DRUG DISPOSITJO

Clin. Pharmacokinet. 26 (6): 439-456, 1994 0312-5963/94/0006-0439/$09.00/0 © Adis International Limited. All rights reserved.

Ifosfamide Clinical Pharmacokinetics Thomas Wagner Section of Hematology and Oncology, Department of Internal Medicine, Medical University of Lubeck, Lubeck, Germany

Contents 440 44f) 440 440 441 442 443 446 446 447 447 447 44X 448 44,,/ 449 449

4

l)

4'i2 4'12

Summary

Summary 1. Analytical Methodology 2. Pharmacokinetic Profile of Intravenous Ifosfamide 2.1 Distribution 2.2 Elimination Half-Life 2.3 Excretion 3. Overview of Metabolism 3.1 Activation of Ifosfamide and Side-Chain Oxidation 4. Pharmacokinetics of Fractionated Intravenous Ifosfamide Therapy 5. Pharmacokinetics of Ifosfamide Administered by Oral or Subcutaneous Routes 6. Influence of Hepatic and Renal Function 6.1 Influence of Hepatic Function on the Activation of Ifosfamide 6.2 Renal Impairment 7. Influence of Age and Bodyweight 8. Influence of Genetic Factors 9. Drug Interactions 10. Toxicity Associated with Ifosfamide 10.1 Urotoxicity 10.2 Prevention of Urotoxicity by Administration of Thiols 10.3 Central Nervous System Toxicity 11. Conclusions

This article reviews the metabolism and pharmacokinetics of ifosfamide and their implications for the cytostatic efficacy and toxicity pattern of this alkylating agent. Ifosfamide is a prodrug that requires biotransformation to become cytotoxic. It is a structural isomer of cyclophosphamide from which it differs only in having the chlorethyl functions on different nitrogen atoms. This causes a considerable change in initial metabolism, although overall metabolism remains the same. Beside the formation of 4-hydroxy-ifosfamide (' activated ifosfamide'), a second pathway with liberation of chloroacetaldehyde exists. Therefore, less activated drug is formed than during cyclophosphamide metabolism. This fact may well explain why higher doses of ifosfamide are required during treatment. Chloroacetaldehyde may account for the adverse effects and therapeutic effects of the parent drug. This metabolite has been associated with central nervous system toxicity during ifosfamide treatment and was shown to deplete intracellular glutathione concentrations. Glutathione depletion may support the activity of alkylating metabolites in tumour cells, thus overcoming the relative

440

Clin. Pharmacokinet. 26 (6) 1994

resistance of the cells to alkylating agents. Possibly, this mechanism explains the lack of complete cross-resistance between ifosfamide and cyclophosphamide as well as the greater anti tumour activity of ifosfamide in some tumours. Urotoxicity of ifosfamide, which was the dose-limiting adverse effect, can be successfully attenuated by the use of mesna. Distinct pharmacokinetic properties of mesna are responsible for the fact that in contrast to other sulphydryl compounds the uroprotective activity of mesna does not imply a loss of therapeutic efficacy. Ifosfamide belongs to the class of alkylating oxazaphosphorines that need to be activated in vivo (Connors et al. 1974). The only difference between ifosfamide and its progenitor cyclophosphamide is a shift of one chlorethyl group from the exocyclic nitrogen to the oxazaphosphorine ring nitrogen (fig. 1). However, this shift causes a considerable change in the initial metabolism of ifosfamide (Brock 1983; see section 3).

1. Analytical Methodology The stability of ifosfamide in vitro makes its determination in body fluids easy in pharmacokinetic studies. Several assays, including gas chromatography (GC) with nitrogen phosphorus flame ionisation detector CJuma et al. 1978; Kaijser et al. 1991; Kurowski & Wagner 1993; Talha & Rogers 1984; Wagner & Drings 1986; Wagner & Fenneberg 1984b), electron capture detector (ECD) [Holdiness & Morgan 1983], mass spectrometry (Lambrechts et al. 1991), high performance liquid chromatography (HPLC) [Burton & James 1988; Margison et al. 1986] and 31P-nuclear magnetic resonance spectrometry (Gilard et al. 1993; Martino et al. 1992), have been described. Assays origi-

Ifosfamide

Cyclophosphamide

Fig. 1. Structure of ifosfamide and cyclophosphamide. Sites 1 and 2 indicate the positions of primary metabolism (for greater detail see section 3).

nally developed for cyclophosphamide (Juma et al. 1978; Wagner & Fenneberg 1984b) usually can be adapted for determination of ifosfamide (Talha & Rogers 1984; Wagner & Drings 1986). Since the ifosfamide molecule exhibits a nitrogen to phosphorus ratio of 2 : 1, nitrogen phosphorus flame ionisation detection GC is best suited for high sensitivity routine measurements. Furthermore, because all oxazaphosphorines have similar physicochemical properties, other compounds of this class (e.g. trofosfamide) may serve as an internal standard (Kaijser et al. 1991; Kurowski & Wagner 1993; Talha & Rogers 1984).

2. Pharmacokinetic Profile of Intravenous Ifosfamide In vitro, ifosfamide has no cytostatic activity, but is relatively stable in aqueous solutions (Radford et al. 1990). When ifosfamide is mixed with the uroprotective agent mesna, aqueous solutions remain stable for at least 9 days during administration by infusion in ambulatory patients (Radford et al. 1990). 2.1 Distribution Volume of distribution (V d) values revealed that ifosfamide largely distributes into body water. The volume of the central compartment (Ve) approximately corresponds to vascular and extracellular space, which might reflect the lack of protein binding with ifosfamide, as it does for cyclophosphamide (Bagley et al. 1973; Voelcker et al. 1978). 2.2 Elimination Half-Life After a single bolus injection or short intravenous infusion of ifosfamide, the terminal elimination half-life (tt;2~) of ifosfamide in the serum,

