Registration Dossier

Administrative data

Endpoint:
additional toxicological information
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979/1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline study, some restrictions in design and/or reporting but otherwise adequate for assessment of the betamethasone mother/fetus transfer.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1980

Materials and methods

Type of study / information:
The plasma concentrations of betamethasone in a maternal peripheral vein (mv) and in the umbilical vein (uv) were measured at delivery in eleven patients after the administration of betamethasone phosphate equivalent to 8 mg betamethasone. Betamethasone concentrations were measured in plasma using a specific and sensitive HPLC assay.
After equilibration across the placenta has occurred, the plasma concentration of betamethasone in the umbilical vein will be approximately 25 to 30% of the concomitant maternal level.
Principles of method if other than guideline:
Examination of the betamethasone concentration on blood of eleven women, aged 27 to 37 years with estimated gestational ages ranging from 31 to 38 weeks, were carried out, after obtaining informed consent from the mother, on samples drawn from a maternal peripheral vein at delivery, and from the umbilical vein of the clamped cord after delivery of the placenta. To all of the women, betamethasone had been prescribed for antenatal administration. Betamethasone was administered as its phosphate ester, equivalent to 8 mg of betamethasone free alcholol, in one or two doses.
The interval from the time of the last dose to the time of delivery varied from 56 to 800 min.
HPLC determination was perrormed with prednisolone as internal standard. The retention time of betamethasone was 6.1 min while prednisolone retention time was 10.3 min. Betamethasone phosphate is not extracted from the biological matrix during the assay procedure and therefore does not interfere with the chromatography of betamethasone.
The specificity of the HPLC assay was also examined by detection at 240 nm and 254 nm, using two ultraviolet detectors connected in series.
The ratio of the absorbance of the chromatographic peak with a retention time of 6.1 rain at 240 nm to that at 254 nm was calculated and compared to the ratio observed when an authentic standard of betamethasone was injected directly into the chromatograph.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Betamethasone phosphate
- Molecular formula (if other than submission substance): C22H28FNa2O8P
- Molecular weight (if other than submission substance): 516.404624 [g/mol]
- Smiles notation (if other than submission substance): CC1CC2C3CCC4=CC(=O)C=CC4(C3(C(CC2(C1(C(=O)COP(=O)([O-])[O-])O)C)O)F)C.[Na+].[Na+]
- InChl (if other than submission substance): InChI=1S/C22H30FO8P.2Na/c1-12-8-16-15-5-4-13-9-14(24)6-7-19(13,2)21(15,23)17(25)10-20(16,3)22(12,27)18(26)11-31-32(28,29)30;;/h6-7,9,12,15-17,25,27H,4-5,8,10-11H2,1-3H3,(H2,28,29,30);;/q;2*+1/p-2/t12-,15-,16-,17-,19-,20-,21-,22-;;/m0../s1
- Structural formula attached as image file (if other than submission substance): see Fig.

Results and discussion

Any other information on results incl. tables

Placental transfer characteristics of betamethasone

Patient  Route of administration  D-Da min  Cmv ng/ml  Cuv ng/ml  Cuv/Cmv
 1  IV  56  83.9  22.9  0.27
 2  IV  61  65.0  16.8  0.26
 3  IM  116  29.8  7.7  0.26
 4  IM  121  36.0  9.8  0.27
 5  IM  137  67.2  19.8  0.29
 6  IM  259  37.8  8.6  0.23
 7  IM  321  34.7  12.7  0.37
 8  IM  331  31.6  9.4  0.30
 9  IM  377  43.4  13.8  0.32
 10  IM  381  33.3  9.6  0.29
 11  IV  800  15.2  3.6  0.24

a Interval between the last dose and delivery

Cmv: Concentration on maternal vein

Cuv: Concentration umbilical vein

Applicant's summary and conclusion

Conclusions:
Betamethasone crosses placenta and it was detectable as unmetabolized free alcohol in approximately 25 to 30% of the concomitant maternal level.