Safety and Pharmacokinetics of Atypical Antipsychotics in Children and Adolescents

Transcription

1 Pediatr Drugs (2013) 15: DOI /s REVIEW ARTICLE Safety and Pharmacokinetics of Atypical Antipsychotics in Children and Adolescents Silvio Caccia Published online: 16 April 2013 Ó Springer International Publishing Switzerland 2013 Abstract Pediatric behavioral and affective disorders often require antipsychotic therapy, in combination with psychotherapeutic interventions, for their treatment and stabilization. Although pharmacotherapy can include either typical or atypical antipsychotics, the latter are generally preferred because of their apparently lower risk of adverse effects. Recent controlled trials have demonstrated the efficacy of some of these agents (including aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone) in adolescent schizophrenia and children or adolescent bipolar mania, or to treat severe aggression and self-injury in the context of autism in children and adolescents. Although few studies have systematically monitored their short- and, more importantly, long-term safety, current evidence indicates that sedation, hyperprolactinemia, and metabolic abnormalities such as excess weight gain, diabetes, and related cardiovascular effects were clinically relevant adverse effects in young patients, with the individual agents differing in their propensity to induce these effects. When prescribing antipsychotics for children and adolescents, physicians should therefore be aware of the specific adverse effect profiles and patients should be closely monitored for the short- and long-term development of adverse events. In pediatric patients, the starting dose, titration plan, and maintenance dose of antipsychotics must be based on their pharmacokinetics and metabolism, as in adults. Because there are significant individual differences in drug and active metabolite(s) pharmacokinetics and metabolism, which may be further affected by a number of confounding S. Caccia (&) Istituto di Ricerche Farmacologiche IRCCS-Mario Negri, via Giuseppe La Masa 19, Milan, Italy silvio.caccia@marionegri.it factors (including demographic variables, phenotype and drug interactions), therapeutic drug monitoring may be a valid tool for individualizing dosage, but its interpretation should also take account of changes in pharmacodynamic sensitivity with the development during childhood and adolescence. 1 Introduction For years, antipsychotic agents were given to younger schizophrenic patients without specific approval, and clinicians generally provided prescriptions on the basis of clinical experience of using these drugs successfully in adults. Some of these agents were also used off-label for other psychiatric disorders that may affect pediatric populations, including bipolar disorder, obsessive-compulsive disorder, tics, and other disorders that have features of aggressive or disruptive behavior. Although the drugs used included either first-generation antipsychotics (sometimes referred to as typical antipsychotics) or second-generation ones (also called atypical ), the latter were generally preferred because of the perceived lower risk of neurological adverse effects [1 4]. Recent randomized controlled trials have demonstrated the efficacy of some atypical antipsychotics (i.e. clozapine, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) in childhood and adolescent schizophrenia and other psychiatric disorders [5 7]. As a result most of these agents have now received formal indications as first-line therapy for specific child and adolescent mental health disorders (Table 1). The so-called third-generation derivative aripiprazole, which is a partial agonist at dopamine D 2 /D 3 and serotonin 5-HT 1A receptors, unlike other antipsychotics, which have varying levels of dopamine D 2 and

2 218 S. Caccia Table 1 Atypical antipsychotic drug indications for pediatric patients Antipsychotic drug Indication (patient age, years; regulatory agency) Aripiprazole Schizophrenia (13 17, FDA) Bipolar I disorder (10 17, FDA; [13 years, EMA) Aggressive behavior in autism (6 17, FDA) Clozapine Schizophrenia in patients unresponsive to or intolerant of other antipsychotics a Olanzapine Schizophrenia (13 17, FDA) Bipolar I disorder (13 17, FDA) Quetiapine Schizophrenia (C13, FDA) Bipolar I disorder (10 17, FDA) Paliperidone Schizophrenia (12 17, FDA) Risperidone Schizophrenia (13 17, FDA) Bipolar I disorder (10 17, FDA) Aggressive behavior in autism and conduct disorder (5 17, FDA; EMA) Ziprasidone Bipolar I disorder (10 17, MPA b ) FDA US Food and Drug Administration, EMA European Medicines Agency, MPA Svedish Medicines Agency a This drug is labelled in Europe only as a third-line strategy b According to the procedure of European mutual recognition the indication(s) are (or will be made) effective in several European countries serotonin 5-HT 2A receptor antagonism, has also recently been introduced for specific pediatric neuropsychiatric disorders [8]. However, it is not free of important adverse effects that can arise with the older drugs older in terms of date of introduction e.g., extrapyramidal symptoms (EPS), neuroleptic malignant syndrome, hyperprolactinemia, weight gain, diabetes risk, sedation, and prolongation of the QTc interval, although the propensity to induce these effects differs for the individual agents [9]. There is also increasing evidence that, because of physiological developmental changes that may affect drug pharmacodynamic and pharmacokinetic profiles, pediatric patients may be especially vulnerable to some antipsychotic effects [10 13]. Focusing on these topics, this review attempts to update the safety data of atypical antipsychotics for children and adolescents. It also summarizes studies on the disposition and metabolism of these agents and compares them, when possible, with those for adults, with special attention to differences that may translate into specific dosage requirements according to the patient s age. In this regard, a literature search was performed on August 2012 in MEDLINE and EMBASE bibliographic databases using the search terms: aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, children, adolescents, safety, pharmacokinetics, and metabolism. No date or language constraints were utilized. Bibliographies from published literature, clinical trial registries/databases, and the product labeling were also considered. The literature search was concentrated on atypical agents for which there are prospective controlled clinical trials or which are now approved in major markets for specific neuropsychiatric disorders in children and adolescents. 