1. Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects Linas Martinaitis Erasmus =)

2. Abstract (1) Aripiprazole, a novel antipsychotic drug, is metabolized by CYP3A4 and CYP2D6 forming mainly its active metabolite dehydroaripiprazole. In this study, aripiprazole and dehydroaripiprazole serum levels of psychiatric patients were measured and related to dose, comedication, and clinical effects including therapeutic and side effects. mean dosesPatients were treated with mean doses of 20 +/- 8 mg/day of aripiprazole (median 15 mg, range 7.5-60 mg). Serum levelsSerum levels correlated significantly with the dose (r = 0.419; P < 0.01), with a mean value of aripiprazole of 214 +/- 140 ng/ml. metaboliteMean concentrations of the active metabolite dehydroaripiprazole amounted to 40% of the parent compound. Comedication with CYP3A4 and CYP2D6 inducers or inhibitors changed serum levels up to 51%.

3. Abstract (2) ImprovementImprovement was best in patients with a serum level between 150 and 300 ng/ml. side effectsNo or only mild side effects were detected in patients, with aripiprazole plasma concentrations between 110 and 249 ng/ml. A total of 32% of the patients who received no other antipsychotic drug besides aripiprazole reported side effects; tension being the most frequent one. Since serum levels of aripiprazole and dehydroaripiprazole were highly variable between individuals, and distinct ranges were associated with good therapeutic response and minimal side effects, it seems likely that therapeutic drug monitoring can be helpful to improve the antipsychotic drug therapy.

5. Introduction

6. Materials and methods Patients: 283 pts; 164 diagnosed with a schizophrenic disorder; 75 of them on monotherapy. Other patients suffered from schizoaffective disorder, affective disorder, and borderline personality disorder. M/F: 109/55. Mean age 33,8 years (19-66). Severity of illness and patient outcome were assessed on the day of blood withdrawal according to the Clinical Global Impressions scale (CGI). Mean initial CGI was 6,0. Determination of drug serum levels: blood samples were collected early in the morning before the first daily dose, at least 12 h after last drug intake to obtain trough concentrations. Analyses were performed with HPLC. Levels were measured under steady state conditions at the earliest 2 weeks after start of aripiprazole therapy.

7. Results: PK Significant serum level to do dose correlations for aripiprazole (r=0,419; P<0,01), dehydroaripiprazole (r=0,355; P<0,01) and their total sum (r=0,482; P<0,01). The mean concentration to dose (C/D) ratio was 11,4±7,3 ng/ml/mg for aripiprazole [A] and 4,0±4,0 ng/ml/mg for dehydroaripiprazole [dA] in patients who received no additional drugs that are inhibitors or inducers of CYPs. +metoprolol [inhibitor of CYP2D6] => ↑ 40% A and ↑ 56% dA serum C/D. +fluvoxamine [inh. CYP1A2, 2C9, 2C19, 3A4] => ↑ 51% A and ↑ 120% dA. +fluoxetine [inh. CYP2C9, 2C19, 2D6, 3A4] => slightly ↑ A. +paroxetine [inh. CYP2D6] => similar to control. +carbamazepine [inducer of CYP1A2, 2C9, 2C19, 3A4] => ↓ 64% A, but the effects did not reach significance.

8. Results: PD (1) Pharmacodynamic analyses were restricted to 164 schizophrenic patients. Doses of 15 and 30 mg/d. were given most frequently, and application rates ranged from 7,5 to 60 mg/d. Mean aripiprazole serum level was 214 +/- 140 ng/ml, dehydroaripiprazole – 78 +/- 59 ng/ml. Of the patients receiving aripiprazole as antipsychotic monotherapy (n=74), 60% were rated as very much or much improved. Defining these patients as responders to A, their 25 th and 75 th percentile serum levels ranged 124 to 286 ng/ml of A. This indicated that 150-300 ng/ml could be a target range for the drug. In patients receiving 150-300 ng/ml of A the response rate was 68%. 300 ng/ml - 50%. Regarding concentrations of dehydroaripiprazole or the total amount of parent substance plus metabolite, optimal blood levels could not be deduced.

9. Results: PD (2) side effectsFor 32% of the 74 patients under antipsychotic monotherapy, side effects were reported: ―Tension 8% ―Sedation 7% ―Extrapyramidal 7% ―Gastrointestinal 3% ―Cardiovascular 3% ―Skin irritation 1% ―Urogenital 1% ―Blurred vision 1% No or mild side effectsNo or mild side effects could be detected in patients with aripiprazole serum level between 110 and 249 ng/ml (25 th to 75 th percentile), with a mean value of 194 +/- 125 ng/ml. moderate to severeSerum levels of patients, who suffered from moderate to severe side effects, ranged between 210 and 335 ng/ml for aripiprazole with a mean value of 296 +/- 151 ng/ml.

11. Discussion (1) C/D correlation significant, nevertheless the spread was wide. Why? —Intrinsic factors: genetic polymorphisms of CYPs, age, morbidity. —Extrinsic factors: smoking, food constituents. metoprololModerate interaction potential of A and dA with CYP2D6 & 3A4 inhibitors and inducers. However, only effects of metoprolol were significant: ↑ up to 51% of A and ↑ up to 120 % of dA. Taking into account supportive results of other studies, daily dose of A should be reduced to a half when taken with strong CYP2D6 & 3A4 inhibitors (metoprolol, itraconazole, quinidine). Due to the high inter-individual variability of serum concentrations it is preferable to control blood in patients comedicated with CYP2D6 or 3A4 instead of blind dose adaptation.

12. Discussion (2) Improvement in CGIImprovement in CGI score was 2,2. Other studies: 3,2; 2,17; 3,5. => long-term Our patients were more severely ill: 6,0 compared to 4,3 and 4,8. Optimal serum concentrations:Optimal serum concentrations: 150-300 ng/ml => 68% responders with at least much improvement according to CGI. less clearWith inclusion of serum levels of dA or the sum the concentration-response relationships were less clear. Therefore and because of the high variability between patients in the metabolite to parent drug ratio, determination of only A serum levels seems to be sufficient for treatment optimization by TDM.

13. Discussion (3) Aripiprazole was well tolerated in our patients with an overall side effect rate of 32%. Frequency of EPS was as low as in other studies – 7%, which is comparable to placebo. Data obtained from this investigation may be used for orientation to confirm or revise the reported plasma concentrations considered to be optimal for treatment. It seemed unlikely that consideration of dA is necessary for treatment optimization, but it can probably be helpful for evaluation of the CYP2D6 & 3A4 phenotype.

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