Plasma quetiapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 2000-2011.

OBJECTIVE: Suggested predose plasma quetiapine target ranges for effective therapy in schizophrenia lie between 50 and 500 µg/l. We aimed to examine data from a quetiapine therapeutic drug monitoring (TDM) service to assess the plasma quetiapine concentrations attained at specified doses in clinical practice. METHOD: We studied TDM data from patients given immediate-release quetiapine in the period 2000-2011. RESULTS: There were 946 samples from 487 patients (257 males, age at time of first sample, median [range] 34 [14-87] years, and 230 females, age at time of first sample, median [range] 38 [10-92] years). The plasma quetiapine concentration was <50 and <100 µg/l in 30% and 50% of samples, respectively (no quetiapine detected in 9% of samples). The relationship between dose and plasma quetiapine was poor. The mean (95% confidence interval [CI]) quetiapine dose was higher (t = 3.6, df = 446, p <0.01) in males versus females (641 [600-1240] and 548 [600-943] mg/day, respectively), although there was no difference in median dose (600 mg/day) or in the mean (95% CI) plasma quetiapine concentrations attained. Smoking habit had no discernible effect on plasma quetiapine concentration. CONCLUSIONS: There was a poor relationship between dose and plasma quetiapine concentration in this study, as found by others. This is probably because of the short plasma half-life of the drug, at least in part. Nevertheless, quetiapine TDM can help assess adherence and measurement of quetiapine metabolites, notably N-desalkylquetiapine, as well as quetiapine itself may enhance the value of quetiapine TDM in future.

Unintentional domestic non-fire related carbon monoxide poisoning: data from media reports, UK/Republic of Ireland 1986-2011.

CONTEXT: Gathering information on the circumstances that give rise to unintentional domestic non-fire related carbon monoxide poisoning and the associated morbidity and mortality is not straightforward because the diagnosis is so often missed in life. METHODS: We searched Newsbank and related databases (at least 332 sources, UK and Republic of Ireland) for reports of domestic carbon monoxide poisoning, 1986-end 2011 inclusive. The search terms were 'carbon monoxide AND (house* OR home* OR caravan* OR tent*) NOT (work OR fire OR suicide*)'. Newsbank includes full-text articles from 19 UK national newspapers and over 140 UK & Irish regional and local newspapers and periodicals. RESULTS AND DISCUSSION: There were reports of 348 incidents (880 victims: 334 male, 352 female, 194 sex not stated). Reports of incidents increased from 1986 (1) to 2011 (28). There were 298 deaths (169 male, 124 female, 5 sex not reported). The likelihood of a fatal outcome increased with age for both males and females (28%, 1-9 years; 71%, 80 + years). The source of carbon monoxide was often a central heating or water boiler (48% of 244 incidents). Many incidents (49%) occurred in private dwellings. However, incidents in caravans, tents, sheds and outhouses had a much higher death rate. If a victim was discovered alive chances of survival were relatively good (87%), even if found unconscious. The estimated duration of carbon monoxide exposure ranged from minutes to years in both fatal and non-fatal incidents. Pets were recorded in 31 incidents (17 died). In 5 cases, carbon monoxide poisoning was identified through illness or death of a pet. Prosecutions were recorded in 49 incidents and at least 7 custodial (prison) sentences resulted, with 34 further convictions resulting in a fine. Charges were preferred against either an installer/maintenance engineer (42%), or the landlord (31%). CONCLUSION: Deaths and permanent injuries from unintentional domestic non-fire related carbon monoxide poisoning continue. Survival rates are relatively high if poisoning is diagnosed in life, but warning signs are often missed and inappropriate behavior such as placing barbecues in tents and failure to perform proper safety checks by gas appliance fitters still kills.

Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged <18 years: data from a therapeutic drug monitoring service, 1994-2010.

AIM: Clozapine is used in children and adolescents to treat early onset schizophrenia, but data on efficacy and on the plasma clozapine concentrations attained are limited. METHODS: We studied data from a clozapine therapeutic drug monitoring (TDM) service, patients in the UK and Eire aged <18 years, 1994-2010. Multiple linear regression analysis was performed to investigate the relationship between plasma clozapine concentration and dose, age, sex, body weight, plasma clozapine:norclozapine ratio (clozapine metabolic ratio (MR)) and smoking habit. RESULTS: There were 1408 samples from 454 patients, 267 (59%) males aged at time of first sample (median = 17; range = 8-17 years) and 187 (41%) females aged 16 (10-17) years. The plasma clozapine concentration was <0.35 mg L(-1) in 36%, and ≥0.60 mg L(-1) in 31% of samples (6.4% samples ≥1.0 mg L(-1) ). Although plasma clozapine was broadly related to prescribed dose, there was much variation: 10% of samples had plasma clozapine >0.60 mg L(-1) at prescribed clozapine doses of 50-150 mg d(-1) (66% <0.35 mg L(-1) ), while 12% of samples had plasma clozapine <0.35 mg L(-1) at doses ≥650 mg d(-1) (62% >0.6 mg L(-1) ). The covariates studied in the 16-17-year-olds had proportionately similar influences to those observed in adults. Together they explained 48% of the variance observed in plasma clozapine, with dose, smoking habit, MR and sex being major influences. In the younger patients, there were very few smokers, and the influence of sex did not reach statistical significance. CONCLUSIONS: As in adults, clozapine TDM may help in assessing adherence and in dose adjustment, for example if smoking habit changes.

Plasma amisulpride in relation to prescribed dose, clozapine augmentation, and other factors: data from a therapeutic drug monitoring service, 2002-2010.