2 Therapeutic Uses The pediatric use of atypical antipsychotics has increased substantially over the past decade, although adult and youth trials do not support their safety advantages over firstgeneration antipsychotics [14 18]. The prototype of the atypical antipsychotic class was clozapine, and is still the only antipsychotic with demonstrated superior efficacy over established first- and second-generation agents [19, 20]. Clozapine was superior in efficacy to haloperidol in adolescent inpatients with treatment-refractory schizophrenia, although four of ten clozapine-treated patients had a drop in absolute neutrophil count [21]. Clozapine was also significantly superior in efficacy to olanzapine after 8 weeks, although it caused more adverse effects in children with schizophrenia [22]. However, a more recent 12-week, randomized, double-blind comparison of clozapine and high-dose olanzapine in refractory early-onset schizophrenia showed that clozapine was superior to olanzapine in reducing psychosis and negative symptoms, but both drugs induced significant weight gain and hypertriglyceridemia [23]. Recent long-term, comparative studies confirmed the unique effectiveness of clozapine in children and adolescents with very early onset schizophrenic disorders, despite a substantial incidence of adverse effects [24]. Studies regarding its efficacy in young patients with diagnoses other than schizophrenia are more limited, but some describe its use in adolescents with bipolar disorder, intermittent explosive disorder, and posttraumatic stress disorder, among others [25]. Unfortunately, its adverse effect profile, which includes neutropenia and rare but occasionally fatal agranulocytosis, has

3 Antipsychotic Drug Toxicology and Pharmacokinetics in Young Patients 219 limited its usefulness in all mental disorders, particularly in children who appear more sensitive to its side effects [26, 27]. Therefore, clozapine remains the medication of last resort for schizophrenia in patients who are unresponsive or intolerant to other agents [28]. In Europe, clozapine is labeled for minors of 16 years and older, but only as a third-line strategy [29]. With the progressive introduction of its pharmacologically (but not chemically) related counterparts (risperidone, olanzapine and quetiapine), safer alternatives for children and adolescents became available. Double-blind, randomized controlled clinical trials demonstrating the effectiveness relative to placebo of the most frequently prescribed atypical antipsychotic, risperidone, contributed to its approval by the Food and drug Administration (FDA) in the USA for the treatment of schizophrenia in adolescents aged years. This benzisoxazol derivative is also approved for the treatment of aggression and irritability associated with autistic disorder in children and adolescents aged 5 17 years and, as monotherapy, for the short-term treatment of acute manic and mixed episodes associated with bipolar I disorder in adolescents aged years [5, 30]. In Europe, it is approved for children with aggression in the context of conduct disorder based on several placebo-controlled trials showing efficacy in aggressive patients with sub-average cognitive abilities [14]. Off-label uses have been reviewed elsewhere [31]. The main risperidone metabolite, 9-hydroxyrisperidone, or paliperidone, has also been approved in its extended release formulation for the treatment of schizophrenia in adolescents (12 17 years). This approval was based on the results of a 6-week clinical study that demonstrated its efficacy, with a safety profile similar to that in adults [32]. It remains to be established whether paliperidone has any real therapeutic advantages or disadvantages compared to its parent drug, as no randomized controlled trials comparing oral paliperidone to risperidone in pediatric patients are yet available [33, 34]. Other recently completed 6-week double-blind, randomized controlled trials found the thienobenzodiazepine olanzapine [35] and the dibenzothiazepine quetiapine [36] superior to placebo in reducing symptom ratings in adolescents with schizophrenia. Both antipsychotics have been approved in the USA for the treatment of schizophrenia in adolescents aged years. Olanzapine and quetiapine are also indicated for the acute treatment of manic episodes associated with bipolar I disorder, the former in adolescents aged years and the latter in children and adolescents aged as monotherapy or as an adjunct to lithium or divalproex [30, 37, 38]. However, the FDA formally stated that clinicians may consider prescribing other drugs first in younger patients, because of lack of long-term safety data and considering the drugs increased potential for adverse effects (weight gain and hyperlipidemia) in adolescents compared with adults [39]. Open-label, randomized comparisons of olanzapine and risperidone and of olanzapine, quetiapine, and risperidone [40, 41] found these drugs comparably efficacious in relieving symptoms in young patients with early-onset schizophrenia and schizophrenia-spectrum disorders, and all had similar adverse effects, mainly sedation, EPS, and weight gain. In a double-blind, randomized, 8-week trial the antipsychotic response with olanzapine and with risperidone was comparable to that with haloperidol, but young people given the atypical antipsychotics experienced weight gain and EPS that appeared to be more prevalent and severe than in adults [42]. In a more recent doubleblind multisite trial by the same authors (the Treatment of Early-Onset Schizophrenia-Spectrum Disorders), olanzapine and risperidone did not show superior efficacy to molindone (which is sometimes described as a typical antipsychotic and sometimes described as an atypical antipsychotic) for early-onset schizophrenia and schizoaffective disorder. Olanzapine and risperidone were associated with significantly more weight gain than molindone, although olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low-density lipoprotein, insulin, and liver transaminase levels [43]. The benzisothiazole derivative ziprasidone has recently been approved in Europe for the treatment of moderately manic or mixed episodes associated with bipolar disorder in children and adolescents aged (but not in the USA, although further review of the