Determination of Guanfacine in Oral Fluid and Serum of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Short Communication.

BACKGROUND: Guanfacine, a selective α2A-adrenoreceptor agonist, is a second-line medication for treating children and adolescents with attention-deficit/hyperkinetic disorder. The dosage administered as milligram per body weight to balance the potential benefits and risks of treatment. Therapeutic drug monitoring (TDM) is useful for identifying a patient's therapeutic window to optimize individual drug dosing and reduce the risk of adverse drug reactions. However, in children and adolescents, intravenous sample collection is especially stressful and thus remains a primary challenge, restricting the use of TDM. Therefore, evaluating alternative specimens to facilitate TDM is a worthwhile task. The aim of this study was to assess the feasibility of using oral fluid for TDM of guanfacine in children and adolescents. METHODS: In this article, 9 patients (median age 8.1 years; 6 boys and 3 girls) undergoing treatment with guanfacine were included. Simultaneously collected oral fluid and serum samples were deproteinized using methanol containing a stable isotope-labeled internal standard before the determination of guanfacine by liquid chromatography-tandem mass spectrometry. Pearson correlation and paired t test were used for statistical analysis. RESULTS: The mean serum guanfacine concentration was 3 times higher than that detected in oral fluid (7.47 ng/mL versus 2.36 ng/mL; t (8) = 5.94; P < 0.001). A strong positive linear correlation (r = 0.758, P = 0.018) was identified between oral fluid and serum concentrations. A strong but nonsignificant negative correlation (r = -0.574, P = 0.106) was detected between the oral fluid pH and oral fluid-to-serum concentration ratio. CONCLUSIONS: The strong correlation between oral fluid and serum concentration and the probable small effect of oral fluid pH on oral fluid-to-serum concentration ratio supports guanfacine as a suitable candidate for TDM in oral fluid.

Relationship Between Amphetamine Concentrations in Saliva and Serum in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Therapeutic drug monitoring (TDM) is a valid tool for the optimization of psychopharmacotherapy; however, in child and adolescent psychiatry, uncomfortable intravenous sample collection is the main challenge and restricts the use of TDM. Therefore, it is important to evaluate alternate specimens to facilitate TDM. The aim of this study was to evaluate the feasibility of using saliva for the TDM of amphetamine in children and adolescents with attention-deficit/hyperactivity disorder. METHODS: In this study, 28 patient samples (mean age, 11.3 years; boys, 23; and girls, 5) treated with lisdexamfetamine were included. The active compound amphetamine was extracted and derivatized before quantification by high-performance liquid chromatography with fluorescence detection. Nonparametric Spearman rank correlations were used for correlation analyses; for clinical validation, Bland-Altman analysis was applied. RESULTS: The median amphetamine concentrations in saliva were 2.7 times higher (range 0.7-23.6) than those in serum (257.8 ng/mL versus 77.2 ng/mL; z = -4.51, P < 0.001). A strong positive linear correlation was observed between saliva and serum concentrations (ρ = 0.628, P < 0.001). The ratio of saliva-to-serum concentration was strongly pH dependent (ρ = -0.712, P < 0.001). Therefore, a transformation formula, factoring in salivary pH, to calculate serum concentrations from the measured saliva concentrations was applied. Theoretical and measured serum amphetamine concentrations were subjected to Bland-Altman analysis. Using an acceptance limit of 20%, only 21% (n = 6) of samples fulfilled this criterion. CONCLUSIONS: Amphetamine paired saliva-to-serum concentrations were highly variable and strongly affected by salivary pH, indicating that saliva is an inappropriate sampling matrix for TDM of amphetamine. Furthermore, Bland-Altman analysis did not support saliva as a suitable matrix for TDM.

Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice.

Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18 years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319 mg, 4.9 mg/kg) and serum concentration (mean 387 ng/ml) of clozapine was found with the variation in dose explaining 30 % of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3 ng/ml, P = 0.018) and moderate ADRs (261.4 vs 416.3 ng/ml, P = 0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs.