PK in healthy adults General PK - Single dose NP28989 * - Multi-dose N/A Bioequivalence †- Single dose NP29040 * - Multi-dose N/A PK in special populations Target population §- Single dose NP28673 - Multi-dose NP28673 NP28761 * * Hepatic impairment (mild) POPPK-1064536 Renal impairment (mild to moderate) POPPK-1064536 Neonates/infants/children/ adolescents N/A Elderly POPPK-1064536 Asian patients, similar to target population but crizotinib-naïve, multi-dose. AF-001JP * Genetic/ gender related PK versus females POPPK-1064536 genetic variable POPPK-1064536 Food effect In healthy adults NP28991 * In target population NP28761 In with ALK+ve NSCLC AF-001JP (Japan) PK interactions Posaconazole (CYP3A inhibitor) – healthy subjects NP28990 * Rifampin (CYP3A inducer) – healthy subjects NP29042 * Esomeprazole (PPI) – healthy subjects NP28991 * Midazolam – in ALK+ve NSCLC patients NP28673 (substudy) * Population PK analyses Healthy subjects N/A Target population PK1064595 (GastroPlus™)
3 recommenced at 450 mg BD Resolved Pulmonary embolism Onset day 107 Grade 3 Interrupted Not resolved (died due to disease prog 7 days Was on nadroparin and diclofenac at time. Rx w tinzaparin. Interstitial lung disease day 110 3 Withdrawn day 113 Not resolved No significant history or meds. CT showed ground-glass opacity, lavage negative for infectious cause. dx as drug-induced Pneumonia 55/M/Asian Onset day 28 4 Interrupted, recommenced day 39 at 600 mg BD, decreased to 450 mg BD day 40. CXR showed consolidation recurring day 41, and alectinib was permanently withdrawn. Resolved day 68 Died due to progressive disease day 102. Constipation ALT increased and AST increased Onset day 21/215 Grade 2/4 Interrupted (due to liver enzymes) day 208 Withdrawn day 215 Resolved day 268 biopsy: centrilobular hepatic injury, consistent with toxic effect. Specified in advised PI text:. Depression 54/F/Asian Onset day 10 Grade 2 Interrupted Resolved History of depression was on sertraline. Depression worsened with restlessness, crying, insomnia and anxiety.
Table 83: Characteristics of the cases identified by the sponsor in their signal analysis by searching for Preferred Terms related to gastrointestinal perforation as part of the end-of-first-round s31 response to clinical question 12. Source dose AE term Age (yrs) Relevant history Relevant concurrent medication Outcome pivotal Study NP28673 Italy 1200 mg intestinal perforation 69 concurrent diverticulitis systemic corticosteroid Fatal surveillance study ALC1401 Japan 600 mg rectal perforation (and diverticulum intestinal haemorrhagic) 79 brachytherapy for prostate cancer at the site of perforation, history of diverticulitis Recovered surveillance study ALC1401 600 mg gastrointestinal perforation 70 concurrent Recovered expanded access ML29453 USA 1200 mg perforated diverticulitis 69 concurrent diverticulosis systemic corticosteroid Recovered compassionate use MO29499 France 1200 mg gastrointestinal perforation 43 concurrent diverticulosis systemic corticosteroid surveillance study ALC1401 Japan 600 mg gastrointestinal perforation 69 advanced disease stage systemic corticosteroid Not recovered compassionate use MO29499 900 mg perforated sigmoid 64 sigmoid diverticulitis systemic corticosteroid Recovered pivotal Study NP28673 China 900 mg perforated appendicitis 27 appendicitis Recovered spontaneous Japan 600 mg intestinal perforation 74 none reported none reported Recovered