Ferrate(1-), [[N,N'-1,2-ethanediylbis[N-[[2-(hydroxy-.kappa.O)phenyl]methyl]glycinato-.kappa.N,.kappa.O]](4-)]-, sodium (1:1), (OC-6-13)-

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

other: study addressed: chelating agent HBED (precursor of Fe(Na)HBED)

Adequacy of study:

supporting study

Study period:

1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented publication

Data source

Reference

Reference Type:

publication

Title:

Preliminary Results from a Phase I Clinical Trial of HBED

Author:

Grady, R.W., Salbe, A.D., Hilgartner, M. W., Giardina, P. J.

Year:

1994

Bibliographic source:

The Development of Iron Chelators for Clinical Use, Raymond J. Bergeron, Gary M. Brittenham, 1994, CRC Press, ISBN:0849386799

Materials and methods

Type of study / information:

A pharmacokinetic study was performed in 4 patients (2 males, 2 females) within the scope of efficacy study on HBED as drug used in chelation therapy.

Endpoint addressed:

basic toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

HBED was tested in humans for its efficacy in treatment of transfusion-induced iron overload in patients with β-thalassemia. Patients were admitted to a Clinical Research Centre for 24 days, during which time they consumed a low iron diet and provided 24-h specimens of urine and stool. DFO (desferrioxamine) (60 mg/kg) was infused subcutaneously over 8 h on days 5 to 10, with HBED being given orally on days 15 to 20. A stool marker was taken orally before the first and the last dose of each drug. Transfusions were given on days 1 and 11 to ensure that the haemoglobin concentration would be the same at the time of administration of each drug. Routine laboratory tests (LT, blood profiles, serum chemistries, and urinalyses) were done approximately every 3 days.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N' diacetic acid

IUPAC Name:

N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N' diacetic acid

Constituent 2

Reference substance name:

35369-53-0

Cas Number:

35369-53-0

IUPAC Name:

35369-53-0

Details on test material:

Pure compound in 250 mg gelatin capsules

Method

Ethical approval:

other: According to FDA permission no IND#36776

Details on study design:

HBED was tested in humans for its efficacy in treatment of transfusion-induced iron overload in patients with β-thalassemia. Patients were admitted to a Clinical Research Centre for 24 days, during which time they consumed a low iron diet and provided 24-h specimens of urine and stool. DFO (desferrioxamine) (60 mg/kg) was infused subcutaneously over 8 h on days 5 to 10, with HBED being given orally on days 15 to 20. A stool marker was taken orally before the first and the last dose of each drug. Transfusions were given on days 1 and 11 to ensure that the haemoglobin concentration would be the same at the time of administration of each drug. Routine laboratory tests (LT, blood profiles, serum chemistries, and urinalyses) were done approximately every 3 days. Special studies (eye examinations, audiograms, and electrocardiograms) were done on days 1-3, 14 and 22-24. A pharmacological study was undertaken upon giving the first dose of HBED. Complete physical examinations were done at admission, before giving HBED and before discharge. Subjective questionnaires were filled out by the patients after each drug treatment.

Exposure assessment:

measured

Details on exposure:

TYPE OF EXPOSURE: oral

TYPE OF EXPOSURE MEASUREMENT: Personal sampling: urine, blood, stool / other: eye examinations, audiograms, electrocardiograms, physical examinations

EXPOSURE LEVELS: The fisrt two patients were given HBED at a dose of 40 mg/kg divided t.i.d. As these patients experienced no difficulties, a permission from FDA was to increase the dose to 80 mg/kg in subsequent patients.

EXPOSURE PERIOD: day 15 to 20

POSTEXPOSURE PERIOD: 4 days

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: not applicable

Results and discussion

Results:

HBED caused an increase in both urinary and faecal iron excretion, with faecal excretion accounting for more than 50% of the total in three of the patients. Upon increasing the dose of HBED from 40 to 80 mg/kg, total iron excretion increased from 11.4% to 16.6%. HBED was significantly less effective than predicted by the animal studies, iron balance ranging from 28 to 48%. While doubling the dose of drug caused an increase in the relative amount of iron excreted, the change was marginal in terms of iron balance. On the other hand, HBED did cause an increase in both urinary and faecal excretion of iron, suggesting that increasing the gastrointestinal absorption of this drug should enhance its efficacy.

Any other information on results incl. tables

TABLE 2 Net Iron Excretion in Response to DFO ami HBED     DFO     HBED     Urine Stool Total Urine Stool Total Patient (mg/d) (mg/d) (mg/d) (mg/d) (mg/d) (mg/d) 1 27.03 33.47 61,40 2.23 8.05 10.78 2 35 .94 43.30 79.24 2,96 2.82       5.78 3 22.92 21.28 44.20 2.54      3.45 5.99 4 11.07 17. I5 28.22 1.53 4.50 6.03     TABLE 3 Iron BaIance in Response to DFO and HBED DFO                                                          HBED   Fe-Ex^a Fe-Tx^b Balance^c Fe-Ex Fe-Tx Balance Patient (mg/kg/d) (mg/kg/d) (%) (mg/kg/d) (mg/kg/d) (%) 1 0.83 0.29 286 0.14 0.29 48 2 1.03 0,29 355 0.08 0.29 28 3 0.96 0.35 274 0.13 0.35 37 4 0.52 0.25 208 0.11 0.25 44 ^aFe-Ex -tolal iron excreted, ^bFe-Tx - iron received in the form of transfused erythrocytes. ^cIron excreted as a percentage of that received.

Applicant's summary and conclusion

Conclusions:

In summary, HBED has proven to be orally effective, inducing iron excretion in both urine and stool. The safety of HBED has been established, the patients experiencing no adverse side effects.

Executive summary:

In summary, HBED has proven to be orally effective, inducing iron excretion in both urine and stool. The safety of HBED has been established, the patients experiencing no adverse side effects. Zinc excretion may be slightly enhanced in response to HBED, but not to levels considered to be toxic. Finally, despite the length of the hospital stay, the patients were enthusiastic about the study and have encouraged others to participate,

In this trial, DFO caused significantly more iron to be excreted than would have been predicted on the basis of serum ferritin levels and past compliance with DFO therapy. This illustrates the danger of using individual serum ferritin values as indicators of body iron load and suggests that serum ferritin levels can be normalized much faster than iron can be removed from the body, Thus, it is suggested that patients whose serum ferritin levels have been reduced to less than 1000 ng/ml be maintained on aggressive DFO therapy until their iron excretion shows a concomitant decrease. Routine measurement of urinary iron excretion should be considered an essential facet of good clinical management in cases of β-thalassemia.

Finally, four additional patients will be given HBED at a dose of 80 mg/kg divided t.i.d. If their levels of iron excretion are not greater than those reported here, they will either increase the dose of HBED to 120 mg/kg or discontinue the study until a prodrug such as the dimethyl ester (dmHBED) is available.