OBJECTIVE: This study aimed to investigate the effect of dose and other factors on plasma amisulpride concentrations in clinical practice. METHOD: Amisulpride therapeutic drug monitoring data 2002-2010 have been studied. RESULTS: There were 296 samples (196 adult patients). Amisulpride was not detected in 10% of samples. In the remainder, the mean plasma amisulpride in relation to the prescribed dose (mg/day) was as follows: 100-200 (111 µg/L), 201-400 (254 µg/L), 400-800 (421 µg/L), and 800-1200 (494 µg/L). For prescribed doses up to 800 mg/day, only 51% of results were within 100-319 µg/L. There were no significant sex differences in mean plasma amisulpride or mean dose. The mean plasma amisulpride, but not the dose, was significantly higher in smokers. Linear regression analysis showed that dose explained only 42% of the variation in plasma amisulpride after log(10) transformation of both variables. There was no significant difference in the mean dose or mean plasma amisulpride in patients co-prescribed clozapine as compared with the remaining samples. CONCLUSION: In practice, dose is a poor predictor of plasma amisulpride concentration. Therapeutic drug monitoring may not only help assess adherence, but also guide dosage.

Risperidone and total 9-hydroxyrisperidone in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 2002-2010.

BACKGROUND: Information on the plasma risperidone and total 9-hydroxyrisperidone concentrations ('total risperidone') attained in clinical practice is scant. The aim of this work was to gather such information to better inform the interpretation of results. METHOD: This involved the audit of plasma total risperidone data from a risperidone therapeutic drug monitoring service 2002-2010. RESULTS: There were 586 samples from 411 patients [289 (70%) males aged at the time of the first sample (median, range) 37 (7-83) years and 121 females aged 42 (10-91) years]. In patients aged 18 years and over, the mode of risperidone administration was oral: 242 samples (163 patients), risperidone long-acting injection (RLAI): 42 samples (39 patients), both oral and RLAI: 18 samples (12 patients), no information: 266 samples (211 patients). No risperidone/9-hydroxyrisperidone was detected in 10% of the samples, including 5 samples from patients prescribed RLAI. In the remainder, the mean (SD) total plasma total risperidone was all samples 35 (36), oral only 33 (29), RLAI only 23 (16), oral and RLAI 50 (21) µg/L. Overall, only 45% of the samples had plasma total risperidone within the range 20-59 mcg/L. Multiple linear regression analysis (95 samples) revealed that sex, smoking habit, and dose explained 21% of the variation in plasma total risperidone after oral dosage (dose alone only explained 11% of the variation). There was no discernable influence of age, body weight, and the plasma risperidone:total 9-hydroxyrisperidone ratio on plasma total risperidone. CONCLUSIONS: Risperidone therapeutic drug monitoring can help assess adherence and guide dosage even after RLAI.

Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged 65 years and over: data from a therapeutic drug monitoring service, 1996-2010.

OBJECTIVE: To investigate the effect of dose and other factors on plasma clozapine concentrations in patients aged 65 years and over. METHOD: Audit of clozapine therapeutic drug monitoring data, 1996-2010. RESULTS: There were 1930 samples [778 patients, 363 men aged (median, range) 67 (65-100) years and 415 women aged 68 (65-90) years]. There was no significant difference in the mean plasma clozapine concentration between men (0.56 mg/l) and women (0.58 mg/l), although the mean dose was higher in men (323 mg/d) than women (264 mg/d). The higher proportion of men (46%) compared with women (37%) smokers could explain this finding. Overall, 32% of samples had plasma clozapine below, and 37% above, a target range of 0.35-0.60 mg/l. Overall, the median dose decreased from 300 (65-70 years) to 200 mg/d (age 85 years and over). However, prescription of >350 mg/d was associated with a 50% likelihood that the plasma clozapine would exceed 0.60 mg/l. For a subgroup of 196 patients (114 men, 82 women), mean plasma clozapine was significantly higher after age 65 despite significantly lower dosage. CONCLUSION: Clozapine dosage in elderly patients should be reviewed regularly to minimise the risk of adverse effects.

Plasma olanzapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1999-2009.

Olanzapine therapeutic drug monitoring (TDM) is the measurement of plasma olanzapine to assess adherence and guide dosage. We have audited data from an olanzapine TDM service, 1999-2009. Multiple linear regression analysis was conducted to investigate the contribution of dose, age, sex, body weight, and smoking status to the plasma olanzapine concentration. There were 5856 samples from 3207 patients. The prescribed olanzapine dosage was 2.5 to 95 mg/d. No olanzapine was detected in 6% of samples. For olanzapine dosages of 2.5 to 20 mg/d, only 35% of results were within a suggested target range of 20 to 39 ng/mL. At doses above 20 mg/d, 30% to 59% of results were 60 ng/mL or greater depending on dose band. In patients aged 17 years or younger (92 samples), median plasma olanzapine was higher than that in adult patients at almost all olanzapine doses. Multiple linear regression analysis of results from 627 adults from whom complete data were available showed that dose, smoking status, sex, age, and body weight together explained 24% the variance in plasma olanzapine. Degree of adherence, timing of sample postdose, drug-drug interactions, and pharmacogenetic factors also may have contributed to the observed variance. However, it is clear that female nonsmokers had higher plasma olanzapine concentrations for a given dose than male smokers. Olanzapine TDM is useful in assessing adherence and may have a role in limiting olanzapine dosage to minimize the risk of long-term toxicity.