Hi
Thanks for writing in.

As you are diagnosed as Bipolar disorder, the dosage of lithium in your condition is as follows:

Bipolar Disorder
May start with lower dose to minimize adverse drug reactions

900-2400 mg/day divided q6-8hr (immediate release tabs) OR 900-1800 mg divided q12hr PO if using extended release tabs

Desirable serum lithium concentrations are 0.6-1.2 mEq/L; although higher serum concentration may be needed not to exceed 1.5 mEq/L

Administration: Take preferably with food

Source: WWW.WWWW.WW

Further information on absorption of Lithium is:
Absorption
Bioavailability: 95-100% (immediate release tablet and syrup); 60-90% (extended-release)

Peak Plasma Time: 0.5-3 hr; 4-12 hr (extended-release)

Peak Plasma Concentration: 0.4-0.9 mEq/L

Steady-state therapeutic plasma concentration: 0.5-1.3 mEq/L

Onset: 5-7 days initial antimanic effect; 10-21 days full effect

Therapeutic Index: Narrow

Source: WWW.WWWW.WW


Further drug information regarding serum concentration in detail is as below: You may please look under dosage and administration of both preparations.

1. Lithium Carbonate Immediate release tablets.

Source: WWW.WWWW.WW




2. Lithium Carbonate Extended release tablets.

Source: WWW.WWWW.WW

Hope your query is answered.

Regards
Dr. A. Rao Kavoor

---

Hi,

Thanks for writing back,

You want to know the effect on serum lithium levels while switching from immediate release to extended release lithium preparations.The consensus on this is not conclusive. Slow release or extended release preparations give rise to more stable levels of lithium in plasma as compared to immediate release preparation. Immediate release tablets cause greater peaks and troughs (ups and downs) in serum level. But the evidence for this is equivocal because some researchers have said that ER/SR preparation leads to delayed peak plasma level (rather than lowered) and some say that the level is lowered.

Researchers who say it is delayed are

•     Fyro B, Pettersson U and Sedvall G (1970) Serum lithium levels and side effects during administration of lithium carbonate and two slow release lithium preparations to human volunteers. Pharmacologia Clinica 2: 236–240.
• XXXXXXX GF and Hunt GE (1984) Pharmacokinetics of lithium preparations in patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry 8: 63–70.
• XXXXXXX PJ, Dunner FJ, Hahn RL, et al. (1981) Lithium kinetics in single daily dosing. Acta Psychiatrica Scandinavica 64: 281–294.

Researchers who give evidence to suggest it is lowered are
•     Grandjean EM and Aubry JM (2009) Lithium: updated human knowledge using an evidence-based approach: Part II: clinical pharmacology and therapeutic monitoring. CNS Drugs 23: 331–349.
• XXXXXXX RK and Silverstone T (1986) Single dose pharmacokinetics of 5 formulations of lithium: a controlled comparison in healthy subjects. International Clinical Psychopharmacology 1: 324–331.

So the change in your plasma levels on switching from immediate release to extended release may show delayed peak serum levels or a lower level. This varies from one individual to another and because of differences in metabolism and gastro-intestinal functioning across individuals and cannot be predicted precisely.

There are a few things to be kept in mind with regard to this as this may affect the serum levels of lithium as well. Doses of extended release tablets are usually given twice a day (approximately 12-hour intervals). While initiating therapy with immediate release or extended release lithium, dosage is individualized according to serum levels and clinical response. While a patient is switched from immediate-release to the Extended Release preparations, the same total daily dose is given whenever possible. For e.g., Most patients on maintenance therapy usually stabilized on say 900 mg IR daily, they will receive 450 mg ER b.i.d. When the previous dosage of immediate-release lithium is not a multiple of 450 mg, e.g., 1500 mg IR, extended release tablet is initiated at the multiple of 450 mg ER nearest to, but below, the original daily dose, i.e., 1350 mg. In the above example, with a total daily dose of 1350 mg, generally 450 mg of Lithium Carbonate Extended Release Tablets maybe given in the morning and 900 mg ER in the evening. Some doctors may give it in three equal 450 mg ER doses. These patients are monitored at 1- to 2-week intervals, and dosage is adjusted if necessary, until stable and satisfactory serum levels and clinical state are achieved.

Some additional information:
•     In a study that compared the various lithium salts, it was found that the chloride and sulfate preparations reach peak plasma concentrations 1 hour after oral administration as compared to 4 hours for the carbonate preparation.
•     Peak lithium plasma levels are reached 1–3 hours after administration of IR preparations and 4–12 hours after SR preparations. Lithium in the brain peaks about 24 hours after ingestion, and this is primarily due to the lower permeability of the blood–brain barrier. After a day or so of lithium administration the mean ratio of its concentration in plasma to cerebrospinal fluid is 3.6:1.