441

Ifosfamide Clinical Pharmacokinetics

plasma or blood ranged from 4 to 8 hours, with wide interindividual variation (table I). In contrast to the results from other investigators, Allen et al. (1976) reported a tI;2~ of 15 hours and a renal excretion of 53.1 %. These results may deviate from those reported previously because of differences in the applied extraction method used by Allen et al. (1976), since without all the separation steps ifosfamide and hydrophobic metabolites, such as 2- and 3-dechloroethyl-ifosfamide may be determined together (Wagner et al. 1981). The dependency of the metabolic activation of ifosfamide on the cytochrome P450 system may well explain the great interindividual variability in the tI;2~ reported in most pharmacokinetic studies. To date, dose-dependent saturation of enzymatic activation has not been reported. When ifosfamide was administered in a single dose of up to 5 g/m2 (Cerny et al. 1986), no prolongation ofthe tI;2~ was observed, and decline in plasma ifosfamide concentrations remained a first-order process. Preliminary data obtained in a dose-intensification study indicate that ifosfamide metabolism may be saturated at doses above 14 g/m2 (T. Cerny and A. V. Boddy, personal communication). However, the mixed function oxidases may act via a suicide mechanism, which may cause a prolongation of tI;1~ at very high doses of ifosfamide. 2.3 Excretion Depending on the age of patients and the method of determination, a broad range in total urinary excretion of ifosfamide was reported (table I). Although no data on the faecal excretion of ifosfamide have been published, on the basis of faecal excretion of cyclophosphamide (Bagley et al. 1973; Brock & Horhorst 1967) it may be assumed that this route of excretion does not exceed 1% of the administered dose of ifosfamide. Thus, in common with cyclophosphamide, total clearance of ifosfamide is mainly via metabolism, which consists of the activation of ifosfamide by mixed function oxidases (via cytochromes P450) predominantly in the liver and to a lesser extent in the lung (Brock & Hohorst 1967).

Table I. Mean pharmacokinetic paramelers of ifosfamide Pharmacokinelic parameler

Dose (glm2)

Reference

Elimination half-life (h) 3.8-5.0

Allen el al. (1976)

2.1"

3.0

Boddy el al. (1993)b

5.9

1 and 2g (Iolal dose) Cerny el al. (1986)

6.4

1.5

Kurowski & Wagner (1993) Lind el al. (1989a)

15.2

6.2

1.5

7.7

1.5-5.0

Philip el al. (1988)

5.9

1.0

Wagner & Drings (1986)

5.7

2.0

Wagner & Drings (1986)

6.0

20 mglkg

Wagner el al. (1981)

Volume of distribution (L) 32.2

1.5

Cerny el al. (1986)

40.3

1.5

Lind el al. (1989a)

33.7

1.5

Lind el al. (1989b)

Volume of the central compartment (L) 34.0

3.8-5.0

Allen el al. (1976)

20.2

2.0g (Iolal dose)

Cerny el al. (1986)

Total body clearance (LJh) 5.04 Uh/m2

3.0

Boddy el al. (1993)b

4.32

2.0g (Iolal dose)

Cerny el al. (1986)

4.15

1.5

Lind el al. (1989a)

4.33

1.5

Lind el al. (1989b)

4.60

1.5-5.0

Philip el al. (1988)

Renal clearance (LJh) 1.28

3.8-5.0

Allen el al. (1976)

0.66 Uh/m2

3.0

Boddy el al. (1993)b

0.66

1.5

Lind el al. (1989a)

Urinary excretion (% of dose) Allen el al. (1976)

53.1

3.8 - 5.0

14-34

1.0 - 3.0

Boos el al. (1992)b

18.0

3.0

Gilard el al. (1993)

18.0

1.6

Gore~

1.5

Lind el al. (1989d)

3.0

Martino el al. (1992)

0-6.34 16.6

a AI Ihe end of a 3-day infusion. b

Sludies undertaken in children.

(1991)

442

Clin. Pharmacokinet. 26 (6) 1994

is present in equilibrium with its acyclic tautomer aldo-ifosfamide. These metabolites split spontaneously into the direct alkylating ifosfamide mustard and the nonalkylating acrolein (Hill et al. 1973). From experience with cyclophosphamide it is known that this metabolic step, also called toxification, can be enzymatically accelerated by a 3',5'exonuclease (Bielicki et al. 1983). In addition to toxification metabolism, enzymatic deactivation to 4-keto-ifosfamide or car-

3. Overview of Metabolism The activation of cyclophosphamide by mixed function oxidases takes place exclusively at cyclic carbon-4 position (position 1, fig. 1). In contrast, ifosfamide metabolism occurs via side chain oxidation, a second competitive pathway (position 2, fig. 1) [Norpoth 1976]. Figure 2 depicts an overview of all known pathways for ifosfamide metabolism. Ring oxidation at the carbon-4 position results in formation of 4-hydroxy-ifosfamide, which

CH 2CH2 CI

I

N~ \-1:0 / \

Chloroacetaldehyde CH 2CH 2 CI

H

0=CH-CH2-CI

H

~

CI CH2CH2

0

2-Dechloroethyl-ifosfamide

\/N-~O\ -""""""------<

H

0

'---I

Dechloroethylation

Ifosfamide Activation

CH2CH2 CI

I

\ /0

CI CH 2CH2

OH

N-P=O

R-SH

3-Dechloroethyl-ifosfamide

/ \0

_________

H

4-Hydroxy-ifosamide )/

CH 2CH 2 CI

\

/

H Deactivation

N

0

/ J N-P=O

\

0

4-Keto-ifosfamide

CH2CH2 CI

~JSR

CI CH 2CH 2

I

CI CH2CH 2

Deactivation

\ N-P=O / /

H

\

0

4-Hydroxy-ifosamide

Toxification

Aldo-ifosfamide

Acrolein Ifosfamide mustard

Carboxy-ifosfamide

Fig. 2. Pathways for ifosfamide metabolism. R-SH represents SH-containing endogenous compounds, primarily low and macromolecular thiols.

