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Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption.

Horton S, Tuerk A, Cook D, Cook J, Dhurjati P - Adv Bioinformatics (2012)

Bottom Line: There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women.We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model.The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus.

View Article: PubMed Central - PubMed

Affiliation: Colburn Laboratory, Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.

ABSTRACT
Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mother's brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day.

No MeSH data available.


Related in: MedlinePlus

Connectivity diagram for the relevant organs of the PBPK model for lithium accumulation in a pregnant woman. Each compartment represents an organ with a certain partition coefficient, denoted by a dashed line, through which blood flows.
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fig1: Connectivity diagram for the relevant organs of the PBPK model for lithium accumulation in a pregnant woman. Each compartment represents an organ with a certain partition coefficient, denoted by a dashed line, through which blood flows.

Mentions: The original model of Bischoff et al. [9] predicted concentrations of the anticancer drug methotrexate in different organs in the body. Because methotrexate is metabolized in the liver and secreted through the colon without a concentration buildup in the upper organs, Bischoff et al. [9] modeled only the lower organs in the body. Our model, however, deals with lithium, for which the brain is a primary site of lithium activity and accumulation. Furthermore, as we are specifically modeling the lithium exposure of pregnant women, the fetus and the uterus are additional physiological regions for which lithium concentrations should be predicted. Therefore, we have modified the original PBPK model to better reflect our system by adding compartments for the brain, the uterus, and the fetus, and modifying the compartment connectivity accordingly (see Figure 1). In our model, we assumed that the fetus was in the first trimester, when lithium exposure is most damaging to its development. Due to the lower development of the fetus at this point in the pregnancy, we modeled the fetus as a single compartment. Our model also included thyroid, gastrointestinal (GI) tract, kidneys, and bone compartments.


Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption.

Horton S, Tuerk A, Cook D, Cook J, Dhurjati P - Adv Bioinformatics (2012)

Connectivity diagram for the relevant organs of the PBPK model for lithium accumulation in a pregnant woman. Each compartment represents an organ with a certain partition coefficient, denoted by a dashed line, through which blood flows.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369391&req=5

fig1: Connectivity diagram for the relevant organs of the PBPK model for lithium accumulation in a pregnant woman. Each compartment represents an organ with a certain partition coefficient, denoted by a dashed line, through which blood flows.
Mentions: The original model of Bischoff et al. [9] predicted concentrations of the anticancer drug methotrexate in different organs in the body. Because methotrexate is metabolized in the liver and secreted through the colon without a concentration buildup in the upper organs, Bischoff et al. [9] modeled only the lower organs in the body. Our model, however, deals with lithium, for which the brain is a primary site of lithium activity and accumulation. Furthermore, as we are specifically modeling the lithium exposure of pregnant women, the fetus and the uterus are additional physiological regions for which lithium concentrations should be predicted. Therefore, we have modified the original PBPK model to better reflect our system by adding compartments for the brain, the uterus, and the fetus, and modifying the compartment connectivity accordingly (see Figure 1). In our model, we assumed that the fetus was in the first trimester, when lithium exposure is most damaging to its development. Due to the lower development of the fetus at this point in the pregnancy, we modeled the fetus as a single compartment. Our model also included thyroid, gastrointestinal (GI) tract, kidneys, and bone compartments.

Bottom Line: There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women.We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model.The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus.

View Article: PubMed Central - PubMed

Affiliation: Colburn Laboratory, Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.

ABSTRACT
Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mother's brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day.

No MeSH data available.


Related in: MedlinePlus