Investigation of Target Plasma Concentration-Effect Relationships for Olanzapine in Schizophrenia

Abstract

Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenia. The present study has examined the potential use of target concentration monitoring of olanzapine in plasma as a marker of clinical response and an aid in patient management. Fifty-three patients (mean age 32 years; 40 M, 13 F) with a DSM-IVR diagnosis of schizophrenia completed a 6-week trial of oral olanzapine. Participants received once-daily olanzapine, and their psychotic symptoms were measured with the PANSS (Positive and Negative Symptom Scale) on admission and again after 6 weeks. Responders were classified as having a >/=20% decrease in PANSS scores. Plasma olanzapine was quantified by high-performance liquid chromatography. Receiver operator characteristic (ROC) curve analysis was used to identify a break point in plasma olanzapine that might serve as a surrogate for PANSS classification, and the two methods were compared using the McNemar chi2 test. After 6 weeks the median olanzapine dose was 15 mg/d (range 5-30 mg/d), and the mean plasma olanzapine was 32 micrograms/L at a mean of 13.5 hours after dose. With the PANSS (total), there were 42 responders and 11 nonresponders. ROC curve analysis for total PANSS identified a break point at 23 micrograms/L plasma olanzapine, with the proportions of responders and nonresponders identified by PANSS and the plasma break point being similar. Similar break points were found for the positive, negative, and global PANSS subscores. Nevertheless, these relationships were very modest, and at best the target plasma olanzapine concentration identified only 20% more responders than nonresponders. We suggest that plasma olanzapine monitoring can be used for dose-response optimization, but only to complement the normal clinical evaluation process.

Clinical Pharmacokinetics of Atypical Antipsychotics: An Update

“…At commonly used daily OLZ doses (5-30 mg/day), mean plasma concentrations can range from 10 to 54 ng/ml. Considerable inter-patient variability has sometimes been observed, possibly due to unreported co-medications, non-compliance, and intrinsic interindividual variability in drug metabolism and/or clearance (Gex-Fabry et al, 2003[56]; Fellows et al, 2003[50]).…”

“…Furthermore, given the large inter-patient variability in plasma OLZ levels at the same doses, the monitoring of blood OLZ concentrations can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of between 20 ng/ml and 50 ng/ml has been found (Lane et al, 2002[78]; Fellows et al, 2003[50]; Mauri et al, 2005[96]).…”

Large Intraindividual Variability of Olanzapine Serum Concentrations in Adolescent Patients

“…28 The second question is much more difficult to answer. Of course, TDM is a necessary tool to secure serum concentrations within the recommended range and to avoid underdosage or overdosage.…”

Clinical Pharmacology of Dopamine-Modulating Agents in Tourette’s Syndrome

“…daily dose and plasma concentration, but close to 9-OH-RSP (Aravagiri, Marder, Nuechterlein, & Gitlin, 2003) Renal excretion with 9-OH-risperidone as the major compound and only 4% unchanged, Minor compound (14%) excreted by feces (Byerly & DeVane, 1996;Mauri et al, 2007) (Baldessarini, 1996) Mainly by 9-hydroxylation in liver: 9-OH-RSP (Mannens et al, 1993) CYP2D6, Lesser extend: CYP3A4 (Mannens et al, 1993) Aripiprazole 87% (Winans, 2003) Well resorbed (Mallikaarjun, Salazar, & Bramer, 2004) After 3-5 h (OA) (Mallikaarjun et al, 2004) Extensively bound to plasma proteins >99% (mainly albumin; DeLeon, Patel, & Crismon, 2004) Steady state after 14 days (Mallikaarjun et al, 2004) Vd: 404 l (4.9 l/kg) (Mallikaarjun et al, 2004) Kidney and liver excretion, 25% recovered in urine (<1% unchanged); 55% in feces (18% unchanged) ( (Callaghan et al, 1999) After 6 h (Callaghan et al, 1999) 93%, mainly albumin 90% and a1-glycoporotein 77% (Callaghan et al, 1999) Vd: 16 AE 5 l/kg, plasma clearance: 26 l/h, range 12-47 l/h, (Callaghan et al, 1999), CYP1A2 (Kassahun et al, 1997) therapeutic range: 20 ng-50 ng/ml (Fellows et al, 2003;Lane et al, 2002;Mauri et al, 2005;Perry, Lund, Sanger, & Beasley, 2001) Smokers and men: greater clearance (Callaghan et al, 1999), 87% excreted, 30% feces, 57% urine (Kassahun et al, 1997) Mean: 33 h, (range 21-54 h); men increased clearance compared to women; smokers have a 20% shorter elimination halflife …”