Scientivic Advisory Department of Chemotherapy of Myeloproliferative disorders
Contributions
Type: Publication Only
Background
The issue of safe usage of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients on late stages of pregnancy is unclear. TKI ability to cross the blood-placental barrier (BPB) in humans and association with the adverse effects is rarely evaluated in practice due to rareness of cases and ethical reasons. The obtained data are scarce. We hypothesized whether BPB crossing can be predicted by a model based on molecular physicochemical properties of available TKIs.
Aims
To compare the theoretical calculations of BPB crossing of TKIs used for CML treatment with the data obtained in practice and association with clinical outcomes.
Methods
The relative rate of TKIs penetration through BPB was evaluated by so called clearance index (CI) in comparison with antipyrine as free passive diffusion reference with CI=1. The CI of imatinib, nilotinib, dasatinib and bosutinib. was estimated using Quantitative Structure-Activity Relations (QSAR) approach (Hewitt et al, Environ Res, 2007) according to the equation (picture 1).
Concentration of imatinib in available cases was simultaneously measured at labour in blood plasma of mother, cord blood and homogenized placenta by HPLC-mass spectrometry technique.
Information of therapy and pregnancy outcomes was taken from Russian CML pregnancy registry and local database of Uzbekistan.
Results
Calculated CI values for imatinib, nilotinib, dasatinib, bosutinib were 0,36, 0,33, 0,44 and 0,67 correspondingly showing moderate but not negligible rate of BPB transfer compared to antipyrine.
In 3 of 17 women with CML who received TKI (15 imatinib, 2 nilotinib) since 2nd-3rd trimester (due to lack of response) imatinib concentration was measured. The fetal:maternal ratio ranged from 0,12 to 0,25 and imatinib concentration in placenta was higher than in maternal blood (table 1). All 17 newborns had no birth abnormalities, low weight <2500 g was in 6 cases. In 5 of 6 cases infants were born preterm at week 35-37, their further development was normal.
Table 1. Concentration of imatinib measured at labour and fetal:maternal ratio
| Imatinib concentration, ng/ml | fetal:maternal ratio | ||
? of case | maternal blood plasma | placenta | cord blood |
|
1 | 896,5 | ND | 109,5 | 0,12 |
2 | 897,5 | 1095 | 226 | 0,25 |
3 | 520,6 | 702,10 | 115,5 | 0,22 |
Summary
A simple QSAR model based on diffusion-like properties of TKIs used for CML treatment showed the moderate rate of BPB transfer compared to antipyrine. Data obtained at practice showed reduced level of imatinib in cord blood plasma and higher level in placenta compared to maternal blood. Factors which were not accounted in the theoretical model (active transportation mechanisms, extensive metabolic clearance at the fetal side) might specifically prevent TKIs from crossing BPB. Cases of preterm delivery with low weight of children in mothers who got TKIs during pregnancy need further evaluation.
Keyword(s): Chronic myeloid leukemia, Imatinib, Pregnancy
Type: Publication Only
Background
The issue of safe usage of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients on late stages of pregnancy is unclear. TKI ability to cross the blood-placental barrier (BPB) in humans and association with the adverse effects is rarely evaluated in practice due to rareness of cases and ethical reasons. The obtained data are scarce. We hypothesized whether BPB crossing can be predicted by a model based on molecular physicochemical properties of available TKIs.
Aims
To compare the theoretical calculations of BPB crossing of TKIs used for CML treatment with the data obtained in practice and association with clinical outcomes.
Methods
The relative rate of TKIs penetration through BPB was evaluated by so called clearance index (CI) in comparison with antipyrine as free passive diffusion reference with CI=1. The CI of imatinib, nilotinib, dasatinib and bosutinib. was estimated using Quantitative Structure-Activity Relations (QSAR) approach (Hewitt et al, Environ Res, 2007) according to the equation (picture 1).
Concentration of imatinib in available cases was simultaneously measured at labour in blood plasma of mother, cord blood and homogenized placenta by HPLC-mass spectrometry technique.
Information of therapy and pregnancy outcomes was taken from Russian CML pregnancy registry and local database of Uzbekistan.
Results
Calculated CI values for imatinib, nilotinib, dasatinib, bosutinib were 0,36, 0,33, 0,44 and 0,67 correspondingly showing moderate but not negligible rate of BPB transfer compared to antipyrine.
In 3 of 17 women with CML who received TKI (15 imatinib, 2 nilotinib) since 2nd-3rd trimester (due to lack of response) imatinib concentration was measured. The fetal:maternal ratio ranged from 0,12 to 0,25 and imatinib concentration in placenta was higher than in maternal blood (table 1). All 17 newborns had no birth abnormalities, low weight <2500 g was in 6 cases. In 5 of 6 cases infants were born preterm at week 35-37, their further development was normal.
Table 1. Concentration of imatinib measured at labour and fetal:maternal ratio
| Imatinib concentration, ng/ml | fetal:maternal ratio | ||
? of case | maternal blood plasma | placenta | cord blood |
|
1 | 896,5 | ND | 109,5 | 0,12 |
2 | 897,5 | 1095 | 226 | 0,25 |
3 | 520,6 | 702,10 | 115,5 | 0,22 |
Summary
A simple QSAR model based on diffusion-like properties of TKIs used for CML treatment showed the moderate rate of BPB transfer compared to antipyrine. Data obtained at practice showed reduced level of imatinib in cord blood plasma and higher level in placenta compared to maternal blood. Factors which were not accounted in the theoretical model (active transportation mechanisms, extensive metabolic clearance at the fetal side) might specifically prevent TKIs from crossing BPB. Cases of preterm delivery with low weight of children in mothers who got TKIs during pregnancy need further evaluation.
Keyword(s): Chronic myeloid leukemia, Imatinib, Pregnancy