data by the FDA is pending). The approval is mainly based on the results of a 4-week, double-blind, placebo-controlled study showing that ziprasidone was effective for the symptoms of bipolar mania in young patients, with a safety profile similar to adults [44]. Its efficacy and tolerability have also been evaluated in pediatric patients with (unlabeled uses) Tourette syndrome and autistic disorders [45, 46]. More limited, at present, is information about its potential for treatment of early-onset schizophrenia-spectrum disorders in children or adolescents, although ziprasidone is marketed as an antipsychotic agent for adult schizophrenia, for the acute treatment of manic/mixed bipolar episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder [47]. However, a recent placebo-controlled trial in adolescents with schizophrenia was discontinued because of lack of efficacy [48]. Few studies for early-onset schizophrenia are available for aripiprazole, but a 6-week randomized controlled trial found dose-dependent efficacy in adolescents (aged years), which led to its (FDA) approval in the treatment of pediatric psychotic disorders [49]. In addition, aripiprazole is indicated as monotherapy for manic or

4 220 S. Caccia mixed episodes with or without psychotic features in pediatric patients, and as add-on treatment to lithium or valproate for those aged who have bipolar I disorder or irritability and aggression associated with autistic disorder (age 6 17 years), as well as for maintenance treatment of bipolar disorder in children (age years) [30, 50, 51]; controlled studies have also be done for pediatric disorders [30, 50 52]. The European Medicines Agency (EMA) has recently approved aripiprazole for the treatment of moderate to severe manic episodes in bipolar I disorder in adolescents (aged 13 and older). 3 Pharmacokinetic and Safety Profiles 3.1 Aripiprazole In the controlled trial for early-onset schizophrenia with fixed doses of 10 or 30 mg/day aripiprazole or placebo the majority of spontaneously reported adverse effects were EPS, including akathisia and somnolence, which were rated as either mild or moderate in severity. Mean changes in prolactin levels from baseline to end of study were observed in all groups (-8.45, and ng/ml for placebo and 10 and 30 mg of aripiprazole, respectively). Mean changes in body weight from baseline were minimal [49]. Less information is available for other pediatric populations, although recent open-label studies in patients with tic disorders, aggression, and disruptive behavior disorders confirm this drug has less impact on the metabolic profile than most atypical antipsychotics, with minimal changes in weight or body mass index, no significant changes in glucose or lipid metabolism, and a decrease in serum prolactin [8, 45]. Fraguas et al. [53] reviewed the studies on the safety and efficacy of this and other antipsychotics in young people with psychotic and bipolar spectrum disorders. Atypical agents were associated with less parkinsonism and akathisia than first-generation drugs, although the potential for these reactions with aripiprazole could be not established. Aripiprazole tended to lower prolactin levels, even below baseline when used as a single drug, whereas risperidone, and to a lesser extent other second-generation agents, caused marked hyperprolactinemia. Aripiprazole was associated with significantly less weight gain than olanzapine, which caused the most weight gain among second-generation agents, which generally caused more weight gain than first-generation agents (haloperidol and molindone). Curran et al. [54] reviewed the short- and longterm safety and tolerability of aripiprazole (2 15 mg/day) in the treatment of irritability in pediatric subjects (6 17 years) with autistic disorder; the long-term study (52- week) indicated that the increase in bodyweight reached a plateau at 3 6 months. In pharmacokinetic studies in children and adolescents with schizophrenia (10 17 years), exposure to aripiprazole was linear up to the maximum approved dose in adults (30 mg/day) [55], in whom this drug is well absorbed with 87 % oral bioavailability, with food not significantly affecting the extent of absorption, only delaying the time to peak concentrations [56]. However, at the equivalent doses of mg/day, after upward titration from 2 mg/day, young patients had higher mean steady-state peak plasma concentrations (C ss ), reached faster than in adults (2 3 vs. 3 5 h), possibly because of the younger patients lower body weight [57]. The same group [58] examined the pharmacokinetics, safety, and effectiveness of aripiprazole in children (2 12 years) and adolescents (13 17 years) with conduct disorder. These patients needed lower starting doses because of vomiting and sedation, from 1 mg/day (\25 kg) to 10 mg/day ([70 kg). After these protocol adjustments, aripiprazole was generally well tolerated, with improvements in aggressive behavior, providing evidence that pediatric patients require smaller starting doses than might be inferred from adult studies. Again, aripiprazole pharmacokinetics were linear across the dose range tested; C ss appeared to be attained within 14 days, and the extent of aripiprazole accumulation was approximately as in adults. Aripiprazole undergoes three primary metabolic pathways, CYP3A4/CYP2D6-mediated dehydrogenation and hydroxylation and CYP3A4-dependent N-dealkylation. The dehydrogenation yields dehydroaripiprazole, which enters the brain and has affinity for dopamine D 2 receptors [55]. Its systemic exposure in adults is reported to be approximately % that of aripiprazole. This and the fact that dehydroaripiprazole has a longer elimination halflife (t 1/2 ) than aripiprazole, i.e., 95 vs. 75 h after a single oral dose of aripiprazole in healthy CYP2D6 extensive metabolizers (EM), suggested that in humans the D 2 receptor occupancy after oral aripiprazole may be maintained by the active metabolite [55, 56]. Although the elimination t 1/2 was not calculated in child/adolescents, the ratios of dehydroaripiprazole-to-aripiprazole plasma C ss and area under the curve over the dosing interval (AUC t ) were similar to those in adults with schizophrenia [57 59]. 3.2 Olanzapine In a recent randomized, placebo-controlled trial of adolescents with schizophrenia, olanzapine was started at 2.5 or 5 mg/day, with a final mean dose of 11.1 mg/day in 4 6 weeks. Patients gained an average of 4.3 kg during this short-term trial, and continued weight gain was observed in patients who enrolled in the 6-month, open-label extension phase [35]. Similarly, in a 3-week, double-blind, placebocontrolled study of olanzapine in adolescents (13 17 years)

