PDFlib PLOP: PDF Linearization, Optimization, Protection

Page inserted by evaluation versionwww.pdflib.com – sales@pdflib.com

483

A Trial to Investigate the Relationshipbetween DFO Pharmacokinetics andMetabolism and DFO-Related Toxicity

J. B. PORTER,a,c A. FAHERTY,a L. STALLIBRASS,b

L. BROOKMAN,b I. HASSAN,b AND C. HOWESb

aDepartment of Haematology, University College London, EnglandbNovartis Pharmaceuticals, Horsham, England

The iron chelator Desferrioxamine (DFO) has been established as a safe, life-savingtreatment for patients with iron overload. With the increased use of more intensive

DFO regimens in the 1980s, a number of unwanted effects were observed, most notablyhigh frequency sensorineural hearing loss, visual electroretinographic disturbances, andimpaired growth and bone development. These effects have been largely associated withthe use of high DFO doses in patients with relatively low degrees of iron overload asshown by a therapeutic (Porter) index of >0.025 (mean daily dose mg/kg divided by serumferritin µg/L).1,2,3 However, because serum ferritin can be an unreliable indicator of ironoverload an additional independent method of identitfying at risk patients would be desir-able. In this study we have sought to establish whether there is an intrinsic difference inDFO metabolism between patients who have demonstrated evidence of previous DFO-related audiometric or retinographic toxicity compared with matched patients lackingthese complications.

In previous preliminary studies a possible relationship between the proportion ofmetabolite B in relation to unmetabolized DFO and DFO toxicity was suggested.4,5 Wetherefore considered it valuable to examine whether there is an intrinsic differencebetween DFO metabolism in patients with and without previous DFO-related audiovisualtoxicity or whether this ratio is more a reflection of current iron overload status in relationto current chelation.

PATIENTS AND METHODS

Sixteen patients with homozygous β thalassemia age >14y < 45y who had previouslyreceived DFO for > 1 yr and had been shown to have audiometric and or electroretino-graphic DFO related toxicity (n = 8) or not to have these disturbances (n = 8) were selected.Ototoxicity was defined as high frequency bilateral sensorineural deficit of greater than20db during pure tone auctiometry not attributable to middle ear disease.2 Retinal toxicitywas defined as previously.6 Additional information about osteopenia, spinal bone densito-metry L1-L4 in g/cm2, spinal x-ray changes, growth history and crown-pubis/total heightratio % was obtained but not included in the stratification criteria (TABLE 1). The two groups

cCorrespondence should be addressed to Dr. J. B. Porter, Reader and Consultant, Department ofHaematology, University College London Hospitals, 98 Chenies Mews, London WC 1 E 6HX; Tel:0171 209 6224; Fax: 0171 209 6222; E-mail: j.porter@ucl.ac.uk

were matched for serum ferritin (+ 500 µgL in the previous 12-month period). DFO waswithheld for 72h prior to the study. Patients with active infections including hepatitis A, Band C, or significant organ dysfunction (renal, cardiac, pulmonary) were excluded.

We then asked whether during and following an infusion of DFO of 50mg/kg over24h there was a significant difference in DFO metabolism between patients with andwithout previous DFO toxicity as defined by audiometric and or retinographic distur-bances and whether DFO metabolism related to current iron status and chelation treat-ment as defined by the therapeutic (Porter ) index.2 Patients were admitted to hospital for24h infusion of DFO (50mg/kg). Two consecutive 24h urine collections were made andblood samples for measurement of plasma DFO and metabolites were taken at time0,2h,4h,7h,22h, and 24h. Blood samples were separated, stabilized using minor modifi-cations to previously described methodology.7 The protocol received full ethical com-mittee approval at UCL Hospitals.

RESULTS

The patient and the DFO metabolism data are shown in TABLE 1. For brevity, onlypatients with marked spinal changes are denoted as “spinal X Ray” in the DFO effects col-umn. It can be seen that although the proportion of metabolite B relative to FO (for ana-lytical purposes “FO” = unmetabolized desferrioxamine plus ferrioxamine) is higher in the“toxicity” group, this does not reach statistical significance. Furthermore there is consid-erable overlap between these ratios in the two groups. It can be seen however that there isa correlation between the current therapeutic index in all patients and the ratio of metabo-lite B/FO AUC (Area Under the Curve) in plasma (r = 0.6) (FIG. 1) and in urine (r = 0.4 ).There is no correlation between spinal densitometry and DFO metabolism (TABLE 1).

