Download Therapeutic Drug Monitoring of Lithium Carbonate

A New Accurate Method for
Predicting Lithium Clearance and
Daily Dosage Requirements
in Adult Psychiatric Patients
Hisham S. Abou-Auda*1, Mohammad J. Al-Yamani1
Rafiq R. Abou-Shaaban2 and Sahal I. Khoshhal3
1.
Department of Clinical Pharmacy, College of Pharmacy,
King Saud University, P.O. Box 2457, Riyadh-11451, Saudi Arabia.
Tel: 966-1-467-7470, Fax: 966-1-467-6229
E-mail: [email protected]
2. Pharmacy Department, King Fahad National Guard Hospital,
Riyadh, Saudi Arabia.
* To whom correspondence should be addressed.
Abstract
2
Introduction
Lithium has been used in the treatment of mania and in the prophylaxis of bipolar
disorder and recurrent depression (Jefferson 1987, Speirs 1978). Despite a growing
number of proposed alternatives, including several anticonvulsants and antipsychotic
drugs, lithium remains useful in the contemporary treatment of bipolar disorders, and
is by far the agent of choice for long-term maintenance treatment in bipolar disorders
(Baldessarini 1996, Johnson 1996). It has a narrow therapeutic index at steady state
and therapeutic ranges of 0.6–1.2 mmol/L used by many clinicians do not distinguish
between the ranges for the treatment of mania and maintenance treatment (Amdisen
1975, Amdisen 1977, American Psychiatric Association 1994, American Psychiatric
Association 2002). Inappropriate dosage can cause poor control of symptoms and
potentially dangerous side-effects. Therefore, the prediction of optimal dosage to
obtain the desired therapeutic level is important. The toxicity of lithium is closely
related to serum lithium levels, and can occur at doses close to its therapeutic level,
therefore, regular clinical and serum level monitoring of lithium is a requirement for
good clinical practice (Moscovich 1993, Johnson 2002). In addition, conditions that
alter electrolyte balance may affect lithium levels in patients (Hopkins 2000). Lithium
removal from the body is achieved almost exclusively via the renal route.
Concomitant medications with lithium may also contribute to the clinical
manifestations of lithium toxicity since its clearance varies proportionally with
glomerular filtration rate (GFR) and is usually 20-30% of GFR (Thomsen 1997). As a
result, any medication that increases GFR or affects electrolyte exchange in the
nephron may influence the pharmacokinetic disposition of lithium. It was also found
that lithium clearance is usually reduced in elderly subjects (Hewick 1977).
Concomitant use of diuretics, angiotensin-converting enzyme inhibitors, calcium
3
channel antagonists, or non-steroid antiinflammatory drugs have been associated with
lithium toxicity through pharmacokinetic interactions (Timmer 1999, Finley 1995,
Jefferson 1981). Viguera et al. (Viguera 2000) analyzed 17 studies on the use of
lithium in bipolar disorder to investigate sex differences in response to lithium. They
concluded that women may clear lithium less efficiently than men or probably they
vary more in lithium clearance.
Although a number of studies have examined strategies for determining optimal
lithium dosages in the treatment of patients with bipolar disorder based on single-dose
plasma concentrations (Cooper 1973, Cooper 1976, Amdisen 1977, Pepin 1980,
Slattery 1980, Slattery 1981, Zetin 1983, Zetin 1986, Kook 1985, Cummings 1988,
Dugas 1983, Gengo 1981, Perry 1983, Perry 1986, Jermain 1991, Terao 1999,
Gervasoni 2003), none of these studies have exclusively gained recognition as the sole
method for lithium monitoring in the routine clinical practice. The purpose of these
methods is eventually to maintain steady-state therapeutic levels of 0.6-1.2 mmol/L.
The most evaluated methods, both retrospectively and prospectively, were the
empirical method (Ref), the Pepin et al. (Pepin 1980) and the Zetin et al. (Zetin 1983,
Zetin 1986, Zetin 1990) methods. Browne and Associates (Brown 1989)
retrospectively compared 5 of these methods and found significant differences in their
accuracy for estimating lithium maintenance dosing requirements in inpatients. When
the accuracy of the Pepin method was tested in 13 healthy volunteers, it was found to
be a safe but conservative method for the prediction of the appropriate daily dose of