5 Antipsychotic Drug Toxicology and Pharmacokinetics in Young Patients 221 with manic or mixed episodes, this drug ( mg/day, titrated in a response-dependent fashion up to 20 mg/day) caused greater mean weight gain (3.7 kg) than placebo (0.3 kg). The olanzapine-treated patients also had higher prolactin levels than the placebo group, particularly the males. At the end of the extended treatment period (up to 26 weeks), 69 % of the participants had a 7 % or more increase in body weight, and 40.5 % had abnormally high prolactin levels [30]. Although orally disintegrating tablets of olanzapine induced less weight gain than standard oral tablets in adolescents, possibly because the interaction time with digestive serotonin receptors mediating satiety is shorter, olanzapine remains the antipsychotic with the greatest risk of weight gain [60]. In a comparison of the weight and metabolic data from a large group of adolescents given olanzapine for as long as 32 weeks and the pooled weight data from adults treated with this drug for up to 32 weeks and pooled metabolic data from adults in four trials, the adolescents gained an average of 7.4 kg compared to 3.2 kg in adults. Pediatric patients also appeared very sensitive to the prolactinincreasing effects (55.5 %) compared to adults (29.0 %). In contrast, adolescents had fewer adverse metabolic changes than adults, with 3 % of young and 11.8 % of older patients moving from normal or impaired glucose to high blood glucose, and % of adolescents compared to % of adults developing borderline dyslipidemias [37]. The efficacy and safety of olanzapine have also been investigated in a wide variety of pediatric disorders including autism spectrum, tic, obsessive-compulsive, disruptive behavior, and eating disorders [61 63]. Olanzapine was effective in reducing all symptoms, although careful monitoring of common side effects was again important in children and adolescents [61 64]. Pharmacokinetic studies have been conducted in young patients (10 18 years) with schizophrenia or bipolar I disorder after mg/day oral olanzapine [65, 66]. The pharmacokinetics of olanzapine were linear in this approved oral dosage range and similar to those in adults with schizophrenia. In treatment-resistant patients, the elimination t 1/2 was h (mean 37 h), comparable to that in older individuals (21 54 h, mean 30 h) [65]. In another prospective study in patients aged 9 19 years with schizophrenia or psychotic disorders, plasma concentrations of olanzapine (mean dose 17.5 mg/day) and prolactin were significantly correlated [67]. Olanzapine is eliminated primarily by biotransformation, which includes glucuronidation to olanzapine 10-N-glucuronide (mediated by uridine diphosphate-transferase, UGT), CYP-dependent oxidation to 4 0 -N-desmethylolanzapine (CYP1A2) and 2-hydroxymethyl olanzapine (CYP2D6), and flavin-containing mono-oxygenase-dependent N-oxidation. Although olanzapine 10-N-glucuronide is the most abundant metabolite, the formation of 4 0 -N-desmethylolanzapine is correlated with the parent drug clearance [68]. 3.3 Quetiapine Studies of quetiapine in children/adolescents with psychiatric disorders suggested this dibenzothiazepine derivative is well tolerated, with the exception of moderate weight gain [36, 69, 70]. Pringsheim et al. [12] reviewed its adverse effect profile from randomized controlled trials in adolescents with mania, bipolar disorder, and conduct disorder. Weight gain was significantly greater in patients treated with quetiapine, with a mean difference of 1.41 kg from placebo. In a comparative trial in adolescents with first-episode psychosis, the patients on quetiapine gained significantly less weight (5.5 kg) than those on olanzapine (15.5 kg) over 6 months, although there seemed to be more side effects with both drugs than in adults [71]. Other adverse effects with quetiapine include sedation and hypotension, presumably secondary to its affinity for histamine and a-adrenergic receptors, respectively. In a 3-week multicenter, randomized, double-blind, placebocontrolled trial of acute mania in patients aged years, 30 % complained of somnolence (placebo 10 %), sedation 25 % (placebo 4.4 %), and dizziness 18.1 % (placebo 2.2 %). Mean weight gain with placebo was 0.4 kg, and 1.7 kg for both doses of quetiapine, also suggesting that this effect is not dose-related. In this study, quetiapine was started at 50 mg at bedtime on day 1, increased to 400 mg/day in divided doses by day 5 and to 600 mg/day in divided doses by day 7 [30]. DelBello et al. [72] also reported significant changes in fasting triglyceride levels and blood pressure in depressed adolescents (aged years) with bipolar I disorder taking quetiapine ( mg/day) compared to placebo. In aggressive children with conduct disorder (6 12 years) quetiapine plasma C ss were dose-proportional, and steady-state pharmacokinetic parameters were essentially similar to those reported for adults [70]. Results were similar in young patients with chronic or intermittent psychotic disorders ( years) and psychotic or mood disorders (10 17 years), providing further evidence that no dosage adjustment may be required in these patient populations. Quetiapine elimination t 1/2 averaged about 3 4 h during the 750 mg/day therapy in children and 5 6 h in the adolescents receiving mg/day immediate release quetiapine [73, 74]. In healthy adults the drug is eliminated with a mean terminal t 1/2 of 5 7 h and is usually given in multiple daily doses [75]. However, in recent studies an extended release (ER) quetiapine fumarate had approximately the same pharmacokinetic profile as the immediate-release drug in patients with schizophrenia,

