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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

Concentration profiles in all physiological compartments resulting from a single, time-release 900 mg dosage of lithium drug. Initial lithium concentration in the body is 0 mEq/mL. (a) Profile of drug release pulse. (b) Lithium concentration time courses in the most important compartments for the study, with fetus labeled. (c) Lithium concentration profiles for less critical compartments.
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fig2: Concentration profiles in all physiological compartments resulting from a single, time-release 900 mg dosage of lithium drug. Initial lithium concentration in the body is 0 mEq/mL. (a) Profile of drug release pulse. (b) Lithium concentration time courses in the most important compartments for the study, with fetus labeled. (c) Lithium concentration profiles for less critical compartments.

Mentions: A typical dosage regimen for an individual suffering from bipolar disorder is to administer 900 mg of lithium drug twice daily. The lithium concentration time course (in mEq Li/mL) resulting from a single 900 mg dose of lithium drug, delivered via two simultaneously administered 450 mg controlled release capsules, results in the concentration profiles shown in Figure 2. The organs shown in Figure 2(b) are important for the aim of this study, which was to provide better guidance for safe lithium dosing for fetal development; the concentration profiles shown in Figure 2(c) are other organs included in the model but less critical for the aim of this study. The drug release occurs over four hours, as described above, in conjunction with the mass-balance development for the GI Tract; after the last of the delivered drug has absorbed into the system, all concentrations decay due to loss of lithium through the urine via kidney clearance. Our simulation uses a flow rate of urine containing lithium of 20 mL/minute; this value is consistent with the standard accepted values of 20–40 mL/minute [3].


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)

Concentration profiles in all physiological compartments resulting from a single, time-release 900 mg dosage of lithium drug. Initial lithium concentration in the body is 0 mEq/mL. (a) Profile of drug release pulse. (b) Lithium concentration time courses in the most important compartments for the study, with fetus labeled. (c) Lithium concentration profiles for less critical compartments.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Concentration profiles in all physiological compartments resulting from a single, time-release 900 mg dosage of lithium drug. Initial lithium concentration in the body is 0 mEq/mL. (a) Profile of drug release pulse. (b) Lithium concentration time courses in the most important compartments for the study, with fetus labeled. (c) Lithium concentration profiles for less critical compartments.
Mentions: A typical dosage regimen for an individual suffering from bipolar disorder is to administer 900 mg of lithium drug twice daily. The lithium concentration time course (in mEq Li/mL) resulting from a single 900 mg dose of lithium drug, delivered via two simultaneously administered 450 mg controlled release capsules, results in the concentration profiles shown in Figure 2. The organs shown in Figure 2(b) are important for the aim of this study, which was to provide better guidance for safe lithium dosing for fetal development; the concentration profiles shown in Figure 2(c) are other organs included in the model but less critical for the aim of this study. The drug release occurs over four hours, as described above, in conjunction with the mass-balance development for the GI Tract; after the last of the delivered drug has absorbed into the system, all concentrations decay due to loss of lithium through the urine via kidney clearance. Our simulation uses a flow rate of urine containing lithium of 20 mL/minute; this value is consistent with the standard accepted values of 20–40 mL/minute [3].

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