Lithium Pharmacokinetic Dosing Information

Indications: Manic episodes of bipolar disorder, bipolar (manic-depressive) disorder, schizo-affective disorders, major depression, cluster headaches, anti-suicide, and syndrome of inappropriate antidiuretic hormone.

Note: Lithium has a narrow therapeutic window and predictable pharmacokinetics.

Bioavailability (F): 1 (0.8-1). Slow-release formulations may have bioavailability as low as 0.85 or 85%.

Fraction IV: Not available in the USA

Salt: Monovalent cation 1 mmol/L = 1 mEq/L, lithium carbonate 300 mg = 8.12 mEq, lithium citrate ~ 300 mg = 8 mEq

Route of Administration: Oral (do not give rectal as it causes painful diarrhea)

Absorption: In the jejunum and ileum. The extent of absorption is unaffected by food, but the rate of absorption may be reduced.

Peak Concentrations:

• Oral solution: 15-45 minutes
• Immediate release carbonate tablets and capsules: 0.5-3 hours
• Extended-release: 4-12 hours

Protein Binding: Not protein bound

Metabolism: Not metabolized

Volume of Distribution (V_d):

• Initial compartment: 0.25-0.3 L/kg of lean body weight
• Final volume of distribution: ~ 0.7 L/kg of lean body weight or fat free mass
• Other references: Children and adolescents 0.93 L/kg, adults 0.85 L/kg, elderly (greater than 59 years) 0.53 L/kg

Clearance (L/hour): 0.25 × creatinine clearance (ml/min) × 60/1000

Renally eliminated, completely filtered by glomerulus with ~ 80% reabsorbed by proximal renal tubules. Reabsorption is closely linked with sodium reabsorption and is influenced by the same factors that affect sodium (dehydration, hypotension). Clearance increases by 50-100% during pregnancy, careful monitoring is required, with downward titration or discontinuation before delivery. Increasing water intake does not increase excretion.

Elimination Rate Constant (K): 0.25 × creatinine clearance (ml/min) × (60/1000) / (0.7 × Fat Free Mass)

Half-life (hours): Distribution half-life is 0.8-1.2 hours, and post-distribution half-life is 18-30 hours in normal renal function after multiple dosing. Half-life is dependent on volume of distribution and clearance.

Dosage Forms: Tablets, capsules, oral syrup

Usual Interval: Every 6, 8, 12, or 24 hours

Initiation of Therapy: Administer doses of 8-8.12 mEq, two to four times a day depending on age, weight, and renal function.

Acute Therapy and Maintenance Therapy:

Therapeutic levels were established with multiple daily dosing regimens when levels were drawn 12 hours after the last evening dose of the day. Serum levels may vary by a factor of 2-3 during a dosage interval; therefore a uniform time for monitoring levels was established at 12 hours post evening dose.

Clinical Note: The risk of relapse decreases with higher levels. Relapse is 2.6 times higher with levels of 0.4-0.6 mEq/L as compared to 0.8-1 mEq/L. Full therapeutic effect is seen 14-21 days from the start of therapy.

Target Levels:

• Prophylaxis of mania: 0.6-1 mEq/L
• Acute mania: 0.5-1.2 mEq/L
• Prophylaxis of depression: 0.4-0.8 mEq/L

Standard Monitoring: Monitor morning levels 12 hours after the evening dose, withhold the normally scheduled morning dose if necessary to obtain the level. Due to the long half-life, serial levels every 3 days during initiation then once weekly are recommended until accumulation is complete.

Important: Longer dosing intervals are associated with higher 12-hour post-dose levels. Once-daily dosing displays an approximately 40% higher 12-hour post-dose level than the same total daily dose divided into 2-4 doses a day. Therapeutic ranges were established with multiple daily doses. No therapeutic range has been established for once daily dosing.

Routine Monitoring: Obtain a serum creatinine every other day during hospitalization and monitor for drug interactions and side effects. Monitor lithium concentration every 3-6 months in stable outpatients.

Pregnant Patients:

• Monitor levels and creatinine every 3-4 weeks until 34 weeks of pregnancy, then once a week until delivery
• Consider twice daily dosing to minimize peak levels
• Avoid non-steroidal anti-inflammatory agents
• Obtain lithium levels twice weekly for two weeks postpartum
• Adjust the dose as necessary to maintain therapeutic levels

Lithium may be modeled with 1 or 2-compartment linear models. A linear one-compartment open model is adequate for dosage predictions, but levels should be drawn 12 hours after post-dose to ensure the level is drawn in the post-distributive phase.

Levels drawn in the distributive phase will be elevated and should not be used for dosing adjustments. When levels are at steady state, doses can be adjusted proportionally for the desired concentration.

Common side effects on initiation:

• Nausea
• Polyuria
• Polydipsia
• Diarrhea

Divided doses with meals helps to minimize nausea and vomiting.