6 222 S. Caccia schizoaffective disorder, or bipolar disorder, supporting clinical evidence for the use of the latter formulation for once-daily quetiapine doses [76]. The primary route of quetiapine elimination is through hepatic oxidation, predominantly mediated by CYP3A4 (yielding norquetiapine and quetiapine sulfoxide, besides many minor metabolites) with a minor contribution of CYP2D6 (7-hydroxy-quetiapine) [75]. Subsequent renal excretion of these metabolites constitutes the primary route of elimination, like for most lipophilic antipsychotics. Quetiapine clearance is slightly reduced (by about 30 %) in adults with hepatic dysfunction but not in those with renal impairment, although the studies focused on the parent drug, and the effect of repeated doses on the pharmacokinetics of the drug and its many metabolites was not examined in patients with these diseases [77]. Winter et al. [74] compared the steady-state pharmacokinetics of quetiapine and its metabolites in young and adult populations. The pharmacokinetics of all compounds were linear in both age groups over the dosing range investigated. Mean t 1/2 of quetiapine sulfoxide and 7-hydroxy-quetiapine was similar to that of the parent drug, whereas that of norquetiapine was about twice that of quetiapine (11 vs. 6 h in pediatric patients and 11 vs. 5 h in adults). Exposure (in terms of area under the plasma concentration-time curve at steady-state, AUCss) to norquetiapine and quetiapine sulfoxide approximated that of the parent drug, whereas the AUCss of 7-hydroxy-quetiapine amounted to only 5 7 % of quetiapine, with large variability within both age groups. Norquetiapine (but not quetiapine sulfoxide) retains the parent drug s affinity for a broad range of neurotransmitter receptors, including 5-HT 2 and D 2 receptor types, and may therefore contribute to the antipsychotic action of quetiapine [75, 77]. 3.4 Risperidone Risperidone was the most often prescribed atypical agent in a naturalistic longitudinal study of early onset first psychotic episodes in children and adolescents (9 17 years; The Child and Adolescent First-Episode Psychosis Study), followed by quetiapine and olanzapine. These antipsychotics did not differ in symptom reduction, but differed in their side effects; weight increase was lower with risperidone or quetiapine than with olanzapine, but risperidone gave more neurologic side effects, while olanzapine caused more weight gain [78]. Fleischhaker and colleagues [79] compared the long-term weight gain with risperidone, clozapine, and olanzapine as well as their clinical risk factors in hospitalized children and adolescents; risperidone caused less weight gain than olanzapine but still much more than that expected in adults. According to the systematic review and meta-analysis by Pringsheim et al. [12], mean weight gain was greater in young patients taking risperidone than placebo, with a mean difference of about 1.72 kg in short trials (meta-analysis from ten trials lasting from 3 10 weeks) and 1.95 kg in longer ones (pooled data from three studies of 6 months duration). In a retrospective review of a clinic-referred sample of young children (\5 years) with an autism spectrum disorder on risperidone, weight gain was still a common side effect, but somnolence influenced treatment discontinuation more [80]. Long-term randomized trials provide evidence of EPS associated with risperidone use. Findings have been reviewed elsewhere [4, 12, 31]. Only three cases of tardive dyskinesia were reported with risperidone and other atypical agents in a meta-analysis of ten long-term pediatric studies, and in two the symptoms resolved after drug discontinuation [81]. As in adults, hyperprolactinemia is also a concern in young patients taking risperidone. In trials in patients with bipolar disorder and schizophrenia, prolactin increases were reported in % of patients receiving risperidone compared with 3 7 % with placebo [82]; in trials in patients with schizophrenia or autism, most patients (up to 71 %) developed this adverse effect within the first 1 2 months, and more than 30 % still had it 1 or more years later [69, 83]. In 7 17-year-old medically healthy children and adolescents, about 50 % of patients treated with risperidone for an average of 2.9 years had hyperprolactinemia. Adverse events potentially related to hyperprolactinemia were more common in girls (45 %) than boys (10 %) [84]. In children (4 15 years old) taking risperidone for psychiatric and neurodevelopmental disorders, exposure parameters were comparable to those in adults in whom single oral doses of risperidone were rapidly and doseproportionally absorbed with 70 % mean absolute availability, regardless of food [85]. Risperidone is cleared by metabolism, primarily involving CYP2D6-mediated hydroxylation to 9-hydroxyrisperidone (which exists as two optical isomers and as such is now available as paliperidone, see below), dihydrorisperidone and 7-hydroxyrisperidone. CYP3A4 contributes in metabolizing risperidone, primarily catalyzing the formation of the negative isomer of 9-hydroxyrisperidone, besides other inactive metabolites. The elimination t 1/2 of risperidone in these young patients averaged 3 h and that of its 9-hydroxyderivative was h, similar to those reported for adults. The 9-hydroxyrisperidone isomers have antipsychotic-like activity comparable to risperidone; thus, risperidone plus 9-hydroxyrisperidone constitutes the total antipsychotic fraction after therapeutic doses of risperidone. In CYP2D6-EM adults, the elimination t 1/2 of this active fraction is about 20 h, and C ss are reached within 5 6 days [85]. Moreover, the pharmacokinetics of risperidone,

7 Antipsychotic Drug Toxicology and Pharmacokinetics in Young Patients hydroxyrisperidone, and the active antipsychotic fraction are essentially comparable in children and adolescents, despite lower plasma protein binding in adolescents [86]. A prospective naturalistic study in children and adolescents found a linear relationship between the serum C ss of the active moiety and the risperidone dose and no correlation between the serum C ss and either the therapeutic or side effects [87]. 