484 ANNALS NEW YORK ACADEMY OF SCIENCES

FIGURE 1. The relationship between the current therapeutic index as defined in the text and the ratioof metabolite B of DFO to unmetabolized DFO (FO+DFO) in plasma is shown, where AUC is thearea under the curve for plasma values obtained during pharacokineticmeasurements for each patient.

PORTER et al.: DFO-RELATED TOXICITY 485

TAB

LE

1.

Sex

Age

Ferr

itin

The

rape

utic

DFO

Eff

ects

Spin

alPa

tient

Uri

nea

AU

Cµg

/LIn

dex

Dex

aW

eigh

tFO

met

Bm

et A

B/F

Ob

FOm

et B

B/F

O(g

/cm

2 )(k

g)(m

g)(m

g)(m

g)(µ

g/m

l/L)

(µg/

ml/L

)

m25

2379

0.00

8A

udio

& S

pina

l X r

ay1.

1483

.071

5.1

497.

835

.10.

7024

043

.90.

183

f29

1590

0.02

3A

udio

& S

pina

l X r

ay0.

6957

.038

5.1

590.

627

.31.

5314

989

.40.

6m

1828

010.

0068

Aud

io &

Spi

nal X

ray

0.85

55.7

713.

430

1.4

44.0

0.42

375

47.7

0.12

7f

3615

53A

udio

& S

pina

l X r

ay0.

8845

.236

6.9

389.

868

.51.

0627

436

.30.

132

f33

1367

0.01

7A

udio

met

ry0.

8162

.249

0.0

682.

410

2.9

1.39

286

125

0.43

7f

1986

10.

025

Aut

liom

etry

0.91

61.0

370.

863

5.4

106.

81.

7119

766

.90.

34f

2694

70.

007

Aud

iom

etry

0.69

50.0

520.

245

3.8

178.

20.

8718

732

.20.

172

m33

1520

0.02

2E

RG

and

Spi

nal X

-Ray

0.77

55.8

611.

336

9.3

40.6

0.60

378

77.9

0.20

6M

ean

2716

27.3

0.01

40.

8458

.752

1.6

490

75.4

1.04

261

64.9

0.27

f20

2297

0.01

7no

ne0.

7356

.035

3.5

395.

916

.31.

1214

545

.50.

314

m21

2099

0.01

5no

ne0.

8860

.052

6.8

321.

819

.30.

6117

227

.90.

162

f32

1877

0.01

56no

ne0.

8359

.446

4.7

507.

310

2.8

1.09

167

44.1

0.26

4f

3418

200.

026

none

0.84

50.0

297.

028

1.1

47.2

0.95

104

33.1

0.31

8f

2517

000.

014

none

0.8

54.5

413.

252

7.4

94.9

1.28

311

53.2

0.17

1m

1717

940.

01sp

inal

x-r

ay0.

8740

.061

7.0

224.

894

.40.

3622

523

0.10

2m

1834

180.

013

none

0.86

50.0

809.

428

0.5

43.4

0.35

284

260.

092

f15

1865

0.01

2sp

inal

x-r

ay0.

9560

.014

0.7

194.

326

.71.

3817

970

.90.

396

Mea

n23

2108

0.01

50.

8553

.745

2.8

432

55.6

0.89

198

40.5

0.23

a Uri

ne v

alue

s re

pres

ent c

umul

ativ

e am

ount

s (m

g) o

ver

the

timec

ours

e.

b B/F

O is

the

ratio

of

met

abol

ite B

to f

erri

oxam

ine

(FO

).

DISCUSSION

The results show that there is a relationship between the current regular DFO treatmentin respect to the degree of iron overload, as defined by the current therapeutic index1,2 andthe ratio of metabolite B to total FO (desferrioxamine plus ferrioxamine) in plasma orurine. This is consistent with the hypothesis that metabolite B of DFO, which is a productof the intracellular metabolism of iron free but not iron-bound DFO, inversely reflects theavailability of iron in the plasma compartment. Thus in patients who receive a high amountof chelation, as mean daily dose of DFO in mg/kg, in relation to the iron stores, as reflectedby serum ferritin in µg/L, the proportion of iron-free DFO which is available for metabo-lism is greater. Therefore the proportion ol’metabolite B is higher in urine or blood inpatients who are relatively well chelated.

