Chromatographie method of Margison et al. (18).

Metabolite Alkylating Activity. Total alkylating activity was measured using a modification of the method of Friedman and Boger (19)in which the color developed by reaction with nitro-benzyl-pyridine wasextracted into ether containing 5% triethylamine. Bischloroethylaminewas used as a standard and values extrapolated from the standard curvewere converted to Mg/ml equivalents of nor nitrogen mustard. Asifosfamide reacts weakly with nitro-benzyl-pyridine a second standardcurve was constructed containing ifosfamide at concentrations in therange found in serum. The contribution of ifosfamide to the totalalkylating activity of the sample could therefore be determined and avalue for the alkylating activity of ifosfamide metabolites could thus beassessed.

Kinetic Analysis. For patients receiving i.v. drug the serum concentration profile was fitted to a two compartment model using thenoniterative computer programme MODFIT as described by Mclntosh(20). The intercept and rate constants were used to calculate the half-lives (Iv,), area under the curve (AUG.) and volumes of distribution

Total body clearance was determined by the formula, C/,0i = D/AUG., where D is the dose administered. By measuring the 24-h urinaryexcretion of ifosfamide the renal clearance of the drug can be calculatedfrom the formula, Cl, = .Y./AUG»,where Cl, is the renal clearance andXu is the amount excreted in the urine over 24 h. From Cl, the nonrenalclearance of the drug could be derived from the formula, CI,0, = Cl, +Cl„„where Cl,, is the nonrenal clearance.

For the oral data a linear regression analysis of the terminal phasewas used to determine the half-life and rate constant. The area underthe curve was calculated by the trapezoidal rule and extrapolated toinfinity using the Nelson Wagner correction factor, i.e., AUG. = AUCi4+ Cu/K,r,m, where AUC34 is the area under the curve for the first 24 h,

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CM is the concentration of drug at 24 h, and AVi,,,,is the eliminationrate constant.

The volume of distribution was calculated from the formula, Vipa=X/Co, where Vdfois the volume of distribution, X is the dose and Co isthe concentration at time 0 when the terminal phase is extrapolatedback to zero. Total body clearance, renal clearance and nonrenalclearance were calculated as described for the i.v. data.

Statistical Methods. To determine any change with time of pharma-cokinetic parameters, a Friedman two-way analysis of variance wasused. To compare parameters between the i.v. and oral groups a Mann-Whitney test was used. To examine any correlations between pharma-cokinetic parameters and toxicity Kendall correlation tests were used.

RESULTS

Ifosfamide Pharmacokinetics

The pharmacokinetic parameters for the i.v. group are summarized in Table 1 and shown graphically in Fig. 1. The valuesare expressed as medians and ranges. The terminal eliminationhalf-life declined from a median of 6.163 (range, 3.894-8.154)hours on Day 1 to 3.762 (range, 2.655-4.780) hours on Day 5(P = 0.018 Friedman). The total clearance of parent drugincreased from a median of 69.185 (range, 60.877-80.500) ml/min on Day 1 to 123.185 (range, 102.15-181.69) ml/min onDay 5 (P = 0.0001 Friedman) and was associated with anincrease in the nonrenal clearance from 60.082 (range, 47.027-65.134) to 104.285 (range, 100.470-167.815) ml/min (P =0.002 Friedman) Table 1. However there was no significantincrease in the renal clearance of ifosfamide or the percentageurinary excretion of drug per 24-h period over the 5 days. Inaddition the area under the serum concentration time curve fellfrom 574.8 (range, 284.000-821.400) to 346.33 (range,200.425-407.800) Mg/ml. (P = 0.0001 Friedman).

Following oral administration of the drug, peak ifosfamidelevels were reached between 1 and 2 h postadministration (seeFig. 2). The median elimination half-life declined from 5.775(range, 4.620-6.93) h on Day 1 to 3.46 (range, 2.230-4.330) hon Day 5 (P = 0.031 Friedman). The total clearance increasedfrom 51.334 (range, 39.000-69.600) ml/min on Day 1 to85.833 (range, 69.166-109.833 mls/min on Day 5 (P= 0.024).This was associated with an increase in the nonrenal clearancefrom 46.554 (range, 34.959-53.308) ml/min on Day 1 to67.881 (range, 57.520-79.323) ml/min on Day 5 (P = 0.02Friedman). However there was no significant increase in therenal clearance of ifosfamide or the percentage urinary excre

tion of drug from Day 1 to 5. In addition the area under theserum concentration time curve fell from 680.651 (range,529.147-1105.535) Mgh/ml on Day 1 to 382.620 (range,323.885-471.871) Mgh/ml on Day 5 (P = 0.008 Friedman).

