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

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.

Figure 1

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.

Figure 2

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.

Figure 3

Terminal concentration profiles in selected physiological compartments for dosage regimens that are known to cause birth defects. In this case, lithium medication is administered twice daily and controlled-release tablets release lithium over 4 hours. A pulse function corresponding to the drug absorption is shown above each figure. (a) One dose of a 450 mg tablet (12 mEq lithium) with a subsequent 900 mg (24 mEq lithium) dose. (b) Two doses of a 900 mg tablet (24 mEq lithium).

Figure 4

Model-predicted pathological dosage regimens. The maximum and average fetus concentrations from the 450/900 dosage regimen are plotted along with two new dosage regimens. A 300/1000 dosage regimen is shown in black and a 700/700 dosage regimen is shown in blue.

Figure 5

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.