PROPRIETARY PREPARATIONS OF LITHIUM CARBONATE (PRIADEL, PHASAL AND CAMCOLIT)

Transcription

1 Br J clin Pharmac (1977), 4, SERUM CONCENTRATIONS OF LITHIUM AFTER THREE PROPRIETARY PREPARATIONS OF LITHIUM CARBONATE (PRIADEL, PHASAL AND CAMCOLIT) EH BENNIE, AKM MANZOOR & AM SCOTT Leverndale Hospital, Glasgow G53 7TU GS FELL University Department of Biochemistry, Glasgow Royal Infirmary, Glasgow I The serum lithium concentration was measured before dosing, and at 2, 4, 6, 8, 1, 2, 22, and 24 h after three proprietary preparations of lithium carbonate (Camcolit, Phasal or Priadel) 2 A total of twenty-eight studies were performed on eleven patients In seven studies the patients received Camcolit, in ten studies patients received Priadel and in eleven the patients took Phasal 3 The dose of each preparation was adjusted during a 1 week run-in period to maintain the serum lithium within the normal therapeutic range (- mmov/) Five patients received one lithium preparation, one patient received three lithium preparations and five patients received four lithium preparations consecutively 4 After a single daily dose of Phasal and Priadel, the serum lithium remained within the therapeutic range for 24 h S After a single daily dose of Camcolit, the serum lithium remained within the therapeutic range for only 12 h 6 After three doses of Camcolit (given at 8 h, 12 h, and 18 h) each day, the serum lithium was maintained in the therapeutic range for 24 h Introduction Lithium carbonate is effective in the management of recurrent affective psychoses (Coppen, Noguera, Bailey, Burns, Swani, Hare, Gardner & Maggs, 1971; Hullin, McDonald & Alsopp, 1972) Schou, Amdisen & Baastrup (1971) have stated that the therapeutic action of the drug depends on the dose being adjusted to maintain the serum lithium between and mmolvl There are now two standard preparations of lithium carbonate, ordinary tablets (eg Camcolit) which are usually taken several times a day, and sustained release tablets (eg Priadel) which are given as a single daily dose The serum lithium concentration in patients on ordinary lithium carbonate tablets ranges from to 15 mmol/l (Amdisen & Sjogren, 1968) Sustained release lithium carbonate has been available since 1968 Coppen, Bailey & White (1969) have measured the average plasma concentration in five patients who took lithium for 9 days They showed that the morning dose of a slow release lithium carbonate maintained satisfactory plasma concentrations for 24 h The aim of the present study was to compare the serum lithium concentration after three proprietary preparations of lithium carbonate (Camcolit, Priadel and Phasal) Each patient received one of these three preparations for at least 1 weeks During this 'run-in' period the serum lithium concentration was measured and the dose adjusted to produce serum concentrations between and mmovil After 1 weeks continuous administration the serum lithium concentration was measured at intervals over 24 h Crammer, Rosser & Crane (1974) have stated that the shape and height of the serum lithium curve depends on the rate of gastric emptying Since these patients continued their normal daily routine and did not receive other drugs that affect the rate of gastric emptying, the results should reflect what occurs in normal clinical practice Methods and patients Camcolit (Camden Chemical Co) contains 68 mmol/l of lithium carbonate in each tablet Each tablet of the sustained release preparation Priadel