Ifosfamide Clinical Pharmacokinetics

boxy-ifosfamide from 4-hydroxy-ifosfamide and aldo-ifosfamide, respectively, may occur. These 2 deactivation products do not have any cytotoxic activity. A further, but reversible, detoxification takes place when 4-hydroxy-ifosfamide reacts with sulphydryl groups of either proteins or amino acids resulting in the formation of 4-thioifosfamide. The second metabolic site in the initial metabolism of ifosfamide leads to the liberation of chloroacetaldehyde and the formation of the cytostatically inactive metabolites 3-dechloroethylifosfamide and 2-dechloroethyl-ifosfamide (Norporth 1976). 3.1 Activation ofIfosfamide and Side-Chain Oxidation In this review we use the terms 4-hydroxyifosfamide and 'activated' ifosfamide synonymously to denote the sum of all ifosfamide derivatives, including 4-hydroxy-ifosfamide, aldo-ifosfamide and 4-thio-ifosfamide (fig. 2), that result in liberation of acrolein and the formation of ifosfamide mustard (Kurowski & Wagner 1993; Wagner et al. 1986). Until now no method has existed for the separate detection of activated ifosfamide metabolites in pharmacokinetic studies. However, in view of their common therapeutic potential, their differentiation appears to be unimportant. All activated metabolites will eventually enter one of the two alternative pathways, toxification to ifosfamide mustard or detoxification to 4keto-ifosfamide or carboxy-ifosfamide (fig. 2). Since the urinary excretion of the latter metabolites was found to be negligible (table II) [Gilard et al. 1993; Lind et al. 1989a; Martino et al. 1992], it appears that nearly all of the activated ifosfamide is converted to ifosfamide mustard. During the first 2 decades of ifosfamide research, few data concerning identification and quantitative estimation of activated ifosfamide in humans and animals were published (Arndt et al. 1988; Ikeuchi & Amano 1985; Kurowski & Wagner 1993; Kurowski et al. 1991; Wagner et al. 1981; Wiedemann et al. 1993). This is probably

443

due to the extreme instability of 4-hydroxyifosfamide in blood (Wagner et al. 1981) and to the relatively low peak plasma ifosfamide concentrations (C max) [l to 5 tJ,mollL] observed after administration of therapeutic doses of ifosfamide in patients (table II). After drawing blood samples, the instability of activated ifosfamide requires that samples are processed immediately (Kurowski & Wagner; Wagner et al. 1981). All detailed pharmacokinetic studies published so far, were based on the liberation of acrolein from the activated metabolites and its subsequent formation of 7-hydroxyquinolone after reaction with 3-aminophenol, which can be detected fluorometrically (Alarcon 1968; Voelcker et al. 1979; Wagner et al. 1981). The toxification products derived from activated ifosfamide, acrolein and ifosfamide mustard can not easily be measured in the blood of patients. Immediately after formation, the highly reactive acrolein is inactivated (Wagner et al. 1981). Furthermore, the ultimate alkylating metabolite ifosfamide mustard is relatively instable and only some pharmacokinetic data regarding this metabolite have been published so far (Bryant et al. 1980a, 1980b). The alkylating activity of ifosfamide mustard represents part of the total activity measured by the nitrobenzylpyridine method (Friedman & Boger 1961). Nitrobenzylpyridine alkylating activity associated with all the metabolites was generally higher (Lind et al. 1989a) than that reported for activated ifosfamide (Kurowski & Wagner 1993; Wagner et al. 1981) from which ifosfamide mustard is derived. However, the nitrobenzylpyridine test for ifosfamide metabolites is very nonspecific (Friedman & Boger 1961) and allows only a rough estimate of the overall alkylating activity because several ifosfamide metabolites react positively in the nitrobenzylpyridine test (Roberts et al. 1988). These metabolites will react with different molar extinction coefficients under the applied conditions ofthe method (unpublished observations). Thus, after administration of similar dosages, patients with similar amounts of alkylating activity (measured by the nitrobenzylpyridine

444

Clin. Pharmacokinet. 26 (6) 1994

Table II. Pharmacokinetic parameters of ifosfamide metabolites Metabolite

Ifosfamide dose (g/m2)

Cmax

AUC

Urinary

(IimoI/L)

(IimoI/L. h)

excretion

Reference

(% of dose)

20mg/kg

1.5

1.5

2.7

6.4

1.5

1.5

11.3

NBP-activity

1.5

7.9 a

Ifosfamide mustard

2.0

Chloroacetaldehyde

1.5

2.7

1.5

8.6

Activated ifosfamide (4-hydroxy-

5.8

0.32

Wagner et al. (1981)

ifosfamide)

2-Dechloroethyl-ifosfamide

3-Dechloroethyl-ifosfamide

4-Keto-ifosfamide

Carboxy-ifosfamide

a

Kurowski et al. (1991) Kurowski & Wagner (1986) Lind et al. (1989a)

132a

Bryant et al. (1980b)

18

Kurowski & Wagner (1986)

30.3

Kurowski & Wagner (1986)

111

1.0-3.0

4.3

Boos et al. (1992)

3.0

4.6

Martino et al. (1992)

3.0

4.0

Gilard et al. (1993)

1.6

7.0

Goren (1991)

1.5

12.9

Kurowski & Wagner (1986)

144

1.0-3.0

13.5

Boos et al. (1992)

3.0

10.4

Martino et al. (1992)

3.0

11.0

Gilard et al. (1993)

1.6

16.0

Goren (1991)

1.5

0.064

3.0

0

Lind et al. (1989a) Martino et al. (1992)

3.0

0

Gilard et al. (1993)

1.5

1.3

Lind et al. (1989d)

3.0

2.3

Martino et al. (1992)

3.0

3.3

Gilard et al. (1993)

mg/L nitrogen equivalents.

Abbreviation: NBP = nitrobenzylpyridine.

test) might have quite different concentrations of the various metabolites of ifosfamide. The pharmacokinetic profile of 4-hydroxyifosfamide parallels the concentration-time curves measured for ifosfamide, but because of its high spontaneous decomposition rate and metabolic clearance, plasma concentrations only reach 1% of the concentration of parent drug (Kurowski & Wagner 1993). Although the overall metabolism is essentially the same for both cyclophosphamide and ifosfamide (Norpoth et al. 1976; Wagner et al. 1981), mean values for the C max of activated cyclophosphamide and the area under the plasma concentration-time curve (AVC) were 3-fold higher

than those reported for activated ifosfamide (Wagner et al. 1981). These findings support earlier results (Norpoth 1976; Norpoth et al. 1976), and have been more recently confirmed by other investigators (Boos et al. 1992; Lind et al. 1989d), who considered that the oxidation of the chlorethyl side chains was the predominant pathway of ifosfamide metabolism. Since chloroacetaldehyde, the primary metabolite of side chain oxidation, does not contribute directly to the cytostatic action of ifosfamide, the different metabolic patterns may well explain the need for higher dosages of ifosfamide to obtain cytotoxic effects equal to cy-

