Lack of effect of amisulpride on the pharmacokinetics and safety of lithium

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1 International Journal of Neuropsychopharmacology (2003), 6, Copyright f 2003 CINP DOI : /S Lack of effect of amisulpride on the pharmacokinetics and safety of lithium ARTICLE Muriel Canal 1, Eric Legangneux 1, Jan Jaap van Lier 2, Andre Antonius van Vliet 2 and Catherine Coulouvrat 3 1 Sanofi-Synthélabo Recherche, 1 ave Pierre Brossolette, F Chilly Mazarin Cedex, France 2 PharmaBio-Research Group, PO Box 200, 9470 AE, Zuidlaren, The Netherlands 3 Sanofi-Synthélabo Recherche, 31 ave Paul Vaillant-Couturier, F Bagneux, France Abstract Lithium may be used as adjuvant therapy in schizophrenic patients and antipsychotics can be employed during the early phases of lithium therapy in patients with bipolar disorder. The issue of interactions between lithium and antipsychotics is therefore important. This study investigates the potential influence of repeated administration of amisulpride, an atypical antipsychotic, on the pharmacokinetics of lithium at steady state. Twenty-four healthy male volunteers (aged yr) received lithium carbonate (500 mg b.i.d.) for 14 d. All subjects were shown to have stable lithium serum concentrations after 5 7 d and were then randomized to receive double-blind administration of amisulpride (100 mg b.i.d.) or placebo bid from day 8 of lithium administration. Complete pharmacokinetic profiles were obtained on days 7 and 14 for lithium and trough plasma concentrations on days 10, 12 and 14 for amisulpride. Co-administration of amisulpride appeared to exert no effect on the pharmacokinetics of lithium. All treatments were well tolerated and safety assessment revealed no differences between the lithium+placebo and lithium+ amisulpride groups. This finding permits the flexible use of amisulpride in patients already receiving lithium therapy. Received 23 December 2001; Reviewed 24 March 2002; Revised 13 February 2003; Accepted 16 February 2003 Key words: Amisulpride, antipsychotic, drug drug interactions, lithium, pharmacokinetics. Introduction Amisulpride (Solian 1, Sanofi-Synthélabo) is an atypical antipsychotic with affinity at dopaminergic D 3 and D 2 receptors, but which is devoid of affinity for dopamine D 1, adrenergic, cholinergic, serotonergic or histaminergic H 1 receptors (Perrault et al., 1997; Schoemaker et al., 1997; Sokoloff et al., 1992). It shows selectivity for limbic and hippocampal structures (thought to mediate affective and cognitive processes), rather than striatal structures (thought to mediate extrapyramidal motor control), thus suggesting a lower propensity to induce extrapyramidal effects than seen with the classical neuroleptics (Perrault et al., 1997). Amisulpride has shown efficacy in patients with acute exacerbation of schizophrenia, in negative and mixed symptoms and during chronic treatment (Boyer et al., 1995; Carrière et al., 2000; Chabannes et al., Address for correspondence : Dr M. Canal, Sanofi-Synthélabo Recherche, 1 ave Pierre Brossolette, F Chilly Mazarin Cedex, France. Tel.: +33(0) Fax : +33(0) muriel.canal@sanofi-synthelabo.com 1998; Colonna et al., 2000; Danion et al., 1999; Loo et al., 1997; Möller et al., 1997; Paillère-Martinot et al., 1995; Peuskens et al., 1999; Puech et al., 1998; Speller et al., 1997; Wetzel et al., 1998). Uniquely, it has effects on positive symptoms at doses of mg/d and on negative symptoms at doses of mg/d. It also has a good safety and tolerability profile, with fewer extrapyramidal symptoms than the conventional antipsychotics and a low incidence of anticholinergic and endocrine side-effects (Coulouvrat and Dondey- Nouvel, 1999). Amisulpride is a racemate comprising 50% S(x)- enantiomer and 50% R(+)enantiomer. Its pharmacokinetic profile is linear and is characterized by rapid absorption, a biphasic absorption profile (peak plasma concentrations occurring at 1 and 4 h) and an apparent elimination half life of approx. 12 h (Ascalone et al., 1996; Curran and Perry, 2001; Dufour and Desanti, 1988; Hamon-Vilcot et al., 1998; Rosenzweig et al., In Press). It has an absolute bioavailability of 48% and low binding to plasma proteins (17%). Amisulpride is primarily excreted in the urine (20 25% is recovered unchanged in the urine after oral dosing) and is only