3.5 Paliperidone Paliperidone ER was generally well tolerated in young patients with schizophrenia and schizoaffective disorder after single and multiple doses (0.086, 0.129, and mg/kg/day, or approximately 6, 9, and 12 mg/day in adults). The most common adverse events were sedation and epistaxis; about 20 % reported EPS-related adverse events, which included dose-related extrapyramidal disorder, akathisia, dystonia, and tremor. Most adverse events were mild or moderate across the dosage groups, were short-lasting and resolved spontaneously, and none of the patients discontinued the study because of an adverse event. No adverse events possibly related with an increase in prolactin were reported, although the study may not have been long enough to assess adverse events frequently associated with high prolactin [88]. Paliperidone pharmacokinetics in these pediatric patients agreed with those in adults. The unchanged drug rose steadily to its peak plasma concentration within 24 h; this was in line with the characteristics of the OROS technology (osmotic-controlled release oral delivery system), which slowly releases paliperidone throughout the 24-h period, with low peak-to-trough fluctuations. Paliperidone C ss were attained within 4 5 days of therapy, with no apparent relationship between dose-normalized plasma exposure and age within the age range investigated (10 17 years). Like in adults, the plasma protein binding of paliperidone was about 74 % [88]. Compared with most atypical antipsychotics, paliperidone is primarily excreted unchanged in the urine with only 32 % of the dose recovered in adults as metabolites; these include an alcohol, a ketone, and a monohydroxy derivative whose formation is partly mediated by CYP2D6, with a minor contribution of CYP3A4 [89, 90]. Paliperidone dosing must therefore be individualized according to the renal function in patients with moderate to severe renal impairment and is not recommended in severely impaired patients. This is also true for risperidone because in patients with moderate to severe renal impairment the clearance of the parent drug, and its active metabolite was reduced 60 % compared to healthy adults. Unlike risperidone, however, paliperidone does not requires dose adjustment in patients with mild or moderate hepatic impairment, although its disposition has not been studied in subjects with severe hepatic impairment [89], and in young patients with schizophrenia and schizoaffective disorder renal clearance may be less than in adults at steady state after oral doses of ER paliperidone [90]. Marino and Caballero [91] recently reviewed three 6-week, double-blind, placebo-controlled trials in young patients (mean age 22.5 years) receiving paliperidone 6, 9, 12, or 15 mg. Treatment-emergent adverse effects (pooled data) were similar in all paliperidone groups and averaged % compared with 70 % in the placebo group. Events related to EPS were dose-dependent, and no glucose- or prolactin-related adverse events were observed in this study. Higher doses of paliperidone ER were associated with more weight gain than with the lower doses and placebo (paliperidone 3 6 mg 0.7 kg, 9 12 mg kg, 15 mg 2.4 kg, and placebo 0.6 kg). The main limitations of this study also included the short duration of treatment and unknown long-term safety profile of paliperidone ER. 3.6 Ziprasidone In a 4-week multicenter, randomized, double-blind, placebocontrolled trial in children and adolescents with acute manic or mixed episodes, subjects receiving ziprasidone ( mg/day) experienced sedation (33 %), somnolence (25 %), headache (21 %), nausea (13 %), fatigue (13 %), and dizziness (11 %). Mean weight loss was respectively 0.6 and 0.2 kg for the ziprasidone and placebo groups. There were no significant changes in mean body mass index, lipids, liver enzymes, or glucose levels. One patient treated with ziprasidone had a QT prolongation to C460 ms [92]. In a single-dose, open-label study in youths with Tourette syndrome or chronic tic disorder, the most frequent adverse effect of ziprasidone (starting at a dose of 5 mg/day and flexibly titrated to a maximum of 40 mg/day) was again sedation, requiring a dose reduction to 28.2 (±9.6) mg during the last 4 weeks [93]. Another patient developed akathisia, which also resolved with dose reduction. No other clinically significant effects were observed on specific ratings of EPS. The mean weight gain from baseline to endpoint in the ziprasidone group (0.7 kg) was similar to that in the placebo group (0.8 kg), supporting findings that ziprasidone is associated with less weight gain than other atypical antipsychotics, possibly because of its lower affinity for the H 1 receptors. This study did not find any clinically significant changes in ECG during ziprasidone treatment [93]. Similarly, no cardiovascular side effects, including chest pain, tachycardia, palpitations, dizziness, or syncope, were reported in a short-term trial in children, adolescents, and young adults with autism, with the most common adverse effect of ziprasidone being again transient sedation [46, 94]. However, Blair et al. [95] found that

8 224 S. Caccia long-term treatment with low-dose ziprasidone (B40 mg/ day) led to prolongation of the QTc interval by 28 ms in children and adolescents, with three patients reaching 450 ms and another experiencing a 114-ms prolongation, although subsequent studies did not confirm these findings [47]. There was also one sudden death, a patient with Tourette syndrome during a clinical trial of ziprasidone [96]. Preliminary pharmacokinetic studies have been done in young patients (7 16 years) with Tourette disorder or chronic tic disorder. Ziprasidone, given as weight-adjusted single oral doses ([60 kg, 20 mg; kg, 10 mg; kg, 5 mg), had linear pharmacokinetics and doserelated exposure, comparable to adult data after similar single oral doses [97]. In adults, absorption was enhanced so interindividual variability was reduced when ziprasidone was given with 500 1,000 kcal meals rather than under fasting or low-calorie meal conditions. Therefore, patients should be advised to take ziprasidone with meals providing at least 500 calories to ensure adequate bioavailability and achieve optimal efficacy [98]. The mean elimination t 1/2 ranged from 2 5 h in both pediatric populations and was comparable to the 4 5 h in adults after single doses of 5 20 mg but shorter than after mg/day at steady state. It was suggested that this might be related to the detection of an additional phase, which only became apparent after multiple dosing. One to three days are required to reach steady-state serum concentrations after twice-daily doses with food [99]. In adults, approximately two-thirds of absorbed ziprasidone is cleared by reduction by aldehyde oxidase and yields S-methyldihydroziprasidone. The remaining third is N-dealkylated/sulphur oxidized by CYP enzymes. Because of this extensive biotransformation, renal impairment is not likely to have a major effect on its pharmacokinetics. In vitro studies indicate that CYP3A4 is responsible for the sulphur oxidation, while N-dealkylation is catalyzed by CYP3A4 and possibly CYP1A2. S-methyldihydroziprasidone achieves serum C ss comparable to those of ziprasidone (the metabolite-to-parent drug ratio is 0.95 after oral doses) and falls within its binding potential for D 2 and 5-HT 2 receptors, suggesting that it may contribute to the parent drug s therapeutic activity [100]. The primary N-dealkylated derivative, 1-(1,2-benzisothiazol-3-yl)-piperazine, which undergoes further metabolism by CYP3A4, had poor in vitro activity at the D 2 and 5-HT 2 receptors and no antipsychoticlike activity in preclinical tests, although it was concentrated in rat brain, raising the acetylcholine content [101]. Likewise, other oxidized metabolites do not appear to play a role in the parent drug s therapeutic activity [100]. 