2 48 EH BENNIE, AKM MANZOOR, AM SCOTT & GS FELL (Delendale Laboratories) contains 1 mmol/l of lithium Phasal (Pharmax Ltd) is a controlled release tablet that contains 81 mmol/l of lithium Eleven male long-term in-patients at Leverndale Hospital, Glasgow, gave informed consent to the study The patients selected for the study were suffering from schizo-affective psychoses all of which are established indications for lithium treatment (Angst, Weis, Grof, Baastrup & Schou, 197) They received one of the three lithium preparations for at least 1 weeks During this time the dose was adjusted to bring the serum lithium within the normal therapeutic range ( to mmol/l) Twenty-eight observations over 24 h were performed Eleven studies were performed with Phasal Priadel was used on ten occasions and Camncolit seven times In all the single dose studies the lithium preparation was given at 12 h When a divided schedule was given the tablets were taken at 12 h, 18 h and 8 h These times were chosen to avoid interference with the patients' work and sleep Venous blood samples were collected and allowed to clot prior to medication and at 2,4, 6, 8, 1, 2, 22, and 24 h after each preparation In the three experimnents where a thrice daily regimne was given, blood samples were collected before administration of lithium tablets, at 12 h, 18 h and 8 h After centrifugation, the serum wjis diluted one in fifty (1-5) ml in a suitable buffer (1% lanthanum chloride) The lithium content of these samples was assayed for lithium with an atomic absorption spectrophotometer, PE 43, with an air-acetylene flame A set of suitable standards (concentration range between 5 and 25 mmol/l) were diluted in the same buffer The precision of this method was less than 3 per cent (Fell, 1968) Although lithium remains stable in blood (Amdisen, 1967), most analyses were performed within 24 h of sampling In twelve instances a duplicate experiment was performed 2 weeks later T'his was done to check that the patients took the prescribed medicine Results Tables 1, 2 and 3 show the mean + sd serum lithium concentrations at each sampling time Table 3 shows the results after a single dose of Camcolit (four patients) and divided dose (three patients) Standard deviations were only calculated where there were more than four results at each sampling time T'he results show that in the patients who received Phasal the mean serum lithium over 24 h was between and 5 mmol/l The mean serum lithium in the patients who received Priadel was between 4 and 5 mmol/l The patients stabilized on a divided daily dose of Camcolit had a mean serum lithium between and 1 mmol/l for 24 h On a single daily dose of Camcolit the mean serum lithium ranged from 48 to 3 mmol/l Table 1 Serum lithium concentration after a single daily dose of Phasal (controlled release lithium carbonate) given at 12 h Dose (mg) 72 h Serum Ifthium concentration (mmol/l) in samples taken at: 14Oh 16Oh 18OOh 2Oh 22Oh 8OOh 1 h ±sd 7+ 8 ± ± 5 ± 5 ± ±

3 SERUM LEVELS OF LITHIUM AFTER THREE PROPRIETARY PREPARATIONS 481 Table 2 Serum lithium concentration after a single daily dose of Priadel (sustained release lithium carbonate) given at 12 h Dose (mg) h 2 8 ± sd Serum lithium concentration (mmol/l) in samples taken at: 14h 16h 18h 2h 22h 8h 1h ± 9± 5± ± Table 3 Serum lithium concentration in patients receiving Camcolit (lithium carbonate) Thrice daily doses of lithium carbonate given at 12 h, 18 h, and 8 h; and a single daily dose at 12 h Serum lithium concentration (mmol/l) in samples taken at: Dose (mg) 12 h 14 h 16 h 18 h 2 h 22 h 8 h 1 h () at 12 h 1 at 12 h at 12 h at 12 h ± sd ± 48± (single doses)