lithium (Stip 2001). Markoff and King (Markoff and King 1992) compared the Zetin
method in 12 patients versus the empirical dosing method in 21 patients to determine
which method would efficiently produce a target concentration predetermined by the
clinician. They concluded that 83% of patients had reached the desired lithium blood
4
level with Zetin method whereas only 38% had done so with the empirical method.
Other studies (Hagino 1998, Wright
2000, Markins 1994) found no significant
differences between methods or no improvement was noted compared with empirical
method.
Most of the reported predictive a priori methods had never been evaluated in
both psychiatric inpatients and outpatients at the same time. Our observations
indicated a probable difference in lithium clearance and consequently a difference in
the predictability of lithium daily dosage requirements between inpatients and
outpatients.
The purpose of this study was to derive new equations for estimating lithium
clearance in inpatients and outpatients. Sex differences in lithium clearance were
considered in this derivation. The bias and accuracy of these equations were compared
with those set forth by Jermain et al. (Jermain 1991), Pepin et al. (Pepin 1980) and the
empirical methods. In addition, new equations for determining lithium daily dosage
requirements in adult psychiatric inpatients and outpatients were derived. The bias
and accuracy of the derived equations were also compared with Pepin et al. (Pepin
1980), Zetin et al. (Zetin 1986) and Terao et al. (Terao 1999) methods.
Methods
Patients
Data were collected from King Khalid University Hospital (KKUH) medical
records at Riyadh, Saudi Arabia. Patients were included in the study if they were
adults aged 18-80 years receiving multiple daily doses of lithium carbonate for, at
least, 7 consecutive days prior to the commencement of the study. The patients were
included if they had no evidence of cardiac, respiratory, hepatic or renal
abnormalities. Patients who were on sodium-restricted diet or taking any other
medication that would affect lithium levels were excluded from the study. The period
between lithium serum and body weight and renal function measurements did not
5
exceed one month. Serum lithium samples were drawn between 12–14 h after the last
dose. The study protocol was approved by King Khalid University Hospital (KKUH),
College of Medicine Research Center (CMRC), King Saud University, Riyadh, Saudi
Arabia.
A total of 60 patients (34 males and 26 females) met the study criteria. Of
these, 53 patients were Saudi nationals (28 males and 25 females). The mean age
(±SD) was 38.83±9.87 years (range, 21-77 years) and the mean body weight was
71.39±17.04 kg (range, 33–120 kg). Only 7 (11.7%) patients were smokers. Fortyfour (73.3%) patients were diagnosed with bipolar affective disorder, 9 (15%) with
manic depressive illness, 3 (5%) with Schizoaffective disorder and the rest were
affected by other psychiatric conditions. Only 3 (5%) patients were taking tricyclic
antidepressant agents. Twenty eight (46.7%) patients have family history of
psychiatric illness. Lithium serum levels were measured both as inpatients and
outpatients for 47 (78.3%) patients, as only outpatients for 9 (15%) and as only
inpatients for the rest. Lithium dose in these patients averaged 1016.7±216.2 mg/day
(range, 375–1800 mg/day) and their average lithium serum level was 0.61±0.13
mmol/L (range, 0.3–1.0 mmol/L) for the outpatient setting. On the other hand, lithium
dose averaged 1016.2±230.1 mg/day (range, 375-1800 mg/day) and lithium serum
level was 0.58±0.18 mmol/L (range, 0.06–1.21 mmol/L) for these patients in the
inpatient setting. BUN averaged 11.36±3.28 mg/dL (range, 6.02–22.13 mg/dL) and
10.85±3.13 mg/dL (range, 4.76-19.05 mg/dL) for inpatients and outpatients,
respectively. The mean serum creatinine level was 0.92±0.17 mg/dL (range, 0.63–
1.37 mg/dL) and 0.92±0.20 mg/dL (range, 0.49–1.86 mg/dL) for inpatients and
outpatients, respectively.
Data Analysis
Data were collected from patient medical records at King Khalid University
Hospital (KKUH), Riyadh, Saudi Arabia, using a specially designed collection form.
The total body clearance (CL) of lithium (L/h) in these patients was estimated from
the following relationship:
CL Li 
F  D  8.12 