Ifosfamide Clinical Pharmacokinetics

clophosphamide both experimentally (Goldin 1982) and clinically (Brade et al. 1985). The first evidence for the existence of side chain oxidation and liberation of chloroacetaldehyde was obtained by the detection and quantification of dechloroethyl-metabolites of ifosfamide in urine (Norpoth 1976; Norpoth et al. 1976). The dechlorethylation metabolites 2- and 3-dechloroethyl-ifosfamide are relatively stable and nonalkylating under physiological conditions. Therefore, cumulative urinary excretion of these metabolites can provide an estimate of side chain oxidation of ifosfamide (table II) [Boos et al. 1992; Gilard et al. 1993; Goren 1991; Martino et al. 1992]. Excretion of 3-dechloroethyl-ifosfamide was approximately 3-fold higher than that of 2dechloroethyl-ifosfamide. This finding was recently confirmed by studies on serum pharmacokinetics (Kurowski & Wagner 1993). Therefore, it appears that side chain oxidation at the nitrogen ring position is more common that oxidation of the exocylic nitrogen of ifosfamide (Kurowski & Wagner 1993). During the first years of ifosfamide research it remained unclear whether free plasma concentrations of chloroacetaldehyde existed or whether this highly reactive metabolite was inactivated as it was being formed, e.g. by reaction with thiol groups. In the meantime several groups have reported greatly differing plasma chloroacetaldehyde concentrations (Cerny & Kupfer 1989; Goren et al. 1986; Kaijser et al. 1993; Kurowski & Wagner 1993; Kurowski et al. 1991). After infusion of ifosfamide 1.6 g/m2, Goren et al. (1986) reported plasma chloroacetaldehyde concentrations of up to 100 IlmollL in children. Similarly, Cerny and Kupfer (1989) found serum ifosfamide concentrations up to 210 IlmollL. In contrast, following a regimen of ifosfamide 1.5 g/m2/day for 5 days, which was a dosage similar to that used by Goren et al. (1986), our group measured mean C max values for chloroacetaldehyde of 5 Ilmol/L in adults (Kurowski & Wagner 1993). It is doubtful, that these considerable differences in chloroacetaldehyde concentrations are exclusively due to a difference in the ex-

445

tent of metabolism in children and in adults. Although chloroacetaldehyde itself is highly reactive and instable because of its aldehyde group, the plasma chloroacetaldehyde concentrations reported by Goren et al. (1986) and Cerny and Kupfer (1989) are more than 1 order of magnitude higher than those measured for activated ifosfamide (Kurowski & Wagner 1993; Wagner et al. 1981). In addition, these high plasma chloroacetaldehyde concentrations also exceeded values obtained for the stable dec hi oro ethyl metabolites (Kurowski & Wagner 1993), nearly reaching concentrations achieved by the parent drug. Unfortunately, the data by Goren et al. (1986) were published as correspondence, and therefore details on trial methodology and pharmacokinetic interpretation were absent. More data on the pharmacokinetics of chioroacetaldehyde and its renal excretion are urgently required, because the formation of this metabolite is an important quantitative difference between ifosfamide and cyclophosphamide metabolism (Norpoth 1976). Furthermore, the chloroacetaldehyde metabolite may also account for difference in side effects and therapeutic effects between ifosfamide and cyclophosphamide (see section 10). For example, the role of chloroacetaldehyde in the development of ifosfamide-associated nephrotoxicity has been discussed recently (see section 10.1). It might well be that ifosfamide-induced renal tubular toxicity, which is not observed during cyclophosphamide treatment (Fraiser et al. 1991), is caused by chloroacetaldehyde. This compound substantially depletes intracellular glutathione at clinically achievable concentrations (Ishikawa et al. 1989; Lind et al. 1989c) and, therefore, may predispose the renal tubules to cellular damage (Lind et al. 1989c; McGown & Fox 1986). Glutathione depletion may also support the cytotoxicity of the alkylating metabolites against tumour cells. This may overcome the relative resistance of cells to alkylating agents as a result of increasing amounts of intracellular glutathione (Ball et al. 1966; Hergcbergs et al. 1992; McGown & Fox 1986; Wang & Tew 1985). This mechanism may

446

explain the lack of a complete cross-resistance between cyclophosphamide and ifosfamide (Bierbaum et al. 1981; Bramwell et al. 1987; Rodriquez et al. 1978), and the greater antitumour activity in some experimental (Goldin 1982) and human malignancies (Brade et al. 1985; Bramwell et al. 1987; Wheeler et al. 1986). However, more experimental and pharmacokinetic data are needed to support this hypothesis.

4. Pharmacokinetics of Fractionated Intravenous Ifosfamide Therapy As clinical and experimental studies have shown that fractionated doses of ifosfamide have a better therapeutic index than a single bolus injection (Klein et al. 1984; Morgan et al. 1982), the drug is usually given in a divided-dose schedule over a period of several days or as continuous infusion (Brade et al. 1985). It has repeatedly been reported that fractionation of the ifosfamide dose over several days produces a time-dependent decrease in the tI;2~ of ifosfamide, without causing an increase in renal clearance (D'lncalci et al. 1979; Kurowski & Wagner 1993; Kurowski et al. 1991; Lewis et al. 1990; Lind et al. 1989a; Nelson et al. 1976; Piazza et al. 1984; Wagner & Drings 1986; Wagner & Ehninger 1987). It has been suggested that ifosfamide induces its own hepatic metabolism (Kurowski & Wagner 1993; Kurowski et al. 1991; Lind et al. 1989a; Wagner & Drings 1986; Wagner & Ehninger 1987), and it has been demonstrated that there is a parallel increase in urinary excretion of metabolites of ifosfamide and AVC values for plasma alkylating activity (Lind et al. 1989a). Recently it was shown that during a 5-day observation period Cmax and AVC values for 4hydroxy-ifosfamide and the dechloroethylation metabolites increased nearly 2-fold (Kurowski & Wagner 1993). Acceleration of ifosfamide metabolism was also found during continuous infusion of the drug over 3 days in children (Boddy et al. 1993). The extent of the increase in metabolism was virtually the same for the 2 initial metabolic path-