3.7 Clozapine As mentioned earlier, clozapine is reserved for patients who are resistant to other agents because of the risk of serious side effects, which require an extensive monitoring protocol (e.g., before starting clozapine therapy there must be no evidence of a myeloproliferative disorder or a history of agranulocytosis or granulocytopenia; the baseline white blood cell count needs to be acceptable, and any concurrent therapy that also has the potential to lower blood counts should be avoided) [28]. Other adverse effects that may present a problem in adolescents and young adults included hypotension and dizziness, sialorrhea, seizures, myocarditis, hypersalivation, sedation, and weight gain. The present recommendations also suggest frequent electrocardiograms in younger populations taking clozapine and other agents that may cause a greater QTc prolongation [102]. Very little is known about exposure to clozapine in younger populations, and information about its disposition comes mainly from studies in adults in whom the absorption is almost complete, but oral bioavailability is only % because of first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 h, and food does not appear to affect the rate and extent of clozapine absorption. Elimination is essentially by hydroxylation, N-oxidation, and N-dealkylation. A comparison of single and multiple doses of clozapine showed that the elimination t 1/2 was significantly longer after multiple dosing (about 12 h, range 4 66 h), suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, linearly dose-proportional changes with respect to clozapine AUC and C ss were observed after oral doses of 75 mg, 150, and 300 mg/day [103]. CYP1A2 is the main enzyme involved in clozapine biotransformation, with CYP2C19 contributing moderately and CYP3A4 contributing only in patients with low CYP1A2 activity. In vitro and in vivo data also suggest a modest role of CYP2D6 [104]. Frazier et al. [105] studied the disposition and metabolism of clozapine in patients aged 9 16 years, with childhood-onset schizophrenia. Clozapine was extensively N-dealkylated to nor-clozapine, but with large variability, which, like in adults, may reflect inter-individual differences in CYP1A2 and CYP3A4 expression and activity. However, the mean nor-metabolite-to-parent drug ratio averaged 1.47 (range ) in these patients, whereas in adults it is lower than unity at the usual therapeutic doses; this might reflect more efficient N-dealkylation of clozapine since children have greater hepatic CYP1A2 and CYP3A4 activity than adults. Whereas the hydroxylated and N-oxide derivatives have no pharmacological activity, the nor-derivative (desmethyl clozapine) retains activity at dopamine D 2, 5HT 2A, and 5HT 1C receptors and has an elimination t 1/2 of about 19 h, comparable to that of clozapine in adults. A summary of studies examining the safety and pharmacokinetics of atypical antipsychotics in young people is given in Table 2.

9 Antipsychotic Drug Toxicology and Pharmacokinetics in Young Patients 225 Table 2 Summary of the pharmacokinetic and safety studies of the atypical antipsychotics in children and adolescents Drug (reference) Population (no.; age, years) Dose (mg/ Clinical outcome Commonly reported side effects day) a Aripiprazole [57 59] Clozapine [105] Olanzapine [65, 113, 122] Quetiapine [70, 73, 74, 119] Quetiapine fumarate Paliperidone [90] Risperidone [85 87, 118] Ziprasidone [97] Psychiatric disorders (21; PK linear; C ss higher than in adults Headache, dizziness, upper abdominal pain 10 17) Conduct disorder (12; 6 12) 1 10 PK linear and similar to adults Mild and similar to adults, after protocol adjustments Schizophrenia (33; ) 5 30 Similarity between adolescents and adult Css Schizophrenia (6; 9 16) C ss of norclozapine exceeded those of clozapine; total antipsychotic Sialorrhea, tachycardia, sedation and enuresis; number fraction C ss was within the range of adult C ss of side effects correlated with norclozapine C ss Schizophrenia (8; 6 18) PK linear from 5 to 20 mg/day; C ss were within the range of those in non smoking adults Psychiatric disorders (122; Great inter-individual variability in olanzapine and metabolite C ss 10 21) Schizophrenia spectrum disorders (85; 10 21) Intra-individual variability in olanzapine and metabolite C ss was also large, potentially limiting the value of TDM Mild; included increased appetite, constipation, nausea/ vomiting, headache and somnolence Conduct disorder (17; 6 12) PK was linear and supported twice daily dosing, as in adults No patients withdrew from the study, although all experienced 1 or more adverse event (but no EPS) Schizophrenia and schizoaffective. psychosis (21;13 18) Psychotic disorders. (28; vs. adults) Psychotic disorders (10; 12 16) Schizophrenia spectrum disorder (25; 10 17) Psychiatric or neurodevelopmental disorder s (19; 4 15) Impulsive-aggressive symptoms (103) Pervasive developmental disorders (25; 5 15) Psychotic and behavior disorders (24; 6 17) Schizophrenia, bipolar I disorder (304; 8 18) Tourette s disorder or chronic tic disorder (24; 7 16) Great variability, with 41 % of C ss below and 24 % above the adult therapeutic range No relationship between dose and side effects (sedation, weight gain, cardiovascular symptoms, EPS) 800 (600) b Similarity between populations in olanzapine and norquetiapine PK Somnolence in youths, and dizziness in adults PK dose-proportional and similar to those in adults Postural tachycardia, insomnia, decreased total thyroxine 4 12 Css were attained within 4 5 days of dosing; PK parameters consistent with those in adults Great variability but PK parameters were consistent with those in adults Dose-related (mild to moderate) sedation, epistaxis; EPS c Linear relationship between total active Css and dose No correlation between serum Css and side effects 0.06 Prolactin levels were correlated with the number of functional The highest levels of prolactin were observed in CYP2D6 genes and 9-hydroxyrisperidone C ss CYP2D6 UM d, Exposure to total active fraction was slightly lower in children than e in adolescents; it was similar in CYP2D6 EM and PM f PK of the antipsychotic fraction were similar in children and adolescents and consistent with adult data 5 20 g Linear and dose-related exposure, which were comparable to adult data Dose-related somnolence, postural hypotension, nausea, nervousness and dizziness a Final dose; b children (10 12 years) unable to tolerate quetiapine 800 mg/day; c mg/kg; as tablets in d children and e adolescents or as solution in f adolescents; g single oral weight-adjusted doses Css steady state blood concentrations, EM extensive metabolizer, PM poor metabolizer, UM ultrarapid metabolizer, PK pharmacokinetics, EPS extrapyramidal symptoms, TDM therapeutic drug monitoring

