Serum Haloperidol Concentrations Research Articles

Pharmacogenomic response of low dose haloperidol in critically ill adults with delirium

PurposeTo characterize the pharmacogenomic response of low-dose haloperidol for delirium treatment in critically ill adults. Materials and methodsSingle-center, pilot study of a convenience sample of ICU adults with delirium treated with low-dose IV haloperidol. Patients were evaluated for delirium with the ICDSC every 8 h. Serum haloperidol concentrations were collected on ICU days 2–6, CYP2D6 and CYP3A4 genotypes were characterized and patients were categorized as extensive (EM), intermediate (IM) or poor metabolizers (PM). ResultsThe 22 patients (median age 67 [IQR 48,77] years; median APACHE III 81[IQR 54,181]; CYP2D6 [EM = 12, IM = 7, PM = 3], CYP3A [EM = 18, IM = 4]) received a median [IQR] daily haloperidol dose of 3.0 [2.4, 4.5] mg. After adjusting for age, SOFA, and ICU day, neither an association between CYP2D6 (IM p = .67/PM p = .25) or CYP3A4 (IM p = .44) metabolizer status and serum haloperidol concentrations was found. After adjusting for age, SOFA, and ICU day, neither an association between daily haloperidol dose (p = .77) or ICDSC score (p = .13) and serum haloperidol concentrations was found. No patient experienced QTc interval prolongation (≥500 ms). ConclusionsThis pilot study, the first to evaluate the pharmacogenomic response of low-dose haloperidol when used to treat delirium in the ICU, suggests CYP2D6/CYP3A4 metabolizer status does not affect the serum haloperidol concentrations.

Interindividual variation of serum haloperidol concentrations in Japanese patients--clinical considerations on steady-state serum level-dose ratios.

Marked interpatient variability in haloperidol (HAL) level-dose (L/D) ratios makes it difficult to use the administered dose for predicting serum concentrations. To investigate the effect of dose, age, total body weight and co-medication on steady-state HAL L/D ratios. Retrospective analysis of dose and HAL blood level data from 168 patients. The HAL L/D ratio decreased curvilinearly with increasing daily dose of HAL. The patients treated with concomitant antiparkinsonian drugs showed a mean HAL L/D ratio that was 24.9% higher than those without antiparkinsonian drugs. The patients treated with concomitant antiepileptic drugs showed a mean HAL L/D ratio that was 27.2% lower than those without antiepileptic drugs. The mean HAL L/D ratio of patients treated with concomitant CYP2D6 substrates was not significantly different from those without CYP2D6 substrates. There is a wide interindividual variability in blood levels of HAL in patients given the same dose. Routine monitoring of HAL serum level is useful, especially in patients who require associated antiepileptic and/or antiparkinsonian medication.

Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients.

To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders. Retrospective population pharmacokinetic study. 218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations. Routine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program. The final pharmacokinetic model was CL = 42.4 * (TBW/60)(0.655) * 0.814(AGE> or = 55) * (DOSE/200)(0.236) * 1.32(ANTIEP) and Vd = 34.4 * TBW * 0.336( AGE> or = 65), where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (microg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE > or = 55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE > or = 65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance. Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.

Coadministration of Fluvoxamine Increases Serum

Four patients with chronic schizophrenia were treated with a combination of fluvoxamine, haloperidol, and benztropine. The combination significantly impaired performance on tests of delayed recall memory and attentional function. Haloperidol concentrations in serum were monitored in three patients and were robustly elevated by fluvoxamine.

Substantial rise in sparteine metabolic ratio during haloperidol treatment.

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).

Haloperidol and Prolactin Concentrations in Asians and Caucasians

Serum haloperidol and prolactin concentrations were measured in 34 normal male volunteers (12 Caucasians, 11 American-born Asians, and 11 foreign-born Asians) over a 7-hour period after haloperidol administration (0.5 mg given intramuscularly or 1.0 mg given orally). The results were similar between the two Asian groups but significantly different between Caucasians and Asians. After controlling for body surface area, Caucasians still had lower serum haloperidol concentrations and less prominent prolactin responses than did Asians. Furthermore, the ethnic difference in prolactin responses could not be fully accounted for by the differences in serum haloperidol concentrations between the two ethnic groups. These results indicate that both pharmacokinetic factors, including absorption and hepatic first-pass metabolism, and pharmacodynamic factors (dopamine receptor-mediated responses) contribute to the difference in responses between Caucasians and Asians.