Clin. Pharmacokinet. 26 (6) 1994

ways of the parent drug, without any evidence of a shift in the metabolic pattern during the treatment period (i.e. the ratio of metabolites remained unchanged although the rate of metabolism was increased) [Kurowski & Wagner 1993]. Several investigators reported that the autoinduction of ifosfamide metabolism, which was also seen during treatment with cyclophosphamide (D'lncalci et al. 1979; Graham et al. 1983; Schuler et al. 1987; Sladek et al. 1980, 1984), had begun by the second day of treatment and increased continuously during the following days of therapy (Boddy et al. 1993; Wagner & Ehninger 1987). Data obtained during treatment with cyclophosphamide revealed that the increase in metabolism was dose-dependent (Schuler et al. 1987; Wagner & Ehninger 1987). If we assume that the Cmax and AVC values for activated ifosfamide reflect the cytostatic activity of a given dose of ifosfamide, then available evidence suggests that administration of ifosfamide in divided doses produces an increase in the antineoplastic effects of the drug. Whether maximal autoinduction is achieved within 5 days of fractionated administration of ifosfamide remains to be determined, but should be subject to further investigation.

5. Pharmacokinetics of Ifosfamide Administered by Oral or Subcutaneous Routes Ifosfamide is usually administered intravenously in divided doses over a period of several days (Brade et al. 1985). These administration protocols often require patients to be hospitalised, when they may be otherwise treated as outpatients. To overcome this problem, oral formulations of the drug have been developed (Wagner & Drings 1986). In common with cyclophosphamide (D'lncalci et al. 1979; Wagner & Fenneberg 1984a), it has been shown that the bioavailability of orally administered ifosfamide is close to 100% (Cerny et al. 1986; Kurowski et al. 1991; Wagner & Drings 1986). Probably as a result of first-pass metabolism, the Cmax values for4-hydroxy-ifosfamide and

Ifosfamide Clinical Pharmacokinetics

chloroacetaldehyde were about 2-fold higher than those obtained during intravenous administration of the same dose of ifosfamide (Kurowski et al. 1991). Other pharmacokinetic parameters were not different after oral administration of the drug. Gastrointestinal tolerance of oral ifosfamide is good. However, oral administration resulted in an unacceptably high incidence of central nervous system (CNS) toxicity (about 50%) [Cerny et al. 1986, 1989; Kurowski et al. 1991; Lind et al. 1989a; Wagner & Drings 1986]. Such a large incidence of CNS toxicity is unusual at conventional doses 1.3 and 2.0 g/m2 of the drug administered intravenously (Brade et al. 1985). Oral administration of ifosfamide resulted in higher concentrations of chloroacetaldehyde than those that were obtained after intravenous administration, and it was suggested that this caused the high incidence of neurotoxic effects (Kurowski et al. 1991). However, this hypothesis becomes doubtful when one considers the recent results obtained in patients receiving fractionated intravenous ifosfamide therapy (Kurowski & Wagner 1993). Although no CNS toxicity was observed in a series of 11 patients treated with intravenous ifosfamide 1.5 g/m 2/day over 5 days, by the fifth day of treatment plasma chloroacetaldehyde concentrations were as high as those achieved after a single oral administration of the same dose (Kurowski & Wagner 1993). Thus, besides chloroacetaldehyde, other as yet unidentified metabolites may be responsible for the unacceptably high incidence of encephalopathy associated with oral administration of ifosfamide. As long as these problems remain, oral administration of ifosfamide cannot be recommended for the treatment of cancer at dosages conventionally administered intravenously (Lind et al. 1989a). Pharmacokinetic data indicate that ifosfamide has a bioavailability of 90 to 100% when the drug is administered subcutaneously with mesna over periods ranging from 10 hours to 5 days (Cernyet al. 1990). This route of administration produced neither significant local toxicity nor neurotoxicity at doses of 1.1 to 16g. Therefore, subcutaneous infusion of ifosfamide for up to 14 days clearly has

447

important applications and may be well suited for administration to outpatients. Additionally, a portable mini pump may be used to administer ifosfamide as a continuous intravenous infusion. This method of administration may result in nonfluctuating concentrations of ifosfamide, and may be useful for outpatient treatment (Lokich et al. 1991).

6. Influence of Hepatic and Renal Function 6.1 Influence of Hepatic Function on the Activation of Ifosfamide Since the enzymatic activation of ifosfamide occurs mainly in the liver (see section 3.1), hepatic dysfunction may disturb the metabolism of ifosfamide and consequently diminish cytostatic efficacy of the drug. Surprisingly, however, no pharmacokinetic and clinical data had been published before the end of 1993. It is known that, in patients with pathologically reduced serum cholinesterase concentrations, the tYz~ of cyclophosphamide increases and, concomitantly, Cmax values for activated cyclophosphamide are significantly reduced (Wagner et al. 1980). However, as a result of the low renal clearance of cyclophosphamide and activated cyclophosphamide, more than 80% of the drug is metabolised even in patients with hepatic dysfunction and the AVC for activated cyclophosphamide remains relatively unchanged compared with that observed in patients with normal hepatic function. Because the hepatic metabolism of ifosfamide is similar to that of cyclophosphamide, it is reasonable to assume that the metabolism of ifosfamide will be similarly affected. 6.2 Renal Impairment With respect to the high extrarenal clearance of ifosfamide, activated ifosfamide and chloroacetaldehyde, the influence of renal impairment on the pharmacokinetic profile of ifosfamide and its primary metabolites should be negligible. However, this assumption was not examined in studies in patients. During treatment with cyclophosphamide

448

there was no change in the pharrnacokinetic profile of the parent drug and its activated metabolite, even in an anuric patient (Wagner et al. 1980). However, accumulation of toxic directly alky lating metabolites occurred in this anuric patient (Wagner et al. 1980) and in 2 earlier studies in patients with renal failure (Bagley et al. 1973; Mouridsen & Jacobsen 1975). On the basis of these data andclinical experience, dosage reduction in patients with renal failure was recommended (Wagner et al. 1980). Therefore, although there is no substantial pharrnacokinetic or toxicity data from clinical trials to support such a recommendation for ifosfamide, it would be prudent in the interests of clinical tolerability for the dosage of ifosfamide to be reduced in patients with renal failure.

