PMID- 37437109 OWN - NLM STAT- MEDLINE DCOM- 20230818 LR - 20230829 IS - 1557-8992 (Electronic) IS - 1044-5463 (Print) IS - 1044-5463 (Linking) VI - 33 IP - 6 DP - 2023 Aug TI - Cariprazine in Pediatric Patients with Autism Spectrum Disorder: Results of a Pharmacokinetic, Safety and Tolerability Study. PG - 232-242 LID - 10.1089/cap.2022.0097 [doi] AB - Objective: Cariprazine is a dopamine D(3)-preferring D(3)/D(2) and serotonin 5-HT(1A) receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies. FAU - Yeung, Paul P AU - Yeung PP AD - Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA. FAU - Johnson, Kimball A AU - Johnson KA AD - iResearch, Decatur, Georgia, USA. FAU - Riesenberg, Robert AU - Riesenberg R AD - Atlanta Center for Medical Research, Atlanta, Georgia, USA. FAU - Orejudos, Amelia AU - Orejudos A AD - Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA. FAU - Riccobene, Todd AU - Riccobene T AUID- ORCID: 0000-0002-3702-1097 AD - Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA. FAU - Kalluri, Hari V AU - Kalluri HV AUID- ORCID: 0000-0002-5863-2452 AD - Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA. FAU - Malik, Paul R AU - Malik PR AD - Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA. FAU - Varughese, Shane AU - Varughese S AD - Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA. FAU - Findling, Robert L AU - Findling RL AD - Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230712 PL - United States TA - J Child Adolesc Psychopharmacol JT - Journal of child and adolescent psychopharmacology JID - 9105358 RN - F6RJL8B278 (cariprazine) RN - 0 (Antipsychotic Agents) SB - IM MH - Adult MH - Humans MH - Child MH - *Autism Spectrum Disorder/drug therapy MH - Treatment Outcome MH - *Antipsychotic Agents/adverse effects MH - *Bipolar Disorder/drug therapy PMC - PMC10458368 OTO - NOTNLM OT - atypical antipsychotic OT - autism spectrum disorder OT - cariprazine OT - pediatric OT - pharmacokinetic COIS- A.O., T.R., H.V.K., and S.V. are employees of AbbVie and shareholders of AbbVie. K.A.J. and R.R. were investigators for this study and received financial support from AbbVie, which funded the study. P.P.Y. and P.M. are former employees of AbbVie and may be AbbVie shareholders. R.L.F. receives or has received research support, acted as a consultant, and/or has received honoraria from Abbvie, Acadia, Adamas, Afecta, Akili, Alkermes, Allergan, American Academy of Child and Adolescent Psychiatry, American Psychiatric Press, Arbor, Axsome, Idorsia, Intracellular Therapies, Iqvia, Lundbeck, Medavante Prophase, MJH Life Sciences, Neurim, NIH, Novartis, Otsuka, PaxMedica, PCORI, Pfizer, Physicians' Postgraduate Press, Radius, Receptor Life Sciences, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Takeda, Tris, and Viatris. EDAT- 2023/07/12 19:07 MHDA- 2023/08/18 06:43 PMCR- 2023/08/16 CRDT- 2023/07/12 14:33 PHST- 2023/08/18 06:43 [medline] PHST- 2023/07/12 19:07 [pubmed] PHST- 2023/07/12 14:33 [entrez] PHST- 2023/08/16 00:00 [pmc-release] AID - 10.1089/cap.2022.0097 [pii] AID - 10.1089/cap.2022.0097 [doi] PST - ppublish SO - J Child Adolesc Psychopharmacol. 2023 Aug;33(6):232-242. doi: 10.1089/cap.2022.0097. Epub 2023 Jul 12.