2 104 M. Canal et al. weakly metabolized, with the metabolites being inactive. Lithium may be used as adjuvant therapy in schizophrenic patients who fail to respond adequately to an antipsychotic alone (Bigelow et al., 1981; Lewis et al., 1986; Terao et al., 1995). Following oral administration, serum concentrations of lithium follow an open two-compartment model, with first order absorption into the central compartment (Ward et al., 1994). Peak plasma concentrations are achieved after 15 min to 3 h and the bioavailability is between 80 and 100%. Lithium is non-protein bound and is distributed unevenly throughout the body, with plasma concentrations being higher than those in red blood cells and cerebrospinal fluid and lower than in saliva, brain and bone (Thornhill, 1981). As the plasma elimination half-life ranges from 18 to 36 h, steadystate blood levels are not achieved until 4 8 days (Thornhill and Field, 1982). The very narrow therapeutic range of lithium ( mequiv./l) is based on a standardized 12-h lithium concentration that requires plasma samples to be collected at steady state (Amdisen, 1977). Concentrations above 1.5 mequiv./l greatly increase the risk of side-effects and these become life-threatening (e.g. impaired consciousness, seizures, coma) at concentrations above 3.5 mequiv./l. The issue of interactions with lithium is therefore important, especially when a switch from a classical to a novel antipsychotic is being considered, because of safety reasons. Both amisulpride and lithium undergo renal elimination and must remain at a steady plasma concentration. If the plasma concentration of amisulpride rises then there is an increased risk of sideeffects and compliance is therefore compromised. In the case of lithium, an increase in plasma concentration is associated with major, life-threatening sideeffects. This double-blind study therefore investigated the potential influence of repeated administration of amisulpride on the pharmacokinetics of lithium at steady-state levels. Methods Subjects Twenty-four healthy male volunteers (aged yr) were included in the study. All subjects had normal clinical and laboratory examinations, including creatinine clearance of >75 ml/min and plasma thyroidstimulating hormone (TSH) levels within the normal range. No concomitant medications were permitted other than for the treatment of adverse events. Study design and treatment This placebo-controlled, randomized, double-blind study was conducted using two parallel groups, each containing 12 subjects. The protocol was approved by the Independent Ethics Committee (Assen, The Netherlands, July 1997) and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All subjects gave their written informed consent prior to inclusion. All subjects entered a 7-d open pre-inclusion phase (days 1 7) during which they received oral lithium carbonate (Teralithe 1 ; Rhône-Poulenc Rorer) 500 mg b.i.d. alone. The subjects were required to visit the clinic twice daily (morning and evening) during this period. All subjects with stable lithaemia, as defined by lithium plasma levels of <1 mequiv./l on day 5 and [Li D6-D5 ] or [Li D7-D5 ]off0.1 mequiv./l or f15%, were then entered into the second phase of the study. This consisted of a 7-d double-blind phase (days 8 14) during which the subjects were randomized to receive oral placebo or amisulpride 100 mg b.i.d. in addition to lithium carbonate 500 mg b.i.d. On the final day (day 14), subjects received only one dose of lithium carbonate and amisulpride or placebo. All subjects were hospitalized from days Assessments Pharmacokinetics Blood samples for determination of lithium levels were collected on days 7 and 14, before the administration of lithium and after 1, 2, 4, 6, 8, 10 and 12 h (also after 24 h on day 14), as well as before dosing on days 10 and 12. The samples were left at room temperature for between 20 min and 1 h in order to obtain fibrin coagulation and allow the serum to separate. The samples were then centrifuged ( rpm for 10 min at 4 xc) and the serum was stored in polypropylene tubes at x20 xc until assay. Urine samples were also collected on days 7 and 14 (immediately before dosing and from 0 6, 6 12 and h) in order to determine lithium clearance and creatinine clearance. Two aliquots of each sample were stored in polypropylene tubes at x20 xc until assay. Lithium levels in serum and urine were determined by atomic absorption spectrometry. Blood samples for the determination of amisulpride trough levels were collected before dosing with the drug on days 10, 12 and 14. The samples were mixed by inversion and centrifuged ( rpm for 10 min at 4 xc) and the plasma was stored in polypropylene tubes at x20 xc until assay. Amisulpride