7. Influence of Age and Bodyweight The effect of age on the pharmacokinetics of ifosfamide in patients with lung cancer was studied by Lind et al. (1990). A positive correlation between the elimination of ifosfamide and age was found in patients with lung cancer, with an increased tYz~ in elderly patients (Lind et al. 1990). This was due to an increase in the V d that occurred with age. Total plasma clearance, renal clearance and nonrenal clearance did not change with age. Furthermore, age did not affect the autoinduction of ifosfamide metabolism (Lind et al. 1990). In children the V12~ of ifosfamide (Boddy et al. 1993) was shorter than values previously reported for adults, and the renal excretion of ifosfamide and its dechloroethyl metabolites seemed to be somewhat higher than that in adults (tables I, II) [Boos et al. 1992; Goren 1991]. The tY2~ of ifosfamide is prolonged in obese patients, probably as a result of an increased V d (Lind etal.1989b). Importantly, however, taking into account the great interindividual variation of ifosfamide metabolism, it seems likely that the small statistically significant differences in pharrnacokinetic parameters in these patient groups will not be clinically relevant when ifosfamide is used as a cytostatic agent in the treatment of cancer.

Clin. Pharmacokinet. 26 (6) 1994

8. Influence of Genetic Factors Most authors reported wide interindividual variation in ifosfamide metabolism (Kurowski & Wagner 1993; Lind et al. 1989a,d; Norpoth 1976). This could result in variability in the therapeutic response and adverse reactions to ifosfamide in individual patients. Since the enzymatic capacity of the mixed function oxidases or cytochrome P450 isoenzymes depends on genetic factors (Kalow 1987), it was assumed that congenital conditions could influence the metabolism of ifosfamide. For example, debrisoquine 4-hydroxylation capacity is bimodally distributed (Mahgoub et al. 1977), with most British Caucasians being extensive metabolisers and a much smaller proportion of the population being poor metabolisers (Evans et al. 1980). Philip et al. (1988) determined the pharrnacokinetic profile of ifosfamide and the plasma nitrobenzylpyridine-alkylating activity in patients who had been phenotyped for debrisoquine oxidation. Of the 33 patients studied, 3 were poor metabolisers. The debrisoquine metabolic ratio did not correlate with either the total plasma clearance of ifosfamide or the AUC of the plasma nitrobenzylpyridine-alkylating activity. Other drugs that are markers for oxidation and are substrates of different cytochrome P450 isoenzymes should be investigated (Philip et al. 1988) to further elucidate the effects of cytochrome P450 isoenzymes on the metabolism of ifosfamide. However, the pharrnacokinetic parameters of ifosfamide and its metabolites follow a normal or log-normal distribution profile in male and female patients with cancer (D'Incalci et al. 1979; Lind et al. 1989d), indicating that metabolic polymorphism has no effect on any route of metabolism.

9. Drug Interactions Many drugs are metabolised by mixed function oxidases. If these drugs are administered repeatedly they either inhibit or induce this enzymatic system (Bums & Conney 1965). In the case of the simultaneous administration of ifosfamide and a drug that interferes with mixed function oxidases,

Ifosfamide Clinical Pharmacokinetics

both drugs may compete with each other for interaction with the enzyme depending on their respective Km (Michaelis-Menten constant) values. Although there is no doubt that these interactions could be clinically relevant, only a single animal study investigating this type of drug interaction has been published (Furusawa et al. 1989), and no clinical data are available to date. Furusawa et al. (1989) found that the toxicity of ifosfamide was potentiated in mice, and that plasma concentrations of active ifosfamide were increased after pretreatment with chlordiazepoxide, diazepam and oxazepam. Studies investigating drug interactions with cyclophosphamide have been published (Grochow & Colvin 1983). Phenobarbital (phenobarbitone), which is known to strongly induce the function of mixed oxidases, decreased the t~~ of cyclophosphamide and concomitantly increased C max values of plasma alkylating activity in patients when a daily dose of phenobarbital 90mg was given (Jao et al. 1972). In contrast, allopurinol 300 mg/day increased the tI/2~ of cyclophosphamide significantly in patients (Bagley et al. 1973). However, the total concentration of metabolites was only slightly affected by concomitant allopurinol. The clinical relevance of this interaction remains unclear. There is an urgent need for further studies investigating the effect of drug interactions on the clinical efficacy and tolerability of ifosfamide in patients with cancer.

10. Toxicity Associated with Ifosfamide 10.1 Urotoxicity Ifosfamide is less myelosuppressive than cyclophosphamide (Wheeler et al. 1986), but is more urotoxic (Brade et al. 1985). In the early stage of ifosfamide evaluation it became evident that for the treatment of some malignancies ifosfamide was more effective than cyclophosphamide (Brade et al. 1985; Goldin 1982). Nonetheless, the extensive urotoxicity associated with ifosfamide use initially deferred its widespread use for the treatment of cancer.