You may also refer,
Malhi, G. S., Tanious, M., XXXXXXX P., & Berk, M. (2012). The science and practice of lithium therapy. Australian and New Zealand journal of psychiatry, 46(3), 192-211.

B. Fyrö, U. Petterson, G. Sedvall (1973) Pharmacokinetics of Lithium in Manic Depressive Patients. Acta Psychiatrica Scandinavica. Volume 49, Issue 3, pages 237–247.
XXXXXXX Emami, Naser Tavakoli and XXXXXXX Movahedian, Formulation of sustained - release lithium carbonate matrix tablets: influence of hydrophilic materials on the release rate and in vitro-in vivo evaluation. J Pharm Pharmaceut Sci. 7(3):338-344, 2004

WWW.WWWW.WW (The National Library of Medicine (NLM) provides this as a public service)

Hope your query is answered.

Regards
Dr A. Rao Kavoor

---

Hi XXXXXXX R.,

I appreciate your acknowledgement to my earlier response.

You have asked a very important question, something that is practically very important for patients to know.

I did come across two studies on the bioavailability (serum levels) of lithium comparing Lithium carbonate immediate release and extended release and would like to discuss them with you.


1.     Kirkwood, XXXXXXX K., et al. "Single-dose bioavailability of two extended-release lithium carbonate products." American Journal of Health-System Pharmacy 51.4 (1994): 486-489.


In their study done by Kirkwood et al. the single dose bioavailability of two extended release of lithium carbonate products as well as a single dose of immediate release product was compared on healthy volunteers (for more accurate results). They were divided into 3 groups and given three treatments, each separated by a one-week period. The treatments, which were given to each group in a different sequence, consisted of three 300-mg immediate-release lithium carbonate tablets (Lithotab), two 450-mg extended-release lithium carbonate tablets (Eskalith CR), and three 300-mg extended-release lithium carbonate tablets (Lithobid).

Blood samples were collected just before drug administration and at intervals up to 48 hours afterward. Urine was collected for 96 hours. Plasma and urine lithium concentrations were determined by flame-emission spectrophotometry, and lithium pharmacokinetic values and the cumulative urinary excretion of lithium were computed.

Mean maximum serum lithium concentration (Cmax) differed significantly among all three lithium carbonate products.
Eskalith CR produced a 40% lower Cmax and Lithobid a 25% lower Cmax than Lithotab; Lithobid produced a 23% higher Cmax than Eskalith CR.
Lithotab had a significantly shorter mean time to maximum plasma lithium concentration than either extended-release product.
Two extended-release lithium and the immediate release lithium carbonate products were not bioequivalent when given in single doses to healthy volunteers.


2.     Vismari, Luciana, et al. "Bioavailability of immediate and controlled release formulations of lithium carbonate." Revista Brasileira de Psiquiatria 24.2 (2002): 74-79.

In this study by Vismari et al. the objective was to compare the bioavailability of controlled-release and immediate-release lithium formulations, after single and multiple doses.

Twelve healthy volunteers received 900 mg of immediate-release or controlled-release lithium carbonate in single or multiple doses during 9 days. After single dose administration, the following parameters were analyzed for each formulation: maximum lithium concentration (Cmax); time to reach Cmax (tmax); area under the curve of serum concentration versus time (AUC0-12 and AUC0-) and the elimination half-life (t1/2 elim.). After multiple doses, Cmax; tmax; AUC0-12; mean (Cmean) and minimum drug concentration (Cmin) and degree of fluctuation (DF) were analyzed.

Following single dose, the two formulations were bioequivalent (questionable from earlier studies and later found to be erroneous); however, they were not after multiple doses. This fact could be a consequence of methodological limitations of lithium level's measurements since, following single dose, these levels could not be detected at time periods 24 and 48h in many volunteers, compromising the calculation of t1/2 elim ,and consequently of the AUC0 and the 90%CI to the ratio of these areas. Therefore, the bioequivalence found after single dose may be an unreliable result.

In conclusion, there is enough evidence to tell that there is significant difference in serum lithium concentration between lithium carbonate immediate release and extended release switchover. There is also difference in serum lithium levels between different dose tablets (300 mg and 450 mg) lithium carbonate when given in single or multiple doses. The 450 mg ER preparation gives least Cmax and lithium immediate release gives highest Cmax.

As you have specifically asked for time duration two to four weeks, the serum lithium level will be in accordance to the exact dosage and formulation of lithium carbonate given to the patient, whether given in single or multiple doses.

Hope your query is answered to the best of my ability.

Dr A. Rao Kavoor

---

Hi XXXXXXX
Thanks for writing back again.

I am sure you have understood that after multiple doses the serum levels reach a therapeutic level and are maintained as such with further medication.

Once this trough is reached, your symptoms will be under control. However, it is important to get your lithium serum levels checked as and when felt necessary.
.
Hope your queries are answered.

Dr A Rao Kavoor

---