3 Amisulpride/lithium: no interaction 105 levels were determined by HPLC with fluorescence detection (Malavasi et al., 1996). Safety A clinical examination (including neurological tests, body weight, heart rate and blood pressure) was performed on days 1, 8, 10, 12 and 14. Cardiovascular safety was also assessed by ECG on days 1, 4, 8, 10, 12 and 14. Adverse reactions were determined using spontaneous reporting. Clinical laboratory tests were performed on days 3 14 and body temperature was measured daily. The subjects also completed the Simpson Angus scale (Simpson and Angus, 1970) on days 1, 7, 9, 11, 13 and 14 to determine the occurrence of any extrapyramidal symptoms. The clinical examination, ECG and laboratory tests were repeated 5 10 d after the final dose. Pharmacokinetic statistical analysis Pharmacokinetic parameters were calculated, using a non-compartmental approach, with PHARM-NCA 1.4b software (Simed, Créteil, France). Lithium After logarithmic transformation, maximum serum concentration (C max ), the area under the serum concentration curve from 0 to 12 h (AUC (0 12) ), urinary excretion from 0 to 12 h (Ae (0 12) ) and renal clearance (Clr) obtained on days 7 and 14 in each group were compared using a split-plot analysis. The model tested the following: treatment-effect, subject-effect, timeeffect, treatment/time interaction and subject/time interaction. Untransformed data were used for determination of the time to reach maximum serum concentration (T max ). Amisulpride After logarithmic transformation, the trough serum concentration (C min ) on days 10, 12 and 14 was compared using a two-way analysis of variance with the factors day and subject taken into account. The 90% confidence intervals were also calculated for C min (the FDA stipulates limits of for equivalence for untransformed data). Results The demographic characteristics of the subjects at inclusion are shown in Table 1. All 24 subjects completed the study. Table 1. Demographic characteristics at inclusion Pharmacokinetics The mean pharmacokinetic parameters of lithium obtained in the placebo and amisulpride treatment group on days 7 and 14 are shown in Table 2. The corresponding serum concentration time curves for lithium at each day are shown in Figures 1 and 2. There were no statistically significant differences between the two treatment groups for any of the pharmacokinetic parameters (Table 3), thus indicating that amisulpride appeared to have no effect on the pharmacokinetics of lithium. Within the treatment groups, split-plot analysis revealed a significant (p<0.05) difference in C max value between days 7 and 14 in the amisulpride group and in AUC 0 12 between days 7 and 14 in both the amisulpride and placebo groups. Mean trough levels of amisulpride were equivalent between days 12 and 14 (90% CI, ); trough levels on day 10 ( ng/ml) were significantly (p<0.05) lower than on day 12 ( ng/ ml) and day 14 ( ng/ml). Safety Age (yr) Height (cm) Weight (kg) placebo Mean S.D Range amisulpride Mean S.D Range During the initial 7-d open lithium-only phase, 16 subjects reported at least one treatment-emergent adverse event; the most common were headache (21%), fatigue (17%), myalgia (17%) and somnolence (17%). During the double-blind, randomized phase, the incidence and type of adverse events was similar in both groups; nine subjects in the lithium/placebo group and seven in the lithium/amisulpride group reported at least one treatment-emergent adverse event. Muscle weakness was the most common adverse event, being reported by two subjects in each group; Table 4 shows the individual adverse events reported in each group. None of the side-effects were related to lithium intoxication (trembling, gastrointestinal disorders, thirst and polyuria). There were no serious adverse events or discontinuations due to adverse events at any time during the study.