449

Urotoxicity associated with ifosfamide and cyclophosphamide was assumed to be caused by the highly reactive metabolite acrolein (Brock et al. 1979; Cox 1979). However, concentrations of acrolein in the urine have not yet been reported. Our group demonstrated a relatively high stability of activated ifosfamide and cyclophosphamide in protein-free urine; however, this was pH-dependent (Wagner et al. 1981). Thus, acrolein was liberated at a low rate (Wagner et al. 1981), and the actual concentration of acrolein was only 0.001 % of the concentration that induced haemorrhagic cystitis when acrolein was directly instilled in the bladder of rats (Brock et al. 1979). Therefore, it is unlikely that acrolein is an important factor in the development of urotoxicity associated with ifosfamide (Wagner et al. 1981). Instead it is possible that 4-hydroxy-ifosfamide directly contributes to the urotoxic adverse effects, since its concentration in the urine, despite a relatively low rate of excretion, is 50-fold higher than its blood concentration (Wagner et al. 1981). Activated oxazaphosphorine metabolites permeate rapidly into cells and are specifically bound there by SH-groups under preservation of their alkylating capacity (Draeger & Hohorst 1976). By the later decomposition of intracellularly bound activated ifosfamide into the directly alkylating ifosfamide mustard, the liberated acrolein may produce a cytostatic effect as it is being formed (Wagner et al. 1981). It would appear that the urotoxicity of ifosfamide may be multifactorial in aetiology, resulting from both the directly alkylating metabolites (Wagner et al. 1981) and chloroacetaldehyde (Colvin 1982; Norpoth 1976). While cyclophosphamide treatment only causes bladder toxicity, long term treatment with highdose ifosfamide also produces nephrotoxicity (Burk et al. 1990; Goren et al. 1987, 1989; Moncrieff & Foot 1989; Sangsteret al. 1984; Skinner et al. 1989a, 1989b). In the kidney, ifosfamide mostly induces renal tubular damage, with excessive potassium loss, which has partially been described as Fanconi's syndrome (Moncrieff & Foot 1989). The pathogenesis of the renal tubular dam-

450

CZin. Pharmacokinet. 26 (6) 1994

4-Hydroxy-ifosamide Deactivation Stabilisation

Acrolein

Mesna

Inactivation

Fig. 3. Supposed mechanism of interaction between mesna and some ifosfamide metabolites.

age has not yet been elucidated. However, as already discussed, chloroacetaldehyde may contribute to this toxicity. 10.2 Prevention of Urotoxicity by Administration of Thiols Urotoxicity, especially haemorrhagic cystitis, of ifosfamide was the dose-limiting adverse effect in the clinical evaluation of this cytostatic drug (Brade et al. 1985). Enhanced diuresis and administration of thiols have been attempted to overcome this problem. The protective action of thiols towards alkylating cytostatic agents has been known for many years (Brandt & Griffin 1951), and has been investigated extensively by Connors (1966). The sulphydryl group of the thiols serve as nucleophilic partners that are preferentially alkylated. As a result of the irreversible loss of their alkylating capacities, not only the toxic effects, but also the antitumour effects, of the alkylating cytostatic agents are substantially restricted. Thus, detoxification procedures would not be expected to provide an overall therapeutic benefit (Connors 1966). With oxazaphosphorine cytostatic agents, such as ifosfamide, the reaction with sulphydryl groups mainly takes place on a second functional group at the 4-hydroxy-position yielding 4-(SR)-sulphidooxazaphorines (fig. 2). From these derivatives the

activated metabolites can be released by hydrolysis, depending upon the molar ratio of the reaction partners (Brock & Hohorst 1967; Draeger et al. 1976; Peter et al. 1976; Voelcker et al. 1984; Wagner et al. 1987). Thus, the alkylating capacity of the activated metabolites is not abolished by the reaction with sulphydryl groups. However, administration of thiols in amounts large enough to prevent adverse effects such as urotoxicity may also attenuate the desired therapeutic activity (Wagner et al. 1987). During treatment with ifosfamide the systemic use of acety1cysteine was evaluated clinically. Acety1cysteine was partially uroprotective if ifosfamide was administered in low and fractionated doses (Holoye et al. 1983; Slavik & Saiers 1983). With higher doses of ifosfamide the administration of acetylcysteine is not recommended because high doses of acetylcysteine, which are themselves accompanied by adverse effects, have to be administered (Brock et al. 1981b). Furthermore, in common with the experimental data reported for cysteine (Connors 1966; Wagner et al. 1987), it may be expected that a partial loss of therapeutic activity will also occur. The thiol compound mesna when given in combination with oxazaphosphorine cytostatics provide an example of successful uroprotective agents. Systemically administered mesna results in regional detoxification of the urinary tract (Araujo

Ifosfamide Clinical Pharmacokinetics

& Tessler 1983; Bryant et al. 1980b; Elias et al.

1990; Scheef et al. 1979; Scheulen et al. 1983). Comparison of the efficacy of acetylcysteine and mesna as uroprotective agents in a clinical trial revealed that mesna provided better urothelial protection and was better tolerated than acetylcysteine (Munshi et al. 1992). The supposed mechanism of interaction between mesna and some ifosfamide metabolites is shown in figure 3. According to the results of experimental data (Brock et al. 1982; Millar et al. 1983) and clinical studies (Araujo & Tessler 1983; Scheef et al. 1979; Scheulen et al. 1983) there is not expected to be an effect on the antitumour activity of ifosfamide. The uroprotective activity of mesna and its negligible effect on cytostatic efficacy of ifosfamide is attributed to the distinctive pharmacokinetic profile of mesna. In the blood, reactive mesna is oxidised partially to the chemically stable and physiologically inert disulphide metabolite (dimesna) [James et al. 1987; Pohl et al. 1981; Shaw 1987]. During renal tubular transport, a substantial proportion of dimesna is taken up in to the renal tubular cells and reduced to reactive mesna (Ormstadt & Uehara 1982; Pohl et al. 1981), which then reacts with urotoxic ifosfamide metabolites, e.g. 4-hydroxyifosfamide (Brock et al. 1981a; Manz et al. 1985). Glutathione plays a particular role in the mechanism of dimesna reduction (Brock & Pohl 1983; Brock et al. 1981a; Ormstadt & Uehara 1982). The formation of the mesna/glutathione disulphide and, finally, glutathione disulphide and regeneration of mesna is catalysed by a thiol transferase (fig. 4). Glutathione can then be regenerated by glutathione reductase (Brock & Poh11983; Brock et al. 198Ia). Mesna may also form mixed disulphides with other physiologically occurring thiol compounds, e.g. cysteine (Brock & Pohl 1983; Duran et al. 1981). As with dimesna, these disulphides can be reduced to mesna and cysteine, which are then excreted into the urine (Jones et al. 1985; StoferVogel et al. 1993b; Wright et al. 1985). Cysteine is able to react with ifosfamide metabolites in the same manner as mesna and, thus, cysteine is also