24 Css 
 300 
6
(Eqn. 1)
where F is the oral bioavailability (usually 100%), Css is the average steady-state
serum concentration of lithium (mmol/L) and D is the daily dose (mg/day) of lithium
carbonate. The creatinine clearance was calculated from Cockcroft and Gault equation
(Cockroft & Gault 1976).
Data collected from the 60 patients retrospectively (both in the inpatient and
the outpatient settings) were applied to published a priori methods either to determine
lithium clearance or lithium daily dosage regimen. The methods applied for clearance
determination are the empirical (Amdisen 1977), Pepin et al. (Pepin 1980) and the
Jermain et al. (Jermain 1991) methods. The methods applied for daily dosage
requirements determinations are Pepin et al. (Pepin 1980), Zetin et al. (Zetin 1986)
and Terao et al. (Terao 1999) methods. The calculated daily dose requirement
required to produce the lithium levels observed in these patients was compared with
the daily dose actually used by these patients during the course of the treatment.
The empirical method assumes that lithium clearance (CLLi) is one fourth of
the creatinine clearance (CLCr) and each 300 mg of lithium increases lithium level by
0.3 mmol/L. On the other hand, the equation used by Pepin et al. was
[CLLi=0.235×CLCr]. The Jermain et al. method (Jermain 1991) utilized a onecompartment open model equation and population pharmacokinetic modeling to
produce the following estimate of CLLi:
CLLi  0.0093  LBW  0.0885 CLCr
where LBW is the lean body weight and was calculated from the following
relationship:
2
LBWMales
W
 1.10W  128  
H
LBWFemales
W
 1.07W  148  
H
2
where W=the total body weight (kg) and H=the height (cm). The ideal body weight
(IBW) is calculated as: IBWMales  50  2.3  H  and
IBWFemales  45.5  2.3  H 
where H is the height in inches.
The daily dosage requirements and serum concentrations were calculated also
by the following formula used by Pepin et al.:
7
min
 300   Css  Vd 
D
1  e k d 

 kd  
8.12
F

e





where D=daily dosage of lithium (mg), Cmin
ss =the desired steady-state trough
concentration (mmol/L), Vd=the apparent volume of distribution (L) (calculated as
CLLi/kd), F=the oral bioavailability of lithium (1.0),  =dosing interval (24 hr) and
kd=elimination rate constant (hr–1) [calculated as ln(2)/lithium t½].
The Terao et al. method (Terao 1999) was given by the following formula:
Daily lithium dose (mg)  100.5  752.7  CLi   3.6  Age   7.2  W  13.7  BUN 
where CLi is the expected lithium concentration in mg/L, age in years, W is weight in
kg and BUN is the blood urea nitrogen in mg/dL.
Validation of Equations
For equations’ validations, the predicted clearance and daily dosage
requirements were correlated with the observed clearance and dosage in another 60
subjects who received different doses of lithium.
Statistical Analysis
The differences between various methods were evaluated by one-way analysis
of variance (ANOVA) at the 0.05 level of significance. The predictive performance of
all methods for clearance and daily dosage requirements was determined by
calculating the percent error (Sheiner 1981) as follows:
 YY
%Error  100 
 Y 


where Y is the predicted value and Y is the observed value. The bias of prediction
was determined by the mean prediction error (MPE):
Y
n
MPE 
i
Y
i 1

n
and precision of prediction was measured by mean absolute error (MAE) and root
mean square error (RMSE):
n
MAE 
Y
i
i 1
n
8
Y