4 106 M. Canal et al. Table 2. Mean S.D. (range) pharmacokinetic parameters for lithium obtained on days 7 and 14 in 24 healthy volunteers after administration of lithium carbonate from days 1 14 and co-administration of placebo or amisulpride from days 8 14 Day 7 Day 14 placebo amisulpride placebo amisulpride T max (h) 1 a (1 2) C max (mmol/l) ( ) AUC (0 12) (mmol/h.l) ( ) Ae (0 12) (mmol) ( ) Clr (l/h) ( ) 1 a (1 4) ( ) ( ) ( ) ( ) 1 a (1 2) ( ) ( ) ( ) ( ) 1 a (1 4) ( ) ( ) ( ) ( ) a Median. Serum concentration (mmol/l) Lithium (+ placebo) Lithium (+ amisulpride) Serum concentration (mmol/l) Lithium (+ placebo) Lithium (+ amisulpride) 0 There were no clinically significant changes in blood pressure, heart rate, ECG, body weight, temperature, clinical laboratory parameters or neurological tests during the study. No extrapyramidal symptoms were observed. Discussion Hours Figure 1. Mean serum concentration time curves of lithium obtained on day 7 in 12 healthy volunteers after administration of lithium carbonate from day 1 (to day 14). Linear plot. A combination of antipsychotic and lithium is generally considered a safe and effective treatment option in a range of patients; for example, in some rare cases, Hours Figure 2. Mean serum concentration time curves of lithium obtained on day 14 in 12 healthy volunteers after administration of lithium carbonate from days 1 14 and co-administration of either placebo or amisulpride from days Linear plot. schizophrenic patients who fail to respond adequately to an antipsychotic alone may benefit from the addition of lithium, whilst bipolar disorder patients who are in the early stages of lithium treatment may be given an antipsychotic as well due to the delayed onset of action of lithium (Baastrup et al., 1976; Juhl et al., 1977; Lerner et al., 1988). However, several publications have reported potential interactions between lithium and various antipsychotic agents. These most commonly involve haloperidol, and include

5 Amisulpride/lithium: no interaction 107 Table 3. Statistical results of the split-plot (F value) on the pharmacokinetic parameters of lithium T max C max AUC (0 12) Ae (0 12) Clr Between treatment Treatment (ns) (ns) (ns) (ns) (ns) Within treatment Periods (ns) (p<0.01) (p<0.001) (ns) (ns) Treatmentrperiod (ns) (ns) (ns) (ns) (ns) ns, not significant. Table 4. Treatment-emergent adverse events during the double-blind phase (n=24) Lithium +placebo Subjects with o1 9 7 treatment-emergent adverse event Pharyngitis 0 2 Fatigue 1 2 Muscle weakness 2 2 Headache 1 2 Tremor 1 2 Somnolence 0 2 Myalgia 1 1 Dizziness 1 1 Impaired concentration 1 1 Insomnia 0 1 Nausea 1 1 Rash 1 0 Maculo-papular rash 1 0 Skeletal pain 1 0 Dysphonia 1 0 Sensory disturbance 1 0 Conjunctivitis 1 0 Diarrhoea 1 0 Abdominal pain 1 0 Total Lithium +amisulpride neurotoxic effects (Addy et al., 1986; Keitner and Rahman, 1984), encephalomyopathy (Gille et al., 1997) and irreversible brain damage (Sandyk and Hurwitz, 1983; Thomas et al., 1982), as well as worsening of extrapyramidal side-effects (Mann et al., 1983). Reversible neurotoxicity (Lee and Yang, 1999), seizures (Garcia et al., 1994) and diabetic ketoacidosis (Peterson and Byrd, 1996) have been reported with a combination of clozapine and lithium, whilst cases of delirium (Chen and Cardasis, 1996) and acute dystonic reaction (Durrenberger and de Leon, 1999) have been reported with risperidone and lithium. More systematic studies appear to refute the existence of a clinically significant interaction (Goldney and Spence, 1986; Callaghan et al., 1999). Various suggestions have been put forward for the cause of these reactions. For example, some authors have suggested that many of the reactions may have simply been undiagnosed neuroleptic malignant syndrome, whilst others have pointed out that the symptoms are often consistent with lithium toxicity alone (Von Knorring, 1990). Indeed, lithium has a narrow therapeutic range and relatively minor increases in serum concentrations may result in serious adverse sequelae (Finley et al., 1995). The safety of combining lithium with other medications is therefore an important issue and extensive clinical experience has identified a number of significant drug interactions (e.g. with non-steroidal anti-inflammatory drugs and thiazide diuretics). However, evidence from animal studies suggests that haloperidol does not have an effect on lithium pharmacokinetics (Smith et al., 1977). The current study was conducted to ensure that a combination of lithium with the novel antipsychotic amisulpride is safe and that the pharmacokinetic profile of lithium is not affected. The doses chosen were in line with those recommended in clinical practice. A lithium dose of 500 mg b.i.d. is the average dose necessary to achieve therapeutic plasma levels; similarly, 100 mg b.i.d. of amisulpride has been shown to be effective in the treatment of schizophrenia (Boyer et al., 1995; Danion et al., 1999; Loo et al., 1997) whilst being well tolerated in healthy volunteers (Rosenzweig et al., In Press). The first 1-wk open phase of the study allowed the subjects to reach stable lithaemia within the therapeutic range. The results revealed no statistically significant differences between the amisulpride and placebo groups with respect to the pharmacokinetic parameters of lithium, thus indicating that amisulpride does not appear to have any effect on the pharmacokinetics of lithium. Similarly, co-administration of amisulpride

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