4 482 EH BENNIE, AKM MANZOOR, AM SCOlT & GS FELL (I) co - ' E C U) U, E E se U) C cn +la E S S I- Lo r- r' '- C5iC en4 Cd Id r +I+l+l D( '- (4 6i +1±+165 I- co 6 6 't~ 66(C q) C C ( co o Q ' ci O, (D CM (" ~~~~-Nr ao) +~~~V) l+ N' o, CeD LO (C'4 ' CD- ' r o wl LO 66 co4 co 1 '- '- wo 1 o O 6 - * ( coo OD "co '-) X o6 r Ḻn o a ) 4 o w- C4 oh~~~~~~~~c 4t ELn o X 8 88 co X *C O C'- 4 U) -9 C) - XL L- v- LO u The following points emerge from Table 4 which shows the mean + sd serum lithium concentrations from 2-24 h after each preparation Firstly a single daily dose of Camcolit does not maintain the serum lithium concentration above mmol/l for 24 h When the patients were given the same amount of Camcolit as divided doses the serum concentrations were adequate Secondly, where the dose was tailored to maintain the serum lithium concentration within the therapeutic range ( to mmol/1), the serum levels in the different subjects are remarkably similar Finally, the comparison between the four subjects who received a daily dose of Phasal ( mg) and the five subjects who received Priadel ( mg daily) shows that the standard deviation between the results on patients receiving Priadel is much smaller than in the patients given Phasal Discussion It has been stated that prophylactic lithium is only effective when the serum lithium is maintained between and mmol/l (Fry & Marks, 1971) Adverse reactions are associated with serum levels over 15 mmol/1 and serum levels over 2 mmol/ may be associated with neurological symptoms and a fatal outcome (Crammer et al, 1974) The maintenance dose of lithium should be adjusted to give effective serum concentrations with a low incidence of toxic reactions A laboratory report of an isolated lithium result is meaningful only in relation to the time of medication, and the lithium dose should be guided by venous sampling prior to the patient taking his tablets The serum lithium levels 1 h after medication with a sustained or controlled release lithium preparation were less than mmol/1 At no time between each dose was the serum lithium concentration above 2 mmol/l Although three times a day medication with ordinary lithium carbonate gave serum lithium concentrations no higher than mmola, once daily medication with ordianry lithium carbonate did not give adequate serum concentrations from 2-1 h After medication with sustained and controlled release preparations lithium levels were some two to three times the average values We would urge that when the laboratory reports a serum lithium of 2 mmol/i the clinician should urgently adjust the dose We studied patients who took a variety of doses of three different types of lithium carbonate Thus it is appropriate after starting a small dose of lithium, to measure the serum lithium for 2 to 3 weeks Should the serum lithium concentrations be less than mmol/, the dose should gradually be increased to produce serum lithium concentrations in the therapeutic range Each dose was adjusted to give a serum lithium level between and mmoli in a

5 SERUM LEVELS OF LITHIUM AFTER THREE PROPRIETARY PREPARATIONS 483 sample taken between 2 and 3 h before the next dose The serum lithium concentrations in the patients who received a daily dose of lithium carbonate (16 mg) did not exceed those who took lithium carbonate ( mg) per day This indicates that the lithium dose must be individualized for each patient The results confirm that three of these four regimes give satisfactory serum lithium concentrations within the therapeutic range We do not recommend a single daily dose of Camcolit Calculation of the standard deviation of the mean serum lithium values showed that Priadel gave the most consistent results and in particular when a comparison is made between the five results of patients on Priadel ( mg) with the four results of patients on Phasal ( mg) Two hours after medication with Priadel the serum lithium concentration was higher than the comparable value after Phasal At 4 h the serum lithium concentrations after both preparations were similar References AMDISEN, A (1967) Serum lithium determinations for clinical use Scand J Clin Lab Invest, 2, AMDISEN, A & SJOGREN, J (1968) Lithium absorption from sustained release tablets Acta Pharmac Suec, 5, ANGST, J, WEIS, P, GROF, P, BAASTRUP, PC & SCHOU, M (197) Lithium prophylaxis in recurrent affective disorders Br J Psychiat, 6, COPPEN, A, BAILEY, JE & WHITE, SG (1969) Slow release lithium carbonate J clin Pharmac, 9, COPPEN, A, NOGUERA, R, BAILEY, J, BURNS, BH, SWANI, MS, HARE, IH, GARDNER, R & MAGGS, R (1971) Prophylactic lithium in recurrent affective disorders Lancet, u', CRAMMER, JL, ROSSER, RM & CRANE, G (1974) Blood levels and management of lithium treatment Br med J, 3, FRY, DE & MARKS, V (1971) Value of plasma lithium monitoring Lancet, L 886 HULLIN, RP, McDONALD, R & ALSOPP, MNE (1972) Prophylactic lithium in recurrent affective disorders Lancet, L SCHOU, M, AMDISEN, A & BAASTRUP, PC; (1971) The practical management of lithium treatment Br J hosp Med, 6,53-57 (Received June 16, 1976, Revised January 18,1977)