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Diss Factsheets

Toxicological information

Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Pharmacokinetics of intravenous and oral sodium 2-mercaptoethane sulphonate (mesna) in normal subjects
Author:
James, C.A., Mant, T.G.K., Rogers, H.J.
Year:
2013
Bibliographic source:
Br. J. clin. Pharmac. (1987), 23, 561-568

Materials and methods

Type of study / information:
Pharmacokinetics
Endpoint addressed:
basic toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The pharmacokinetics of mesna (sodium 2-mercaptoethane sulphonate) and its inactive disulphide, dimesna, were investigated using high performance liquid chromatography in six normal subjects following intravenous and oral administration of 800 mg mesna.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Mesna
EC Number:
243-285-9
EC Name:
Mesna
Cas Number:
19767-45-4
IUPAC Name:
sodium 2-sulfanylethanesulfonate
Test material form:
other: solution (for injections)
Details on test material:
- Name of test material (as cited in study report): mesna (Uromitexan, Boehringer Ingelheim, Bracknell, Berks)
- Molecular formula (if other than submission substance): C2H5NaO3S2
- Molecular weight (if other than submission substance): 164.18
- Smiles notation (if other than submission substance): C(S)CCS(=O)(=O)O{-}.[Na]{+}
- InChl (if other than submission substance): 1S/C2H6O3S2.Na/c3-7(4,5)2-1-6;/h6H,1-2H2,(H,3,4,5);/q;+1/p-1
- Structural formula attached as image file (if other than submission substance): see Fig.1
- Substance type: organosulphur compound

Method

Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
Six healthy Caucasian subjects (three male, three female; ages 26-54 years; body weights 44-72) took part in the study. Treatments were randomised at each dosing period so that three subjects were randomly assigned to receive an intravenous dose of mesna of 800 mg and three to receive the same solution containing 800 mg mesna orally, diluted in approximately 200 mL orange drink immediately before ingestion. After an interval of 7 days the subjects received the alternate form of medication. Blood samples (3 mL) were collected at the following times: 0 (baseline), 5, 10, 15, 20, 30, 45 min, and 1, 2, 3 and 4 h after intravenous dosing and at 0, 15, 20, 30, 45 min, and 1, 1.25, 1.5, 2, 2.5, 3 and 4 h after oral dosing. Urine was collected during the following periods: 0 (baseline), 0-4
and 4-8 h. Mesna and dimesna were measured in specimens; elimination rate constants (k), half-life, and total body clearance were determined.
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE: i.v. and oral dosing

TYPE OF EXPOSURE MEASUREMENT: Personal sampling

EXPOSURE LEVELS: 800 mg/person

EXPOSURE PERIOD: 2 times/14 days

POSTEXPOSURE PERIOD:

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES:
Treatments were randomised at each dosing period so that three subjects were randomly assigned to receive an intravenous dose of mesna of 800 mg and three to receive the same solution containing 800 mg mesna orally, diluted in approximately 200 mL orange drink immediately before ingestion. After an interval of 7 days the subjects received the alternate form of medication. Subjects reported to the Drug Research Unit at approximately 08.00 h. Each dose was administered after an overnight fast, and no oral intake other than water was allowed until 4 h after drug administration when a light meal was taken. Subjects remained at rest for the first hour of the study but subsequently were allowed to move about at will.

Results and discussion

Results:
I.v. administration:
Plasma: Cmax = 111 ± 28.3 nmol/mL (mesna); Cmax = 183 ± 41.6 nmol/mL (dimesna); t1/2 = 21.8 min (mesna); t1/2 = 1.17 hour (dimesna); total body clearance (CL) = 1.23 ± 0.31 L/ kg x h (mesna + dimesna)
Oral administration:
Plasma: Cmax = 19.6 ± 10.2 nmol/mL (mesna, 5 subjects); Cmax = 22.5 ± 12.4 nmol/mL; No half-lives after oral administration were determined.