The Relationship of Haloperidol Concentrations to Therapeutic Response

Data from pharmacokinetics studies that examined the relationship of haloperidol serum concentrations and therapeutic response in schizophrenic patients were reexamined utilizing the method of logistic regression analysis. A linear rather than a curvilinear relationship was obvious between serum haloperidol concentration and therapeutic response according to both the regression analysis and inspection of the distribution of the data. It was concluded that a serum haloperidol concentration in the range of 9 to 15 ng/ml was associated with a 30% decrease in the total Brief Psychiatric Rating Scale (BPRS) score. Haloperidol concentrations above these appear unlikely in the majority of patients to produce any additional reduction of symptoms. The BPRS psychosis factor finding suggested an analogous finding for serum haloperidol concentrations between 12 and 17 ng/ml. The analyses suggest that the probability of response to haloperidol seems to reach a point of diminishing return at concentrations of approximately 9 to 17 ng/ml. Serum concentrations above this limit do not appear to either decrease or increase the probability of response.

Serum haloperidol concentration and choreiform movements in Huntington's disease

The relationship between serum haloperidol concentration and improvement in abnormal movements was investigated in 20 adult Huntington's disease (HD) patients. Serum samples and assessments of severity of chorea were simultaneously obtained from each patient. Data were obtained prior to and at one or more doses following the initiation of haloperidol in ten patients. Serum was analyzed for haloperidol by two different methods, gas chromatographic/mass spectrometric (GC/MS) and radioreceptor (RR) assays. Steady-state serum haloperidol concentrations (GC/MS) of 0.5 to 24 ng/ml were observed following administration of doses of 1 to 40 mg/d and varied markedly between patients. Only results from the GC/MS assay were used for examining relationships with dose and clinical response because of insensitivity of RR assay. Significant improvement of abnormal movements, greater than 30% from baseline, occurred at serum concentrations between 2 and 5 ng/ml, which corresponded to doses of 1.5 to 10 mg/d. Further improvement in abnormal movements at serum concentrations above this range was minimal.

Serum haloperidol concentration and clinical response in schizophrenia.

Previous studies have reported a therapeutic window (i.e., a curvilinear relationship between clinical response and drug level) for haloperidol concentrations in serum or plasma. The authors treated 30 acutely decompensated schizophrenic inpatients with a fixed dose of haloperidol (.4 mg/kg/day). After 6 weeks there was no statistically significant correlation between clinical improvement and serum haloperidol concentration. Fifteen subjects with serum concentrations of 5-15 ng/ml did not differ in clinical improvement compared with 15 subjects who had concentrations above 15 ng/ml. These data are consistent with a therapeutic plateau, rather than a window, and suggest that in most cases there is no clinical advantage to the use of haloperidol doses greater than approximately 30 mg/day in schizophrenic patients.

Neuroleptic Radioreceptor Activity and Clinical Outcome in Schizophrenia

The relationship between serum haloperidol concentration and clinical response was examined in 27 schizophrenic inpatients between the ages of 18 and 56 years. All patients were treated with haloperidol, 20 mg/day for the first 2 weeks. Dosage adjustment after 2 weeks of treatment was made in seven subjects based on poor clinical response or side effects. Haloperidol activity was determined by the radioreceptor assay for neuroleptics on weeks 2 and 4 serum samples. The results indicated that higher radioreceptor activity levels, particularly above 22 ng/ml, were associated with poorer clinical response. The data suggest that radioreceptor activity levels are not at a steady state after 2 weeks drug treatment. Additionally, problems secondary to low sensitivity of the radioreceptor assay may limit its utility at low serum concentrations.

Does carbamazepine-induced reduction of plasma haloperidol levels worsen psychotic symptoms?

Seven psychotic patients' plasma haloperidol levels, determined with gas-liquid chromatography, fell a mean of 60% when carbamazepine treatment was instituted. Two patients' levels became undetectable, and their symptoms worsened. Haloperidol level monitoring may be required for patients given both haloperidol and carbamazepine.