10 226 S. Caccia 4 Intra- and Inter-individual Variability and Therapeutic Drug Monitoring 4.1 Demographic Variables and Phenotype The wide inter- and intra-individual variability of aripiprazole and dehydroaripiprazole C ss found by Bachmann and colleagues [59] in adolescents with schizophrenia was comparable with previous pharmacokinetic observations in adults; it was possibly caused by the well-known individual differences in the activities of CYP2D6 and CYP3A4, which are essentially comparable in adolescents and adults [59, 106]. Aripiprazole and dehydroaripiprazole pharmacokinetics did not differ in healthy adults and schizophrenic patients, and there is no need for dosage adjustment based on race, sex, or eliminating organ impairment, according to the prescribing information [107]. However, poor metabolizer (PM) and intermediate metabolizer (IM) patients have higher exposure to the total active drug than EM at CYP2D6 [107]. The clinical significance of this for the overall outcome is still poorly understood. Hendset et al. [108] suggested that adult Caucasian PM would typically need % lower doses to achieve similar serum concentrations as EM. Similarly, Kubo et al. [109] suggested that the same therapeutic effect could be achieved in Japanese CYP2D6 IM with % of the aripiprazole dose required by EM. Although no therapeutic window has been described for aripiprazole, the polymorphic metabolism and the wide variability in the expression levels of CYP3A4 and the potential for drug interactions at both enzymes suggest that in many clinical situations therapeutic drug monitoring (TDM) based on blood concentrations of the total antipsychotic fraction (aripiprazole? dehydroaripiprazole) should guide appropriate treatment decisions [110]. The genetic status is also important in the pharmacokinetics of risperidone because CYP2D6 is the most important enzyme in the 9-hydroxylation of this drug [111]. In children and adolescents the relative bioavailability of risperidone estimated by population pharmacokinetic analysis was 1.23 for PM and 1 in EM, and oral clearance was approximately three times lower in PM than EM. However, exposure to the active antipsychotic fraction was similar in PM and EM, like in adults [86]. Although no specific studies have evaluated the effect of demographic variables on the disposition and metabolism of risperidone in pediatric patients, a recent population pharmacokinetic analysis, including young and adult subjects, suggests that age, sex, and race may not affect the pharmacokinetics of risperidone or the antipsychotic fraction [86]. As regards sex, however, results have been contrasting in other pediatric studies of risperidone [112, 113]. Although there are contradictory findings regarding the use of TDM in optimising risperidone therapy [114], it is recommended because some studies have suggested therapeutically effective ranges in adults, and others but not all also reported a relationship between total active drug and severity of EPS. TDM of the total active antipsychotic fraction may also be useful when switching from one formulation to another [115]. Thus far, the data in adults suggest little influence of CYP2D6 polymorphism on the disposition of its 9-hydroxylated derivative after 3 15 mg/day of paliperidone ER [116]. Marino and Caballero [91] mention in their review an unpublished 6-week study, showing no differences between CYP2D6 phenotypes in the frequency of EPS-related events and other adverse effects, although these aspects require further studies because the methods and results of this study were not described. Knegtering et al. [117] found prolactin plasma levels were correlated with 9-hydroxyrisperidone plasma C ss in adult patients with psychosis taking risperidone 3 mg/day. This suggested that 9-hydroxyrisperidone plays a major role in the strong prolactin elevation with oral risperidone. It also suggested that CYP2D6 PM would experience less prolactin elevation than EM. Troost et al. [118] further examined serum prolactin, risperidone, and 9-hydroxyrisperidone in children genotyped for CYP2D6 polymorphisms after an oral risperidone regimen. Serum prolactin levels were correlated with the number of functional CYP2D6 genes and serum 9-hydroxyrisperidone concentrations (3 h after the morning dose), but not with the risperidone serum concentrations. Prolactin levels were highest in ultrarapid metabolizers (UM), suggesting they may be at higher risk of prolactin-related adverse effects, although no clear relationship was found in this study between prolactin levels and adverse effects. CYP2D6-mediated oxidation is a minor metabolic route of quetiapine, which undergoes extensive pre-systemic and systemic metabolism by CYP3A4 [75]. Serum C ss ranged from 19 to 877 ng/ml after oral doses from 100 to 800 mg/day of the immediate-release formulation in schizophrenic adolescents, with about 40 % of the values below and 24.5 % above the therapeutic range recommended for adults in a clinical setting examining the relationship between pharmacokinetics, treatment response, and side effects [119]. As mentioned, Winter et al. [74] further compared the steady-state pharmacokinetics of quetiapine and its main metabolites in pediatric and adult patients after similar dose-escalation regimens (final dose 800 mg/day). The wide variability within age groups and substantial overlap of quetiapine and norquetiapine parameters in children and adults suggested the absence of clinically relevant, age-related differences in the disposition of this drug [74]. Studies in adults also provided evidence that sex did not significantly affect the pharmacokinetics of