Erratum to: No clinically significant drug interactions between lenalidomide and P-glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers

3029 Background: Rash and diarrhea are a class effect of ERBB1 inhibitors. These events are relatively mild with Lapatinib (a dual ERBB1/ERBB2 kinase inhibitor). Finding a genetic basis for patients who may be predisposed to these adverse events, from the outset of clinical development, may improve the understanding of the mechanisms of these side effects and may have implications for use and dosing. Methods: DNA was isolated from peripheral blood of 107 Caucasian subjects from eight monotherapy phase I studies including 73 healthy volunteers and 34 cancer patients, 100 of whom had associated pharmacokinetic data. 284 single nucleotide polymorphisms (SNPs) from five candidate genes of transporters (ABCB1, ABCG2) and enzymes (CYP 3A4 and 3A5, and 2C19) for which lapatinib is a substrate were genotyped and examined for associations with pharmacokinetic variables (dose-normalized AUC, Cmax, and Tmax) as well as rash (15 cases) and diarrhea (18 cases). Results: Skin rash and diarrhea in this phase I cohort were only mild, (i.e. grade I or II). Statistically significant associations were observed between 34 SNPs in CYP2C19, rash (22 SNPs) and diarrhea (6 SNPs), and between 15 SNPs in ABCB1 and Tmax. Notably, 3/3 subjects (2 healthy volunteers, one patient) homozygous for the CYP2C19*2 allele experienced both mild rash and diarrhea. Extensive linkage disequilibrium was observed among these associated SNPs. Conclusions: Our results suggest that it is possible to determine pharmacogenetic associations with side effect phenotypes during the earliest phase of clinical drug development. These results are currently being validated on a larger cohort of patients from phase II lapatinib clinical trials. [Table: see text]

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Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): Results from two phase I studies in healthy volunteers

Clinical Pharmacology in Drug Development ◽

10.1002/cpdd.161 ◽

2014 ◽

Vol 4 (4) ◽

pp. 315-321 ◽

Cited By ~ 13

Author(s):

Meng Zhang ◽

Christine Xu ◽

Lei Ma ◽

Elias Shamiyeh ◽

Jianyun Yin ◽

...

Keyword(s):

Phase I ◽

Healthy Volunteers ◽

Selective Inhibitor ◽

Two Phase ◽

Phase I Studies ◽

Effect Of Food

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Demonstration of Clinical Comparability of the Biosimilar Filgrastim to Neupogen, in Terms of Safety and Efficacy, in Healthy Volunteers and Patients Receiving Myelosuppressive Chemotherapy

European Oncology & Haematology ◽

10.17925/eoh.2014.10.2.107 ◽

2014 ◽

Vol 10 (02) ◽

pp. 107 ◽

Cited By ~ 7

Author(s):

Bernd Jilma ◽

Agnieszka Jagiełło-Gruszfeld ◽

Piotr Tomczak ◽

Himanshu Gadgil ◽

Grzegorz Orlik ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Healthy Volunteers ◽

Reference Product ◽

Phase Iii ◽

Published Data ◽

Efficacy And Safety ◽

Phase I Studies ◽

Safety And Efficacy ◽

Phase Iii Study

Aim: To demonstrate biosimilarity as evidenced by the pharmacokinetic (PK), pharmacodynamics (PD), efficacy and safety comparability of AccofilR/GrastofilR (filgrastim), a recombinant human granulocyte colony-stimulating factor, and the reference product, NeupogenR. Patients and methods: Four phase I studies were conducted to demonstrate the comparative efficacy of Accofil/Grastofil and Neupogen. PD and PK parameters of Accofil/Grastofil (filgrastim) at and around the main clinical dose (5 μg/kg), using both the intravenous (IV) and subcutaneous (SC) routes of administration, were compared with Neupogen (EU) in healthy volunteers in three phase I clinical studies in a single-dose setting and following multiple-dose administration. An additional phase I PK/PD study was performed to compare Accofil/ Grastofil (filgrastim) to both EU-approved Neupogen and US-licensed Neupogen following the administration of a fixed SC dose of 300 μg. The efficacy and safety of Accofil/Grastofil was also evaluated in chemotherapy-naive women with stage IIA, IIB and IIIA breast cancer receiving docetaxel, doxorubicin, cyclophosphamide (TAC) chemotherapy. No comparator arm was included in this study so the efficacy and safety comparison was made with published data for the reference product, Neupogen. Results: A total of 235 healthy subjects were enrolled in the phase I studies and 120 patients in the phase III study. The PK and PD data demonstrated high comparability of the Accofil/ Grastofil and Neupogen products, with the 90 % confidence interval (CI) for primary PK parameters and 95 % CI for primary PD parameters falling within the pre-defined equivalence limits. In the phase III study, Accofil/Grastofil (filgrastim) demonstrated a safety and efficacy profile that was similar to the published data for the reference product Neupogen for the reduction of the duration of neutropenia in patients with breast cancer who were undergoing chemotherapy. Conclusion: Lack of clinically meaningful differences was convincingly demonstrated between Accofil/Grastofil (filgrastim) and the reference product, Neupogen.

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