Population pharmacokinetics of durvalumab and fixed dosing regimens in patients with advanced solid tumors
| Autor: | Vincent Dubois, Lorin Roskos, Ashok Kumar Gupta, Xuyang Song, Xiaoping Jin, Chaoyu Jin, Rajesh Narwal, Pralay Mukhopadhyay, Paul Baverel, Phillip A. Dennis, Yong Ben |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Volume of distribution Cancer Research medicine.medical_specialty education.field_of_study Durvalumab business.industry Population Urology Population pharmacokinetics Pharmacology NONMEM 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis medicine Disease characteristics In patient Dosing education business |
| Zdroj: | Journal of Clinical Oncology. 35:2566-2566 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | 2566 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, to quantitate the effect of patient/disease characteristics on PK, and to compare weight (WT)-based versus fixed dosing regimens. Methods: Data were pooled from two studies: Study 1108 (Phase 1/2; various tumor types) and ATLANTIC (Phase 2; NSCLC). A total of 1324 patients provided data following 0.1 to 20 mg/kg IV durvalumab. The population PK was performed using a non-linear mixed effects modeling approach in NONMEM software. The impact of demographics, clinical indices, and biomarkers on PK was explored. Results: Durvalumab PK was best described using a 2-compartment model with both linear and non-linear clearances. The mean (between-patient variability) linear clearance (CL) and central volume of distribution (V1) were 226 mL/day (~29%) and 3.51 L (~21%), respectively. Although population PK analysis identified a few statistically significant covariates (WT, sex, CrCL, post-baseline ADA, ECOG performance status, LDH, sPDL1 levels, tumor type, and albumin), none were found to be clinically relevant (effect on PK parameters < 30%), indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following WT-based (10 mg/kg Q2W) and fixed dosing regimens (1500 mg Q4W or 750 mg Q2W); with all regimens expected to maintain target trough exposure of ~50 µg/mL in ≥95% patients. In a post-hoc analysis, durvalumab clearance was found to decrease slightly over time, with a mean maximal reduction from baseline value of 15.5%. The decrease in CL was associated with tumor shrinkage, decreased LDH, increased albumin and decreased neutrophil to lymphocyte ratio. The small decrease in CL was not considered relevant to PK exposure or dosing. Conclusions: A population PK model of durvalumab was developed and validated. No dose adjustments were needed based on any patient or disease characteristics. The analysis demonstrated the feasibility of switching to a fixed dose regimen. Clinical trial information: NCT02087423 and NCT01693562. |
| Databáze: | OpenAIRE |
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