Serum Haloperidol Concentrations and Clinical Response in Acute Psychosis

Steady state serum haloperidol concentrations measured by gas-liquid chromatography and a neuroleptic radioreceptor assay were compared to clinical response in 21 acutely psychotic inpatients. Serum concentrations measured by the two assay methods correlated well with each other, although the neuroleptic radioreceptor assay was much less sensitive. There was also a significant linear relationship between haloperidol dose (mg/kg/day) and steady state serum concentration. The correlation between haloperidol serum concentrations and clinical response after 2 to 3 weeks was nonlinear and most pronounced in the intermediate range (15 to 40 ng/ml). Further studies will be needed to establish with certainty the existence and exact limits of a therapeutic window.

Enhancement of avoidance-suppressing effect after repeated administration of haloperidol and serum haloperidol in rats

Adult male rats of the Wistar strain, which were trained under a discriminated lever-press avoidance schedule (intertrial interval; 25 sec, presentation of conditioned stimuli; 5 sec), were given SC 0.025–0.05 mg/kg of haloperidol at fixed intervals of 1, 3–4 and 7 days. The avoidance-suppressing effect of haloperidol was enhanced in parallel to the number of drug administrations until it attained a maximum level. The intensity of the maximum effect tended to be stronger, and the number of administrations necessary to attain it was smaller, when a higher dose was given. When the administration interval exceeded one day, the enhanced effect remained irreversible one month after withdrawal of drug administration. The enhancement of the effect was produced after repeated administrations in an experimental chamber, but not in a home cage. Temporal changes in serum haloperidol concentration were determined 30–90 min after 0.035 mg/kg given SC to the haloperidol-pretreated and saline-pretreated groups. No significant difference in the pharmacokinetic change was detected between the two groups. These results suggest that learning during the drug effect under repeated exposure to a fixed experimental situation influences the enhancing effect.

Radioimmunoassay of haloperidol in human serum: Correlation of serum haloperidol with serum prolactin

A radioimmunoassay (RIA) for measurement of serum haloperidol is described. Compared to gaschromatography (GC), RIA values average 40% higher. However, a simple organic extraction of serum yields statistically equivalent RIA and GC haloperidol determinations. For both men and women combined, there was a positive correlation between dose (mg/kg/day) and steady-state serum haloperidol level (r = +0.86) and between steady-state serum haloperidol and serum prolactin (PRL) concentration (r = +0.87).

3H and 125I radioimmunoassays of haloperidol compared with fluoroimmunoassay involving antibody coupled to magnetizable solid phase.

Radioimmunoassays for haloperidol are described, involving use of tritium- or 125I-labeled drug or tritium-labeled spiroperidol, and a rabbit antiserum to a drug/bovine serum albumin conjugate. The 125I-labeled drug was prepared by the Chloramine T iodination technique. A fluoroimmunoassay for haloperidol is also described in which the antiserum is coupled to magnetizable solid-phase medium, and fluorescein-labeled haloperidol is used. The assays have acceptable accuracy, precision, and reproducibility, and are specific for haloperidol and similar butyrophenones, with no significant interference from known metabolites and other drugs. Only the radioimmunoassays have sufficient sensitivity to cover the whole range of haloperidol concentrations in serum. The fluoroimmunoassay can be used to monitor high concentrations of haloperidol in 150-microL samples or the complete concentration range of 1-mL serum samples that are extracted and concentrated before assay.

Haloperidol concentrations in saliva and serum: determination by the radioimmunoassay method.

Haloperidol concentrations in saliva and serum were measured by radioimmunoassay using conjugate III-bovine serum albumin as an antigen. The results were as follows: (1) There was a statistically significant correlation between saliva and serum levels, with the former being higher than the latter. (2) There were significant correlations between daily dosage and salivary and serum concentrations, and the regression lines were shown in the equivalent exponential form. (3) Serum and salivary concentrations remained constant over a 24-hour period in a steady state. (4) The saliva-serum ratio was inversely proportional to salivary pH, but there was no significant correlation between the ratio and the volume of saliva.