Long-term therapy side effects:

• Hypothyroidism
• Fine intentional tremor
• Weight gain
• Acne
• Worsening psoriasis
• Nephrotoxicity

Toxicity: Usually occurs with 12-hour post-dose levels > 1.5 mEq/L. Levels above 3-3.5 mEq/L are considered life-threatening.

Treatment: Whole bowel irrigation is used to prevent the absorption of unabsorbed lithium. Hemodialysis may be used; it removes lithium from the central compartment but is ineffective in removal from deep compartments. Repeat levels should be drawn 6-8 hours post-dialysis due to redistribution with a goal of lithium levels less than 1 mEq/L.

Pregnancy & Lactation:

Pregnancy Category D: Avoid use in the first trimester. Use in second and third trimester has not been associated with fetal risk. Lithium crosses the placenta with concentrations similar in fetal and maternal serum.

Breastfeeding: Breast milk concentrations are 50% of maternal concentrations.

With clearance adjustment factors:

Decreased Clearance:

• Non-thiazide, thiazide diuretics: 0.5
• Loop diuretics: 0.5
• NSAIDs
• ACE Inhibitors (ACEI)

Increased Clearance:

• Cisplatin: 1.6
• Caffeine: 1.2
• Theophylline: 1.21
• Sodium-containing IV fluids: 1.2

Decreased Clearance:

• Acute mania: Clearance 60% of usual
• Renal dysfunction
• Cirrhosis of liver
• Dehydration
• Sodium loss
• Low salt diet: Clearance 80% of usual

Note: Renal excretion has not been shown to increase with increasing water intake or acidification of urine.

Increased Clearance:

• Pregnancy: Clearance increases by 50-100%. Increase starts in the first trimester, peaks mid-pregnancy, and returns to non-pregnancy value immediately postpartum
• Strenuous exercise: 20% increase in clearance

There are multiple published dosage methods including Pepin, Jermain, Zetin and Winter to determine the initial dose. The method of Winter is shown below. Due to the long half-life, serum level monitoring is the key to preventing toxic levels.

Body Mass Index (BMI):

BMI = Actual Body Weight(kg) / (Height in meters)²

Ideal Body Weight (Devine Formula):

IBW(kg) Adult Males (18 years and older) = 50 kg + 2.3 × (Height in inches greater than 60 inches)

IBW(kg) Adult Females (18 years and older) = 45.5 kg + 2.3 × (Height in inches greater than 60 inches)

Fat Free Mass (Janmahasatian Formula):

FFM(kg) Adult Males = [9270 × Actual Body Weight(kg)] / [6680 + (216 × BMI)]

FFM(kg) Adult Females = [9270 × Actual Body Weight(kg)] / [8780 + (244 × BMI)]

Body Surface Area (meters²):

BSA (m²) = [(Weight in kg)^0.425] × [(Height in centimeters)^0.725] × (71.84/10000)

Dosing Weight:

Dosing Weight(kg) = Fat-Free Mass for V_d and Creatinine Clearance Calculation

Creatinine Clearance (ml/min):

Adult Males: CrCl (mL/min) = (140 - age(years)) × Fat Free Mass(kg) / (serum creatinine(mg/dL) × 72)

Adult Females: CrCl (mL/min) = 0.85 × [(140 - age(years)) × Fat Free Mass(kg) / (serum creatinine(mg/dL) × 72)]

Note: Serum creatinine is rounded up to 0.7 mg/dL for all adult patients at my institution without paralysis or malnutrition. FFM is recommended to be used in the creatinine clearance equations, including obese patients, as dosing predictions are improved. The calculations below use the lower of FFM or actual body weight in the calculation of creatinine clearance and volume of distribution.

Clearance (L/hr):

Males: Clearance = 0.25 × (140 - age) × FFM × 60/1000 / (72 × Serum Creatinine(mg/dL))

Females: Clearance = 0.25 × 0.85 × (140 - age) × FFM × 60/1000 / (72 × Serum Creatinine(mg/dL))

Volume of Distribution (L):

V_d(L) = 0.7 × Fat Free Mass(kg)

Elimination Rate Constant:

K(1/hours) = Clearance(L/hr) / V_d(L)

Maintenance Dose:

Maintenance Dose(mEq) = [Cp_average(mEq/L or mmol/L) × Tau(Hours) × Clearance(L/hr)] / Fraction

Average Concentration:

Cp_average(mEq/L) = [Fraction × Dose(mEq)] / [Clearance(L/hr) × Tau(hours)]

Maximum Concentration:

Cp_maximum(mEq/L) = [Fraction × Dose(mEq)] / [V_d(L) × (1 - exp(-K × Tau))]

Concentration 12 Hours Post-Dose:

Cp 12 hours post-dose(mEq/L) = Cp_maximum(mEq/L) × exp(-K × 12)

Minimum Concentration:

Cp_minimum(mEq/L) = Cp_maximum(mEq/L) × exp(-K × Tau)