Urine:
- after i.v. administration: C(0-4h) = 9.6 µmol/mL (mesna); CL (Renal; 4 h) = 0.413 L/kg x h (uroprotective mesna)
- after oral administration: C(0-4h; 4-8h) = 2.5 ± 1.7 µmol/mL. The urinary availability as mesna alone after oral dosing was 53.0 ± 19.5% of that following i.v. administration. After both i.v. and oral mesna the urinary excretion of mesna is predominantly during the first 4 hours

Any other information on results incl. tables

No subject suffered significant adverse effects due to participation in this study and there were no adverse sequelae following its completion.

Table 1. Pharmacokinetic parameters derived from i.v. administration of mesna
Subject CO
(nmol/ mL)
k(h-1) t1/2 (h) V(L/kg) CL (L/ kg x h) AUCiv
(nmol/ mL x h)
CLR4 h renal clearance
(L/kg xh)
1 157 1.95 0.356
(21.3 min)
0.425 0.829 70.5 0.288
2 106 1.80 0.385
(23.1 min)
0.648 1.17 52.6 0.513
3 145 2.43 0.285
(17.1 min)
0.533 1.30 51.2 0.351
4 164 1.85 0.375
(22.5 min)
0.675 1.25 73.5 0.621
5 151 2.06 0.337
(20.2 min)
0.520 1.07 64.8 0.431
6 73.4 1.58 0.439
(26.4 min)
1.11 1.75 43.5 0.273
Mean 133 1.95 (0.363)
(21.8 min)
0.652 1.23 59.4 0.413
s.d. 35.5 0.287 0.0514
(3.1 min)
0.242 0.305 12.0 0.136

Table 2. Terminal constant of elimination, half-life and AUC calculated from plasma dimesna data following i.v. mesna

Subject k(h-1) (h) AUC
(nmol/mL x h)
1 0.631 1.10 167
2 0.608 1.14 177
3 0.697 0.994 103
4 0.807 0.859 152
5 0.387 1.79 153
6 0.611 1.13 108
Mean 0.624 1.17 143
s.d. 0.138 0.322 30.8

Table 3. Estimations of constant of elimination, half-life and AUC for mesna and dimesna following oral administration of mesna. Calculation of k and t1/2 was not possible in all cases

Mesna. Dimesna
Subject k(h-1) t1/2 (h) C max (nmol/mL) tmax(h) AUC
(nmol/ mL x h)
k(h-1) t1/2 (h) C max (nmol/mL) tmax (h) AUC
(nmol/ mL x h)
1   _ 12.0 4.0 30.2 _ _ 18.0 2.5 48.0
2 1.29 0.54 26.5 1.0 46.6 0.897 0.773 45.5 2.0 97.4
3 _ _ 27.7 2.5 57.8 0.303 2.28 22.6 2.0 52.6
4 _ _ 5.5 3.0 7.0 19.7 3.0 46.7
5 26.2 3.0 55.9 0.399 1.74 20.7 2.5 43.1
6         20.5

Table 4. Percentage of dose excreted in urine as mesna or dimesna over 4 h and 24 h collection periods

Subject Mesna excretion over 4 h Mesna excretion over 24 h Dimesna excretion over 4 h Dimesna excretion over 24 h
i.v. oral i.v. oral i.v. oral i.v. oral
1 30.4 11.6 31.3 25.5 32.8 18.4 39.4 39.4
2 39.3 19.5 41.2 22.6 26.6 19.6 31.6 30.7
3 23.2 11.7 23.2 12.8 30.8 8.7 38.5 26.6
4 41.2 15.6 43.2 27.9 26.9 18.6 29.9 37.3
5 35.5 5.6 37.0 12.5 26.9 11.1 31.7 22.8
6 14.6 0.054 14.8 4.3 26.2 5.1 28.5 33.3
Mean 30.7 10.7 31.8 17.6 28.4 13.6 33.3 31.7
s.d. 10.2 7.0 11.0 9.2 2.7 6.1 4.6 6.3