 n
  Yi  Y
RMSE   i 1
n




2






1
2
The statistical significance of bias and precision was tested using ANOVA.
Results
The data from 60 psychiatric patients were utilized to develop new equations
for the prediction of lithium clearance and daily dosage requirements by performing
stepwise linear regression. Lithium clearance was correlated with creatinine clearance.
In addition to sex-dependent variability in lithium clearance, we have reasons to
believe that lithium clearance may also vary between inpatients and outpatients. The
correlation between creatinine clearance (L/hr, independent variable) vs. lithium
clearance (L/hr, dependent variable) was evaluated by multiple linear regression. The
regression equations which gave the best correlation coefficient (r) were the
following:
 For inpatients:
CLLi  Males   1.415  0.124 CLCr
CLLi  Females   0.534  0.228 CLCr
 For outpatients:
CLLi  Males   1.055  0.137 CLCr
CLLi  Females   0.979  0.148 CLCr
These equations were further simplified to produce for both males and females
as follows:
CLLi  Inpatients   0.932  0.185 CLCr
CLLi  Outpatients   1.021  0.141 CLCr
The variables chosen by the stepwise linear regression analysis for the
prediction of daily dosage requirements (mg) were lithium concentration (mmol/L),
age (years), weight (kg), tricyclic antidepressants (TCA, yes=1, no=0), CLCr (L/hr),
blood urea nitrogen (BUN, mmol/L) and sex (male=1, female=0). The determination
coefficients (r2) with this combination of variables were 0.59 (p=0.00458, ANOVA)
and 0.746 (p=0.00017, ANOVA) for inpatients and outpatients, respectively. The
9
resulting regression equations for the prediction of daily dosage requirements of
lithium carbonate (mg) in these patients as follows:
 For inpatients:
Daily dose  350.15  289.92  desired lithium level   0.84  weight 
 1.76  Age   34.43  TCA   62.1  CLCr 
 13.1  BUN   40.9  sex 
 For outpatients:
Daily dose  784.92  530.22  desired lithium level   8.61  weight 
 12.09  Age   11.14  TCA   7.63  CL Cr 
 42.62  BUN   23.43  sex 
If the patients are not concomitantly administering tricyclic antidepressants, a
simplified version of both equations could be used for the preliminary estimation of
daily dosage requirements of lithium for both sexes:
Daily dose  382.54  348.29  desired lithium level   67.19  CLCr 
Comparison with other methods
When the developed equations were applied to another set of data for the same
60 psychiatric patients, the predicted total body clearance of lithium was found to be
2.09±0.045 L/hr and 1.88±0.051 L/hr for inpatients and outpatients, respectively,
compared with the observed values of 2.09±0.112 L/hr and 1.98±0.086 L/hr for
inpatients and outpatients, respectively. The lithium clearance calculated by Pepin et
al. method averaged 1.46 L/hr and 1.44 L/hr for inpatients and outpatients,
respectively. On the other hand, the empirical and Jermain et al. methods produced
estimates of 1.56 L/hr and 1.026 L/hr for inpatients, and 1.53 L/hr and 1.0 L/hr for
outpatients, respectively. Table 1 shows the lithium clearance values predicted by
various methods. All methods, with the exception of our method, tended to underestimate lithium clearance for both inpatients and outpatients. The Jermain et al.
method proved to be the least accurate among all methods for the prediction of
lithium clearance and the empirical method produced better estimates of clearance
than Pepin et al. method (Table 2).
The predicted daily dosage requirements in the 60 psychiatric patients by the
Pepin et al. method averaged 1140.3±87.0 mg (range, 90.7–4008.1 mg) compared
10
with 1014.5±19.9 mg (range, 650.8–1498.4 mg) predicted by our method for
inpatients. On the other hand, Zetin and Terao methods predictions of daily dosage
requirements averaged 1088.7±26.1 mg (range, 611.8-1571.3 mg) and 743.8±26.1 mg
(range, 228.6-1196.0 mg), respectively. One-way ANOVA for the mean prediction
error (MPE), mean absolute error (MAE) and root mean square error (RMSE) showed
statistically significant differences (p<0.001) between all methods. The post hoc
pairwise comparisons using Student-Neuman-Keuls and Duncan tests revealed that
Zetin method was not significantly different from our method with respect to MPE
