Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder:Linking blood levels to weight gain and effectiveness

Aims: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side-effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side-effects and drug effectiveness. Methods: Twenty-four children and adolescents (15 males, 9 females) aged 6–18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side-effects and drug effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed-effects models. Results: For both aripiprazole and dehydro-aripiprazole, one-compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations best predicted higher BMI z-scores (P &lt;.001) and higher Hb1Ac levels (P =.03) during follow-up. No significant association was found between sum concentrations and effectiveness. Conclusions: Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems.</p

Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder

Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods: Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. Results: A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P <.001). Higher sum trough concentrations also predicted more sedation (P <.05), higher prolactin levels (P <.001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P <.01). Conclusion: Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems

Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder

Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods: Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. Results: A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P <.001). Higher sum trough concentrations also predicted more sedation (P <.05), higher prolactin levels (P <.001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P <.01). Conclusion: Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Objective. Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods. Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results. We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 034, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions. rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers. (C) 2015 Elsevier Inc. All rights reserved.Peer reviewe

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

<p>TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.</p>