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.
Highlights
A standard treatment for bipolar disorder involves treatment with the element lithium, which was the first mood-stabilizing medication approved for treatment of “mania,” which later came to be known as bipolar disorder, in 1970 [2]
Bodily lithium concentrations are reported in milliequivalents lithium/mL tissue volume; the unit mEq is equivalent to a millimol
The results of this study should be taken as a guide to safely treat patients rather than universal canon. This model has taken the first steps toward predicting the maximum acceptable lithium dosage regimen for pregnant bipolar women
Summary
Bipolar disorder, which affects approximately 1% of the population (mostly women), is a type of mood disorder which has periods of manic behavior and periods of depressive behavior. Animal models describing fetal lithium toxicity or teratogenic effects are lacking In lieu of these experimental methods, lithium concentration in various organs can be predicted by the construction of a pharmacokinetic model, such as that presented by Bischoff et al [9]; this provides a means to predict lithium concentration within the fetus during various dosage regimens based upon the concentrations in other parts of the mother’s body which are easier and safer to sample. By modeling the effect of dosage regimens previously associated with high incidence of birth defects, improved dosage regimens with lower likelihoods of causing birth defects can be proposed To this end, we have employed a modified version of the biological model first proposed by Bischoff et al [9] (the Physiologically Based Pharmacokinetic (PBPK) model). This work applies a modified PBPK model to the problem of impaired fetal development due to maternal lithium treatment in order to propose maximum recommended dosage regimens
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