{"doi":"10.1002/jcph.1958","title":"Population Pharmacokinetics and Exposure‐Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies","abstract":"Abstract Population pharmacokinetic (PK) and exposure‐safety analyses of alisertib were performed in children enrolled in 2 clinical trials: NCT02444884 and NCT01154816. NCT02444884 was a dose‐finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45 to 100 mg/m 2 as powder‐in‐capsule once daily or twice daily for 7 days in 21‐day cycles. Serial blood samples were collected up to 24 hours after dosing on cycle 1, day 1. NCT01154816 was a phase 2 single‐arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m 2 as enteric‐coated tablets once daily for 7 days in 21‐day cycles. Sparse PK samples were collected up to 8 hours after dosing on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed‐effects modeling to support dosing recommendations in children and adolescents. A 2‐compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area across the age range of 2 to 21 years, supporting the use of body surface area–based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m 2 once daily enteric‐coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg twice daily (recommended adult dose). Statistically significant relationships ( P < .01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism‐related toxicities.","journal":"The Journal of Clinical Pharmacology","year":2021,"id":195677,"datarank":0.46931369151276636,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.1397300049123334,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.1397300049123334,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":8,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02444884","NCT01154816"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":767081,"name":"Diane R. Mould","orcid":"0000-0002-8908-0136","position":1,"is_corresponding":false},{"id":767082,"name":"Ying Yuan","orcid":"0000-0002-3323-6912","position":2,"is_corresponding":false},{"id":232646,"name":"Elizabeth Fox","orcid":"0000-0002-9998-5326","position":3,"is_corresponding":false},{"id":767083,"name":"Emily Greengard","orcid":"0000-0002-2963-5638","position":4,"is_corresponding":false},{"id":289288,"name":"Douglas V. Faller","orcid":"0000-0002-2454-3478","position":5,"is_corresponding":false},{"id":767084,"name":"Karthik Venkatakrishnan","orcid":"0000-0003-4039-9813","position":6,"is_corresponding":false},{"id":767080,"name":"Xiaofei Zhou","orcid":"0000-0003-0319-1327","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:50:07.691929Z","pmid":"34435684","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}