Lithium Pharmacokinetic Information and Dosing Calculators

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Lithium Dosing Tools
Lithium Dosing Using Non-Steady State or Steady State Levels, Single Level After Test Dose, Or Multiple Levels After Test Dose Calculator Download

Lithium Dosing Calculator and Data Fitting for 12-hour post-dose Levels, Web-Based

Lithium Pharmacokinetic Dosing Information
Usage: manic episodes of bipolar disorder, bipolar (manic-depressive) disorder, schizo-affective disorders, major depression, cluster headaches, ant-suicide, and syndrome of inappropriate antidiuretic hormone.  It has a narrow therapeutic window and predictable pharmacokinetics.
Bioavailability (F): 1 (0.8-1), slow-release formulations may have bioavailable 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 capsule 0.5-3 hours, extended-release 4-12 hours
Protein binding: not protein bound  
Metabolism: Not metabolized
Vd(L/kg): initial compartment 0.25-0.3 L/kg of LBW,  final volume of distribution ~ 0.7 L/kg of lean body weight or fat free mass. Other references have: Children and adolescents 0.93 l/kg, adults 0.85 l/kg, elderly (greater than 59 years) 0.53 l/kg.
Cl (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, care monitoring is required, with downward titration or discontinuation before delivery. Increasing water intake does not increase excretion.
K (1/hours): 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 of volume of distribution and clearance.
Dosage Forms:
  tablets, capsules, oral syrup
Usual Interval:  every 6, 8, 12, 24 hours
Usual Oral Dose: Acute Therapy and Maintenance Therapy:
      Children (not FDA approved less than 12 years of age):
            6-11 years old: initiation of acute therapy less of 15-20 mg/kg/day or 150 mg twice daily, maintenance 150 mg once daily
           12 years and older: initiation of acute therapy lesser of 15-20 mg/kg/day or 300 mg twice,  maintenance 300 mg once daily
      Adults: Initiation of acute therapy 900-1800 mg/day,  maintenance 900-1200 mg/day, 15 mg/kg/day
Initiation of therapy 600-900 mg/day, maintenance 600-900 mg/day
Initiation of therapy:  Administer doses, 8-8.12 mEq, two to four times a day depending on age, weight, and renal function.
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. 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.
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
Serum Sampling Times and Recommended 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. 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. 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 3-4 weeks unit 34 weeks of pregnancy, then once a week unit 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.
Pharmacokinetic Model:  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 in 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 proportional for the desired concentration.
Side effects: Common side effects on initiation are nausea, polyuria, polydipsia, and diarrhea. Divided doses with meals helps to minimize nausea and vomiting. Hypothyroidism, fine intentional tremor, weight gain, acne, worsening psoriasis, and nephrotoxicity may develop with long term therapy
Toxicity: usually occurs with 12-hour post-dose levels > 1.5 mEq/L. Levels above 3-3.5 mEq/L are considered life-threatening. Whole bowel irrigation is used to prevent the absorption of unabsorbed lithium. HD 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 Category D, avoid use in the first trimester. Use in second and third trimester has not been associated with fetal risk. Breast milk concentrations are 50% of maternal concentrations. Lithium crosses the placenta with concentrations similar in fetal and maternal serum.
Common Drug interactions: with clearance adjustment factors
     Decrease clearance: non-thiazide, thiazide diuretics 0.5 and loop diuretics; NSAIDs, ACEI
     Increased clearance: cisplatin (1.6), caffeine (1.2), theophylline (1.21), and sodium containing IV fluids (1.2)
Disease state or physiologic condition interactions:
     Decrease clearance: acute mania clearance 60% of usual, renal dysfunction, cirrhosis of liver, dehydration, sodium loss, low salt diet clearance 80% of usual. Renal excretion has not been shown to increase with increasing water intake or acidification of urine. 
     Increase 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

Dosage Calculations: 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.

BMI: Actual Body Weight / (Height in meters)^2

Body Weight Calculations:
Ideal Body Weight
IBW(kg)  (Devine Formula) Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches greater than 60 inches)
IBW(kg) (Devine Formula) Adult Female (18 years and older): 45.5 + 2.3*(Height in inches greater than 60 inches)

Fat Free Mass (Janmahasatian Formula):
FFM(kg) Adult Males    = 9270 * Actual Body Weight(kg) / (668 + (216* BMI))
FFM(kg) Adult Females = 9270 * Actual Body Weight(kg) / (8780 / (244*(BMI))

Body Surface Area in Meters Squared = ((Weight in kg)^0.425)*((Height in centimeters)^0.725)*(71.84/10000)

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

Creatinine Clearance(ml/min):
Adult Males: Creatinine Clearance (mL/min)= (140-age(years))*(Fat Free Mass(kg)) / (serum creatinine(mg/dl)*72)
Adult Females: Creatinine Clearance (mL/min) = 0.85 *( (140-age(years))*(Fat Free Mass(kg)) / (serum creatinine(mg/dl)*72))

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.

     Males =   0.25 * (140-age) * FFM *60/1000 / (72*Serum Creatinine(mg/dL))
     Female = 0.25 * 0.85 * (140-age) * FFM * 60/1000 / (72 * Serum Creatinine(mg/dL))
Volume of Distribution(L) = 0.7 * Fat Free Mass(kg)
K(1/hours) = Clearance / Vd
Vd(L) = 0.7*Dosing weight(kg)
Maintenance Dose(mEq) = Cpaverage(mEq/L or mmol/L) * Tau(Hours) * Clearance(L/hr) / Fraction
Cpaverage(mEq/L) = Fraction * Dose(mEq) / (Clearance(L) * Tau)
Cpmaximum(mEq/L) = Fraction * Dose(mEq) / (Vd(L) * (1-exp(-K*Tau)))
Cp 12 hours post-dose(mEq/L) = Cpmaximum(mEq/L) * exp(-K*12)
Cpminimum(mEq/L) = Cpmaximum(mEq/L) * exp(-K*Tau)

Lithium Dosing Using Non-Steady State or Steady State Levels, Single Level After Test Dose, Or Multiple Levels After Test Dose Calculator Download

Winter's Lithium Dosing Method


Comparison of dosing weight equations

Devine Calculation of Lean Body Weight


Janmahasatian S. Quantification of lean body weight

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If you have questions or suggestions concerning the dosing tools please contact Marshall Pierce PharmD.

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