Comparing the pharmacokinetic parameters between i.v. andoral administration in Tables 1 and 2 there was no significantdifference on any one day between elimination half-life, areaunder the curve, and renal clearance, with respect to route ofadministration. However the total clearance and nonrenal clearance were significantly less on any one day when the drug wasadministered orally (P< 0.05 Mann-Whitney). In addition Vd(p0)was significantly less than Vdw (P < 0.05 Mann-Whitney) onany one day.

Despite the wide variability in pharmacokinetic parametersthere was no correlation between any such parameter and thedevelopment of hematological (measured as the nadir absolutewhite blood count or percentage change in white blood cellcount) or CNS toxicity.

Metabolite Alkylating Levels and Excretion of 4-Ketoifosfamide

These results are summarized in Tables 3 and 4 and graphically in Figs. 3 and 4.

i.v.. In those patients receiving the drug i.v. there was anincrease in the area under the metabolite alkylating curve onsuccessive days of administration but this did not reach statistical significance. However, the peak metabolite alkylating activity rose from 7.96 (range, 5.600-17.700) (/ig equivalents ofnornitrogen mustard/ml) on Day 1 to 14.05 (range, 7.880-24.660) on Day 5 (P = 0.005 Friedman). In addition there wasa significant increase in the 24-h urinary excretion of 4-keto-ifosfamide from 0.064 (range, 0-0.32) (percentage of parentdrug administered) on Day 1 to 0.32 (range, 0.15-0.72) on Day5 (/>= 0.001 Friedman).

Oral. In patients receiving the drug orally the peak metabolitealkylating levels and area under the metabolite alkylating curveincreased over the 5 days. However the difference was notstatistically significant. Likewise urinary levels of 4-ketoifos-famide increased over this period of time but was not statistically significantly.

Oral Versus i.v.. There was no statistical significant differencein metabolite alkylating levels between oral and i.v. administration.

Wide variability in the serum concentration of alkylatingmetabolites was seen; some patients produced virtually no suchmetabolites in the serum on certain days and others very high

Table 1 Pharmacokinetic parameters in 10 patients with non-small cell lung cancer receiving 1.5 g/m1 of i.v. ifosfamide per day, Days 1-5

Values are medians and ranges.

ParameterTvß(h)°C/,,,,

(ml/min)*CI,

(ml/min)fCl„

(ml/min)''AUC_G<gri/ml)'Va

(liters/16.163(3.894-8.154)69.185(64.600-112.300)11.101(4.218-17.973)60.082(47.027-65.134)574.800(284.000-821.400)40.330(28.700-51.900)24.620(3.640-7.790)82.139(85.300-143.999)12.823(3.439-20.727)72.309(54.358-93.995)488.251(334.082-724.899)40.350(28.500-61.810)Day34.330(2.390-4.950)94.003(81.8300-147.900)15.070(7.042-20.365)81.443(69.733-126.000)385.668(238.250-555.203)34.800(19.730-61.810)44.318(3.300-4.620)112.820(102.150-181.690)17.159(9.680-29.947)93.020(71.143-123.360)346.330(227.082-468.600)41.540(28.870-51.390)53.762(2.655-4.780)123.185(60.870-80.500)14.836(5.369-29.988)104.285(100.470-167.815)284.036(200.425-407.800)39.920(31.260-34.640)P0.0180.00010.1440.0020.00010.970"

T*ß,terminal eliminationhalf-life.*C/10„total bodyclearance.'CI,, renalclearance.dCl„,nonrenalclearance.'AUG., area under thecurve.fVa, volume of distribution.

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TIME/hrs0 10 20 30

Fig. 1. Mean ifosfamide levels in patients receiving i.v. ifosfamide (l.S g/m2)Days 1-5.

10°

DAY 1

DAY 2

DAY 3DAY 4

DAY 5

20

Fig. 2. Mean ifosfamide levels in patients receiving oral ifosfamide (l.S g/m2)Days 1-5.

levels. However there was no correlation between metabolitealkylating activity and hematological or neurological toxicity.

Clinical Data

Toxicity. The median nadir WBC (measured at 10 days afterthe start of chemotherapy) experienced in the i.v. group was3.8 x lO'/Hter and that in the oral group 5.45 x 109/lher (/>>0.05 Student's t test).

Five of the patients in the oral arm experienced CNS toxicity> WHO Grade III (20) requiring early termination of theirtreatment course as opposed to none of the patients in the i.v.arm (0.01 < P < 0.02, eh i-squared). Two of these patients inthe oral arm became comatosed for 24-48 h but recoveredcompletely without any neurological sequelae. Mild degrees ofencephalopathy, consisting mainly of somnolence (<50% ofwaking hours), were seen in the i.v. arm of the study. Nauseaand vomiting were mild and identical in both arms.

Tumor Response. A total of eight partial responses were seen;four occurring in each arm.