451

involved in regional detoxification (Shaw 1987; Stofer-Vogel et al. 1993b). Mesna is very effective in the prevention of ifosfamide-induced bladder toxicity (Araujo & Tessler 1983; Bryant et al. 1980b; Elias et al. 1990; Scheef et al. 1979; Scheulen et al. 1983). However, its influence on renal tubular toxicity, which is only observed after administration of multiple highdoses of ifosfamide, remains unclear (Goren et al. 1989; Stofer-Vogel et al. 1993b). No data from clinical studies comparing administration of ifosfamide with and without mesna are available. From a theoretical point of view the role of mesna in renal tubular toxicity may be crucial, since the depletion of protector thiols such as glutathione and cysteine by chloroacetaldehyde may be temporarily enhanced by enzymatic reduction of dimesna (Stofer-Vogel et al. 1993b). Although mesna is used as a uroprotective agent, which effectively prevents ifosfamide-induced haemorrhagic cystitis, it may also enhance tubular toxicity as a result of associated glutathione depletion. The relatively rapid elimination of mesna (Goren 1992; James et al. 1987) in the urine compared with the prolonged urinary elimination of ifosfamide metabolites requires repeated injections of mesna be given at 4-hourly intervals for at least 8 hours after bolus injection or short term infusion of ifosfamide. If ifosfamide is given in a high dose by continuous infusion, simultaneous infusion of mesna during ifosfamide treatment and for at least 8 hours after the end of ifosfamide in-

MSSM+ GSH

MSSG+MSH

MSSM+ GSH

GSSG+MSH

GSSG+NADPH

Fig. 4. Mechanism of dimesna reduction in renal tubular cells (according to Ormstadt & Uehara 1982). Abbreviations: GSH = glutathione; GSSG = glutathione disulphide; MSH = mesna; MSSM = mesna disulphide (dimesna); MSSG = mesnalglutatione disulphide; NADPH and NADP+ = reduced and oxidised form of nicotinamide-adenine dinucleotide phosphate, respectively.

452

fusion is preferable (Brade et al. 1985). Furthermore, the drugs may be given together through the same infusion device. When administered orally, mesna is rapidly absorbed with an average bioavailability of about 50% (James et al. 1987; Jones et al. 1985). These preparations may be more practicable for outpatient therapy (Goren 1992). However, bad taste and odour limits the use of mesna solutions in patients with cancer, who often have concurrent nausea and vomiting. To overcome this problem mesna was formulated as tablets, and this formulation is now undergoing clinical evaluation (Stofer-Vogel et al. 1993a). Approximately 51 % of the administered dose was available in the urine (Stofer-Vogel et al. 1993a). Mesna is a very polar thiol. By virtue of this polarity it does not passively cross lipid cell membranes (Shaw et al. 1986). Therefore, it does not enter most cells, with the exception of renal tubular and intestinal cells (Brock et al. 1984). The polarity of mesna may well explain why mesna does not attenuate the cytostatic efficacy of active ifosfamide metabolites. The dose of mesna required for successful uroprophylaxis is about 60% of the ifosfamide dose corresponding to a molar mesna-to-ifosfamide ratio of about 1 (Brock et al. 1981a, 1982). At these doses the cytotoxic efficacy of ifosfamide should not be reduced (Araujo & Tessler 1983; Elias et al. 1990; Scheef et al. 1979; Scheulen et al. 1983). However, when mesna is administered in doses exceeding a molar mesna-to-ifosfamide ratio of 2, experimental data demonstrates a partial loss of ifosfamide cytostatic efficacy (Wagner et al. 1987). Therefore, dosages of mesna between 60 and 100% of ifosfamide dosages (on a weight for weight basis) should be used so that a molar ratio of 2 to 1 (ifosfamide to mesna) is not exceeded. 10.3 Central Nervous System Toxicity Chloroacetaldehyde has been associated with CNS toxicity, occasionally observed during treatment with ifosfamide (Brade et al. 1986; Cerny & Kupfer 1989; Delepine et al. 1986; Goren et al.

Clin. Pharmacokinet. 26 (6) 1994

1986; Kellie et al. 1987; Lewis & Meanwell1990; Pratt et al. 1986; Salloum et al. 1987; Watkin et al. 1989). This toxicity is plausibly related to chloroacetaldehyde because this metabolite is structurally related acetaldehyde, the metabolite of alcohol (ethanol), and the hypnotic chloral hydrate (Goren et al. 1986; Kurowski et al. 1991). Furthermore, no CNS toxicity is associated with cyclophosphamide administration, even when the drug is given in the high dosages administered for conditioning before bone marrow transplantation. During treatment with cyclophosphamide negligible amounts of ch10roacetaldehyde are usually detected (Bagley et al. 1973; Colvin 1982). Goren et al. (1986) have reported that in 2 paediatric patients who developed CNS symptoms during treatment with ifosfamide treatment, chloroacetaldehyde concentrations were higher than those observed in a child who did not develop CNS toxicity. However, this observation has not been confirmed to date by other investigators. In one patient, who was treated with continuous infusion of ifosfamide 1.5' g/m2/day, we observed severe CNS toxicity after the second day of treatment. Surprisingly, chloroacetaldehyde concentrations at this time were, immediately prior to discontinuation of ifosfamide infusion, only 3.5 ~mol/L (unpublished observations). Thus, the relevance of chloroacetaldehyde for the development of CNS adverse effects remains unclear. Furthermore, during oral ifosfamide treatment (1.3 to 2.0 g/m2) the majority of patients suffered from CNS toxicity (Cerny et al. 1986; Wagner & Drings 1987; Wagner & Fenneberg 1984b), whereas the same doses given intravenously were not usually followed by CNS toxicity.

11. Conclusions Despite the fact that the metabolic and pharmacokinetic properties of ifosfamide are similar to that of its progenitor compound cyclophosphamide, there is no complete cross-resistance between the 2 drugs. This may be due to the metabolic generation of chloroacetaldehyde by side-chain oxidation of ifosfamide, which contrasts with the

Ifosfamide Clinical Pharmacokinetics

metabolism of cyclophosphamide. Glutathione depletion caused by chI oro acetaldehyde may enhance not only the drug action in the tumour cells, but also the systemic toxicity, particularly the eNS and renal tubular toxicity,

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Correspondence and reprints: Professor T. Wagner, Section of Hematology and Oncology, Department of Internal Medicine, Medical University of Lubeck, D-23538 Lubeck, Germany.