title: Characterisation of liver chemistry abnormalities associated with pazopanib monotherapy: a systematic review and meta-analysis of clinical trials in advanced cancer patients.
abstract: Drug-induced liver chemistry abnormalities, primarily transaminase elevations, are commonly observed in pazopanib-treated patients. This meta-analysis characterises liver chemistry abnormalities associated with pazopanib. Data of pazopanib-treated patients from nine prospective trials were integrated (N=2080). Laboratory datasets were used to characterise the incidence, timing, recovery and patterns of liver events, and subsequent rechallenge with pazopanib. Severe cases of liver chemistry abnormalities were clinically reviewed. Multivariate analyses identified predisposing factors. Twenty percent of patients developed elevated alanine aminotransferase (ALT) >3×ULN. Incidence of peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN was 8%, 5%, 5% and 1%, respectively. Median time to onset for all events was 42days; 91% of events were observed within 18weeks. Recovery rates based on peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN were 91%, 90%, 90% and 64%, respectively. Median time from onset to recovery was 30days, but longer in patients without dose interruption. Based on clinical review, no deaths were associated with drug-induced liver injury. Overall, 38% of rechallenged patients had ALT elevation recurrence, with 9-day median time to recurrence. Multivariate analysis showed that older age was associated with development of ALT >8×ULN. There was no correlation between hypertension and transaminitis. Our data support the current guidelines on regular liver chemistry tests after initiation of pazopanib, especially during the first 9 or 10weeks, and also demonstrate the safety of rechallenge with pazopanib.
authors.affiliation: Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London EC1A 7BE, UK. Electronic address: Thomas.Powles@bartsandthelondon.nhs.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Medical Oncology Unit, San Donato Hospital, Arezzo 52100, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bracarda
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania 17426-0989, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania 17426-0989, USA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Norry
authors.affiliation: GlaxoSmithKline, Uxbridge, Middlesex UB11 1BT, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Compton
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania 17426-0989, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Heise
authors.affiliation: Texas Oncology and Baylor Sammons Cancer Center, Dallas, TX 75246, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hutson
authors.affiliation: Departments of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Essen 45136, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Harter
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania 17426-0989, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Carpenter
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Lini
authors.initials: L
authors.lastname: Pandite
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D007191:Indazoles; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D000410:Alanine Transaminase
keywords: ALT elevation; Drug-induced liver injury; Hepatotoxicity; Hyperbilirubinemia