DISCUSSION

Our initial values for the terminal half-life, clearance, andvolume of distribution in the i.v. group compare well with thoseof other investigators (21-23). The results presented here indicate that fractionation of either an i.v. or orally administereddose of ifosfamide over 5 days results in increased nonrenal andtotal clearance of the parent drug. This was associated with adecrease in the elimination half-life, and an increase in the peak

metabolite alkylating activity, the AUC of the metabolite alkylating activity time curve, and production of 4-ketoifosfamide.

One possible explanation is that fractionation of the ifosfamide dosage leads to induction of those enzymes responsible formetabolism of the drug. Similar results have been obtained withfractionating cyclophosphamide administration (24). Furtherevidence for auto induction of cyclophosphamide metabolismcomes from D'Incaici et al. (25) who compared the pharmaco-

kinetics of the first and last courses of patients receiving cyclophosphamide continuously for 1 year and found the half-life tobe shorter after continual exposure to the drug. In support ofthis theory Tchekmedyian et al. (26) have shown that the areaunder the alkylating activity time curve following a 5-day continuous infusion of cyclophosphamide was three times thatexpected when the same dose was given as a bolus.

More recently it has been shown that fractionating the doseof cyclophosphamide over 2 days leads to increased peak levelsof the 4-hydroxy metabolite (27). Wagner (28) has also pub

lished data on the pharmacokinetic of i.v. ifosfamide dosagefractionated over a 2-day period and has shown a decrease inelimination half-life from 6.4 ±2.4 h on Day 1 to 5.3 ±2.8 hon Day 2. A reduction in ifosfamide half-life from 8.3 h to 6.3h over a 3-day period has also been demonstrated (29). Ourdata show that a further reduction in the elimination half-life

occurs with more prolonged administration of the drug.This phenomenon of auto induction of metabolism may also

explain why fractionation of ifosfamide dosage is associatedwith an improved therapeutic index (30, 31). Of particularinterest was the high incidence and severity of CNS side-effects

in patients receiving the drug by the oral route. A metaboliterather than the parent compound is likely to be responsible forthis toxicity and imply with a first-pass effect is producing more

active metabolites with the oral route. However, the near 100%

Table 2 Pharmacokinetic parameters in 10 patients with non-small cell lung cancer receiving 1.5 g/m2 of oral ifosfamide per day, Days 1-5

Values are medians and ranges.

ParameterT*(h)cC/,,»

(ml/min)"Cl,

(ml/min)'Cl„

(ml/min/AUC.

Gigh/ml)"K^,

(liters)*15.775(4.620-6.930)51.334(39.000-69.660)7.829(0.058-16.358)46.554(34.959-53.308)680.651(529.147-1105.535)24.035(16.730-36.410)23.745(3.300-5.330)63.167(39.833-88.333)6.610(3.480-16.348)60.860(51.823-76.727)525.321(422.230-732.915)21.865(11.970-33.170)Day3"3.850(3.300-5.330)66.666(37.166-121.500)12.153(3.480-27.659)57.420(29.553-93.841)464.482(269.830-563.522)22.930(10.650-39.220)4»3.460(3.150-5.770)70.833(54.000-127.333)12.500(0.000-34.184)70.138(44.166-93.1490)441.016(291.270-552.000)23.605(16.200-39.600)5»3.460(2.230-4.330)85.833(69.166-109.833)16.705(0.000-21.930)67.881(57.520-79.323)382.620(323.885-471.875)25.960(16.590-32.900)P0.0310.0240.1500.0200.0080.910

" Median of nine patients.'' Median of six patients.' /.:. terminal elimination half-life.a C/ioi, total body clearance.' <'/,. renal clearance.1CI,,, nonrenal clearance.* AUG., area under the curve.* KI/»,volume of distribution.

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Table 3 Metabolic parameters in 10 patients with non-small cell lung cancer receiving 1.5 g/m2 of i.v. ifosfamide per day, Days 1-5

Values are medians and ranges.

ParameterMetabolite"AUC (Mgh/ml

equivalents of nornitrogenmustard)Peak

metabolite alkylating activity (*igh/ml equivalents ofnornitrogenmustard)4-Keto

I (%)*1132.595

(34.570-182.595)7.960

(5.360-17.700)0.064

(0.000-0.320)2135.845

(71.170-212.010)10.800

(4.390-14.360)0.222

(0.028-0.340)Day3130.570

(86.510-312.750)8.845

(7.900-20.400)0.217

(0.100-0.376)4120.790

(69.800-226.720)9.590

(5.120-15.400)0.233

(0.115-0.430)5166.555

(70.080-238.720)14.050(7.880-24.660)0.320

(0.150-0.720)P0.0950.0050.0006

°Metabolite AUC, area under the metabolite alkylating activity time curve.* 4-Keto I, the percentage of the administered dose excreted as 4-ketoifosfamide.