The finding that the ratio of metabolite B to FO in urine or plasma is not significantlydifferent in patients with or without previous DFO toxicity, as defined by auditory or reti-nal disturbances, is most likely because the ratio of metabolite B to FO reflects the cur-rent state of iron availability at the time of the study, rather than any geneticpredisposition to different DFO metabolism in the two groups. The patients chosen in thisstudy all had demonstrable electroretinographic or audiometric disturbances at the timeof the study but had developed these initially over 5 years previously and since then thetreatment regimes had been adjusted. Thus “at risk” patients are those with a high thera-peutic index2 and a high ratio of B to FO at any point in time. However if the treatmentregime is adjusted, the toxicity risk is corrected together with the therapeutic index andthe ratio of metabolite B/FO. This study suggests that DFO metabolism as measured byB/FO is a surrogate marker for the availability of iron at any point in time, and could inprinciple be used to identify “at risk” patients. However the ratio B/FO only reflects theavailability of chelatable iron, rather than an intrinsic qualitative difference in DFOmetabolism in high risk patients.

It would be of potential value to examine prospectively the relationship between theratio of B/FO in the urine of children with thalassemia on current relatively conservativechelation regimens compared with those employed in the 1980s. This would be of partic-ular interest with regard to growth and bone changes. The latter were not included in thestratification criteria of this study although the patients in TABLE 1 showed these effects.However it is unlikely that inclusion of these as stratification criteria would have alteredthe outcome of this retrospective study because 2 patients in the “no toxicity” groupalthough showing DFO related effects on growth and bone development do not show con-sistent differences from the “no toxicity” group with respect to B/FO ratios (TABLE 1).

It is also possible that B/FO measurement will be of particular value in patients wherethe serum ferritin is an especially unreliable index of iron overload status, such as patientswith active hepatitis C and patients with sickle cell disorders. In these circumstances,because the ferritin can be elevated owing to factors independent of iron overload, the ther-apeutic index will be distorted. However, the ratio of B/FO should not be altered by thesechanges. It would thus be of value to examine the ratio of B/FO in patients with sickle dis-orders, particularly those in whom audio, or other, toxicity has been a recent problem. Itwould also be of value to examine B/FO in patients in whom poor growth or radiologicalchanges associated with DFO over treatment has been a problem. For these studies to beclinically useful, it would be of value first to establish a reference range for the ratio ofB/FO in urine of a larger number of patients without demonstrable DFO toxicity, asdefined by absence of audiometric, retinographic, growth or skeletal clisturbances, using asimplified protocol which would be applicable to outpatients receiving standard doses ofDFO and collecting urine over 24h.

486 ANNALS NEW YORK ACADEMY OF SCIENCES

In conclusion, this study suggests that the ratio of B/FO, plasma AUC or urine concen-tration, reflects the availability of chelatable iron, and hence risk from excess DFO treatmentat the time the measurement is taken but that there is unlikely to be an inherent qualitativedifference in DFO metabolism in “at risk” patients. Further prospective studies are indicatedto determine whether this is of value in identifying “at risk” patients prospectively.

REFERENCES

1. PORTER, J. B. & E. R. HUEHNS. 1989. The toxic effects of desferrioxamine. Clin. Haem. 2:459–474.

2. PORTER, J. B., et al. 1989. Desferrioxamine ototoxicity: Evaluation of risk factors in thalassaemicpatients and guicdlines for safe dosage. Brit. J. Haemat. 73: 403–405.

3. OLIVIERI, N. F., et al. 1992. Growth failure and bony changes induced by deferroxamine. Am. J.Ped. Hematol./Onc. 14(1): 48–56.

4. PORTER, J. B. et al. 1992. Osteopaenia thalassaemia major: The relevance of desferrioxaminedrug metabolism. (abstract) 24th International Society of Haematology 1992, 184(7).

5. KRUCK, T. P. A. et al. 1993. A predictor for side effects in patients with Alzheimers diseasetreated with deferoxamine mesylate. Clin. Pharmacol. Ther. 53: 30–7.

6. ARDEN, G. B. et al. 1989. Ocular changes in patients following long term desferrioxamine treat-ment. Brit. J. Opthal. 68: 873–877.

7. LEE, P. et al. 1993. Intravenous infusion pharmacokinetics of Desferrioxamine in thalassaemiapatients. Drug Metab. Dispos. 21(4): 640–644.

PORTER et al.: DFO-RELATED TOXICITY 487