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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

Model-predicted reduced risk dosage regimens. The maximum and average fetus concentrations from the 450/900 dosage regimen are plotted along with two new dosage regimens. The values for average and peak concentrations are listed in Table 2.
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fig5: Model-predicted reduced risk dosage regimens. The maximum and average fetus concentrations from the 450/900 dosage regimen are plotted along with two new dosage regimens. The values for average and peak concentrations are listed in Table 2.

Mentions: In order to find safer dosage regimens, we modeled several regimens to find ones with peak and average concentrations below the pathological dosage. Drug ingestion does not have to occur only twice daily, and the regimens we tested reflect this. However, we did not consider the effect of nonevenly spaced dosages which, due to its complexity and questionable clinical relevance, is beyond the scope of the current work. We modeled the following regimens: 300/300, 600/600, 300/300/500, 400/400/400, and 300/300/300/300 (all in mg). We included the 300/300 dosage regimen because this has been suggested as an average lowest effective dosage regimen [2]. Although this varies for each patient, it is a good starting value for minimum effective dose. The 300/300/500 dosage regimen simulates two low doses with breakfast and lunch and a slightly higher dosage with dinner to go through the night. Figure 5 show the results of several of these simulations. Table 2 shows the maximum and average concentration values of these dosage regimens.


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)

Model-predicted reduced risk dosage regimens. The maximum and average fetus concentrations from the 450/900 dosage regimen are plotted along with two new dosage regimens. The values for average and peak concentrations are listed in Table 2.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Model-predicted reduced risk dosage regimens. The maximum and average fetus concentrations from the 450/900 dosage regimen are plotted along with two new dosage regimens. The values for average and peak concentrations are listed in Table 2.
Mentions: In order to find safer dosage regimens, we modeled several regimens to find ones with peak and average concentrations below the pathological dosage. Drug ingestion does not have to occur only twice daily, and the regimens we tested reflect this. However, we did not consider the effect of nonevenly spaced dosages which, due to its complexity and questionable clinical relevance, is beyond the scope of the current work. We modeled the following regimens: 300/300, 600/600, 300/300/500, 400/400/400, and 300/300/300/300 (all in mg). We included the 300/300 dosage regimen because this has been suggested as an average lowest effective dosage regimen [2]. Although this varies for each patient, it is a good starting value for minimum effective dose. The 300/300/500 dosage regimen simulates two low doses with breakfast and lunch and a slightly higher dosage with dinner to go through the night. Figure 5 show the results of several of these simulations. Table 2 shows the maximum and average concentration values of these dosage regimens.

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