Table 4 Metabolic parameters in 10 patients with non-small cell lung cancer receiving 1.5 g/m2 of oral ifosfamide per day, Days 1-5

Values are medians and ranges.

ParameterMetabolite'AUC (jigh/ml

equivalents of nornitrogenmustard)Peak

metabolite alkylating activity Gjgh/ml equivalents ofnornitrogenmustard)4-Keto

I (%f183.735

(0.689-211.170)6.015

(1.990-11.380)0.158

(0.004-0.450)290.085

(6.886-291.170)7.120

(2.750-16.310)0.165

(0.098-0.340)Day3"124.315

(61.458-247.275)7.580

(4.720-16.080)0.240

(0.020-0.590)4*188.207

(87.900-248.390)10.035

(5.810-20.740)0.280

(0.070-0.370)5*90.489

(56.301-202.669)8.380

(5.350-19.590)0.250

(0.000-0.610)P0.2750.1340.355

" Median of nine patients.* Median of six patients.c Metabolite AUC, area under the metabolite alkylating activity time curve.d 4-Keto I, percentage of the administered dose excreted as 4-ketoifosfamide.

10-

g8

Fig. 3. Mean metabolite alkylating levels in patients receiving i.v. ifosfamide(1.5 g/m2) Days 1-5.

I 8

I

DAYlDAYS

Fig. 4. Mean metabolite alkylating levels in patients receiving oral ifosfamide(1.5 g/m2) Days 1-5.

bioavailability demonstrated by other investigators fails to demonstrate any significant first-pass effect.

One explanation may be that rather than quantitative differences, there may be qualitative differences in the metabolismbetween the two routes of administration. Oral administrationof cyclophosphamide results in a greater production of alkylating metabolites than i.v. administration supporting this theory.

Juma et al. (32) speculated that a different profile of metabolites was produced by oral administration. Others however

have failed to show any significant difference in the levels of 4-hydroxy cyclophosphamide and phosphoramide mustard between oral and i.v. routes of administration (33). It is howeverimportant to realize that the metabolism of ifosfamide is notidentical to that of cyclophosphamide. Dechloroethylation canaccount for up to 25% of the metabolism of ifosfamide (34),while this pathway is a very minor one for cyclophosphamidemetabolism. In this context, dechloroethylation of ifosfamideresulting in the production of chloracetaldehyde has been suggested by Goren et al. (35) as a possible cause of the CNStoxicity and it may be that this pathway predominates in oraladministration.

When the area under the metabolite alkylating activity timecurve and the peak alkylating metabolite level attained on eachday of ifosfamide administration in the two patient groups inTables 3 and 4 are compared, there was at no time a significantdifference between i.v. and oral routes of administration. It ishowever important to realize the limitations of the NBP reaction. Certain metabolites of cyclophosphamide and ifosfamideare nonreactive or only weakly positive in this test e.g., acroleindoes not alkylate. It is therefore possible to envision a situationwhere two patients have identical alkylating activity in theserum but quite different profiles of metabolites. For this reasona simple method of assaying all the metabolites individuallywould be useful. Oral administration could result in a differentprofile of metabolites which is not reflected in the NBP test.

In our study none of the pharmacokinetic parameters measured correlated with either CNS toxicity or levels of leucopenia.Furthermore there was no correlation between the AUC for theplasma metabolite alkylating activity and the nadir white bloodcell count or percentage change in white blood count. Our datais in contrast to the data of Mourisden et al. (36). This is againprobably a reflection of the lack of specificity of the NBP

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reaction and the complexity of the metabolic pathway of ifos-famide.

The values obtained for the renal clearance of ifosfamidewere very much lower than the creatinine clearance and therewas no correlation between the creatinine clearance and renalclearance of the drug unlike the results of Nelson (29). For adrug as water soluble as ifosfamide this data suggests somedegree of tubular reabsorption.

With regard to the comparative pharmacokinetics betweenoral and i.v. administration, the total body clearance, nonrenalclearance, and volumes of distribution were statistically significantly less with oral administration. Our value for V^p,agreesclosely with that obtained by Allen (21) and approximatesclosely to the total body water. This suggests that when administered i.v. ifosfamide is distributed throughout the total bodywater with little tissue binding. The lower value of Va^ isdifficult to explain, but Vd(mand Vd(p0)are not strictly comparable as both parameters are model dependent. There is noclear explanation of this discrepancy but it suggests that ifosfamide is distributed differently with oral administration. Weconclude that ifosfamide fractionated over 5 days leads toautoinduction of its metabolism. The clearance of the drug islower by the oral route and may be related to the higherincidence of CNS side-effects.

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1989;49:753-757. Cancer Res   M. J. Lind, J. M. Margison, T. Cerny, et al.   Bronchogenic CarcinomaFractionated Intravenous and Oral Ifosfamide in Patients with Comparative Pharmacokinetics and Alkylating Activity of

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