Table 5. Total urinary excretion (mesna plus dimesna) expressed as % of dose excreted over 4 h and 24 h. Urinary availability calculated as amount of mesna recovered as both mesna and dimesna and as mesna alone in urine over 24 h following oral administration—expressed as % of similar recovery following i.v. dose

Subject % excretion over 4 h % excretion over 24 h % urinary availability of total drug administered % urinary availability as mesna alone
i.v. oral i.v. oral
2 65.9 39.1 72.8 53.3 73.2 54.7
3 54.0 20.4 61.7 39.4 63.9 55.0
4 68.1 34.2 73.1 65.2 89.2 64.4
5 62.4 16.7 68.7 35.3 51.4 33.8
6 40.8 5.2 43.3 37.6 86.8 28.8
Mean 59.1 24.3 65.1 49.3 76.1 53.0
s.d. 10.2 12.5 11.4 13.7 16.1 19.5

Applicant's summary and conclusion

Conclusions:
In men, mesna undergoes rapid oxidation to dimesna in plasma. After i.v. administration, the mean half-life of mesna is 22 min and that of dimesna is 1.17 hours. Following oral administration, the maximum peak concentration of mesna in plasma occurred late in the sampling period (at 1, 2.5, 3 and 4 hours) and for dimesna (at 2, 2.5 and 3 hours). Compared with i.v. administration, the onset of significant plasma levels of mesna/dimesna following oral administration is delayed approximately 1 h.
Following intravenous administration of mesna, maximum concentrations occurred in the 0-4 h urine collection, while the maximum mesna concentration occurred in either the 0-4 h or 4-8 h urine sample after oral mesna. Compared with i.v. administration of mesna, overall availability of mesna in urine after oral administration is approximately 50%. The onset of urinary excretion of mesna after oral administration is delayed and more prolonged, perhaps due to sustained absorption from the gastrointestinal tract. After both i.v. and oral mesna the urinary excretion of mesna is predominantly during the first 4 hours.
Executive summary:

1 The pharmacokinetics of mesna (sodium 2-mercaptoethane sulphonate) and its inactive disulphide, dimesna, were investigated using high performance liquid chromatography in six normal subjects following intravenous and oral administration of 800 mg mesna.

2. The mean maximum mesna concentration after i.v. administration was 111 (s.d. ± 28.3) nmol/mL and the mean maximum dimesna concentration was 183 (s.d. ± 41.6) nmol/mL. Following oral mesna dosing the mean peak mesna concentration was 19.6 (s.d. ± 10.2) nmol mL but mesna was only found in the plasma of five of the six subjects. The mean peak dimesna concentration was 22.5 (s.d. ± 12.4) nmol/mL.

3. Following i.v. mesna administration, the mean half-life of mesna was 21.8 (s.d. ± 3.1) min and total body clearance 1.23 (s.d. ± 0.31) 1 kg-' h-1. The mean half-life of dimesna was 1.17 (s.d. ± 0.32) h. It was not possible to determine their half-lives after oral mesna administration.

4. The mean mesna concentration in the 0-4 h urine collection was 9.6 (s.d. ± 10.7; range 1.4-28.7) µmol/mL following i.v. mesna injection. After oral mesna the highest mesna concentration occurred in either the 0-4 or 4-8 h urine collections. The mean peak mesna concentration was 2.5 (s.d. ± 1.7) µmol/mL (c.f. estimated uroprotective concentration of 1.7 µmol/mL).

5. The mean 4 h urinary clearance of the uroprotective species mesna was 0.413 (s.d. ± 0.136) L/ kg x h. After both i.v. and oral mesna the urinary excretion of mesna is predominantly during the first 4 h. The urinary availability as mesna alone after oral dosing was 53.0 ± 19.5% of that following i.v. administration.

6. It should be possible to use oral mesna as a uroprotective agent in conjunction with oxazaphosphorine treatment either by giving an oral dose of 40% of the cytotoxic dose 2 h before the cytotoxic or using both i.v. (20% cytotoxic dose) and oral (40% cytotoxic dose) mesna doses with the oxazaphosphorine followed by oral mesna (40% of oxazaphosphorine dose) every 4 h.