and MAE. Table 2 shows the bias and precision of prediction of both lithium
clearance and daily dosage requirements predicted by various methods for psychiatric
inpatients. Our method proved to be statistically superior to all other methods
described in this study for the prediction of lithium clearance as well as the prediction
of daily dose. The Terao et al. method extremely underpredicted the daily dosage
requirements for these patients by almost 25%, whereas Pepin and Zetin methods
overpredicted the dosage by about 13%. The deviation in our method was less than
4%.
Similar analysis was performed for outpatients revealed that the empirical,
Jermain and Pepin methods also significantly underpredicted lithium clearance for
outpatients (Table 1). The deviation in our method was less than 7%, while the
deviation in Jermain method exceeded 44% (Table 3). The Pepin method predicted
the lithium daily dosage requirements to be 1212.4±99.9 mg (range, 440.3-3408.0
mg) compared with 1003.7±26.3 mg (range, 651.1-1463.4 mg) predicted by our
method with a deviation of less than 3% from the observed dose actually prescribed
for these patients, whereas the deviation in Pepin method was more than 18%. Again,
the Terao and Associates method significantly underpredicted the dose. Conversely,
dosage prediction by Jermain method was reasonably unbiased for these patients
compared with other a priori methods, but it still falls short when compared with the
present method (Table 3).
Discussion
11
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14
Table 1. Lithium clearance determined by various methods. The observed
lithium clearance in 60 patients was 2.09±0.112 (range, 0.58 – 3.29)
for inpatients and 1.88±0.0.45 (range, 0.57 – 5.07) for outpatients.
Method
Lithium Clearance (L/hr)
Mean±SEM (Range)
Inpatients
Outpatients
Empirical
1.56 ± 0.064
(0.73 – 3.02)
1.53 ± 0.08
(0.61 – 2.92)
Jermain
1.026 ± 0.031
(0.53 – 1.58)
1.00 ± 0.036
(0.53 – 1.52)
Pepin
1.46 ± 0.06
(0.69 – 2.84)
1.44 ± 0.076
(0.58 – 2.74)
Abou-Auda et al.
(This method)
2.088 ± 0.051
(1.22 – 3.29)
1.88 ± 0.045
(1.37 – 2.67)
15
Table 2: Bias and precision of prediction of lithium clearance and daily dosing regimen of various methods (mean±SEM) compared
with the method described in this study for the inpatients.
% Error
MPE*
MAE**
RMSE***
Empirical
-19.53±3.72
-0.53±0.104
0.63±0.09
0.89±0.51
Jermain
-46.37±2.69
-1.066±0.107
1.07±0.105
1.29±0.67
Pepin
-24.36±3.50
-0.618±0.103
0.68±0.10
0.95±0.54
Abou-Auda et al.
(This Method)
10.31±5.77
0.002±0.10
0.49±0.07
0.69±0.45
Pepin
13.39±6.39
143.13±74.39
357.97±57.37
534.92±355.38
Zetin
12.45±4.66
68.36±32.64
181.13±20.98
229.36±110.72
Terao
-23.13±3.39
-265.72±33.51
282.64±30.49
352.85±161.56
3.96±3.32
0.68±26.6
142.9±16.86
184.57±95.99
Parameter
Method
Clearance
Daily Dose
Abou-Auda et al.
(This Method)
* Mean Prediction Error
** Mean Absolute Error
*** Root Mean Square Error
16
Table 3: Bias and precision of prediction of lithium clearance and daily dosing regimen of various methods (mean±SEM) compared
with the method described in this study for the outpatients.
% Error
MPE*
MAE**
RMSE***
Empirical
-16.37±3.56
0.34±0.073
0.47±0.05
0.58±0.24
Jermain
-44.34±2.75
-0.902±0.068
0.91±0.07
0.99±0.35
Pepin
21.39±3.34
-0.437±0.071
0.52±0.055
0.624±0.255
Abou-Auda et al.
(This Method)
6.62±4.80
0.004±0.063
0.334±0.035
0.40±0.165
Pepin
18.47±7.20
208.74±82.93
374.48±66.79
546.5±110.06
Zetin
8.76±3.92
47.79±26.68
147.24±17.55
190.95±94.92
Terao
-18.83±3.34
-218.43±27.74
248.08±20.59
280.17±108.30
2.95±3.12
0.026±23.47
111.5±15.5
148.46±72.16
Parameter
Method
Clearance
Daily Dose
Abou-Auda et al.
(This Method)
* Mean Prediction Error
** Mean Absolute Error
*** Root Mean Square Error
17
Figures’ Captions
Figure 1:
Relationship between lithium clearance and creatinine clearance in 60
adult psychiatric inpatients.
Figure 2:
A plot of predicted dose by the current method described in this study
versus administered dose for 60 inpatients.
Figure 2:
A plot of predicted dose by the current method described in this study
versus administered dose for 60 outpatients.
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