Serum concentrations with the continuous 240?mg Q2W routine at month 4 were also approximately 90% of simulated steady-state levels of 240?mg Q2W. Open in a separate window Figure 2. Predicted geometric imply nivolumab concentrationCtime profiles of 240?mg Q2W and 240?mg Q2W (eight doses) followed by 480?mg Q4W over 1?year (on-line). Exposure assessment by BW group is presented in supplementary Number S2, available at online. to evaluate clinical safety of the Q4W routine. Individuals and methods Nivolumab PK exposure for the 480?mg Q4W routine was simulated for 3817 individuals across multiple tumor types and compared with those for the 3?mg/kg Q2W and 240?mg Q2W schedules. The security profile of the Q4W routine was assessed by analysis of medical data from 61 individuals who transitioned to nivolumab 480?mg Q4W from 3?mg/kg Q2W during four phase III clinical tests. Results Compared with 3?mg/kg Q2W, nivolumab CAPRI 480?mg Q4W produced related time-averaged concentration, approximately 16% lower trough concentration, and 45% higher maximum concentration at constant state. The peak concentration for 480?mg Q4W was significantly lower than that of 10?mg/kg Q2W, a dose previously shown to possess an acceptable tolerability and security profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3?mg/kg Q2W to 480?mg Q4W were reported in 14.8% of individuals, with 1.6% of individuals reporting grades 3C4 TRAEs. Pooled security data for these individuals are consistent with those for the 3?mg/kg Q2W schedules, and no paederosidic acid methyl ester fresh safety signs were identified. Conclusions The time-averaged steady-state exposure and security profile of nivolumab 480?mg Q4W are consistent with that of 3?mg/kg Q2W across multiple tumor types. Nivolumab 480?mg Q4W represents a new dosing routine option, and in addition to 240?mg Q2W, provides convenience and flexibility for patient care. Clinical trial figures “type”:”clinical-trial”,”attrs”:”text”:”NCT01721772″,”term_id”:”NCT01721772″NCT01721772, “type”:”clinical-trial”,”attrs”:”text”:”NCT01668784″,”term_id”:”NCT01668784″NCT01668784, “type”:”clinical-trial”,”attrs”:”text”:”NCT01673867″,”term_id”:”NCT01673867″NCT01673867, “type”:”clinical-trial”,”attrs”:”text”:”NCT01642004″,”term_id”:”NCT01642004″NCT01642004 on-line) [9C12]. Study designs for these studies have been published previously and are offered in supplementary Number S1, available at online [9C12]. In open-label extension phases of these studies, eligible individuals who experienced received nivolumab 3?mg/kg Q2W without disease progression could transition to nivolumab 480?mg Q4W administered IV over 30?min, and eligible individuals in comparator arms no longer deriving benefit could cross over to nivolumab, either 3?mg/kg Q2W or 480?mg Q4W, until documented disease progression, discontinuation, or consent withdrawal. To compare the treatment-related adverse event (TRAE) rates for the 480?mg Q4W dosing regimen with those of the 3?mg/kg Q2W dosing regimen, TRAEs were characterized from 1st dose of nivolumab 480?mg Q4W until 30?days following last dose and graded according to the Common Terminology Criteria for Adverse Events v4.0. In addition, TRAE rates with the 480?mg Q4W dosing regimen were compared paederosidic acid methyl ester with respect to BW to assess whether the TRAEs were associated with differences in exposure across the BW range. Results Assessment of nivolumab exposures on-line). Serum concentrations with the continuous 240?mg Q2W routine at month 4 were also approximately 90% of simulated steady-state levels of 240?mg Q2W. Open in a separate window Number 2. Expected geometric mean nivolumab concentrationCtime profiles of 240?mg Q2W and 240?mg Q2W (eight doses) followed by 480?mg Q4W over 1?year (on-line). Exposure assessment paederosidic acid methyl ester by BW group is definitely offered in supplementary Number S2, available at online. Despite the higher expected exposures in lighter individuals receiving the smooth dosing, exposure measures in the low BW group ( 70?kg) are well below those with nivolumab 10?mg/kg Q2W (Number?1). Clinical security of nivolumab 480?mg Q4W Clinical security data with 480?mg Q4W were available for 61 individuals [CheckMate 066 (on-line). There were a limited number of individuals (on-line). Average duration of exposure to nivolumab 480?mg Q4W was 2.06?weeks, with 19.7% of individuals treated with nivolumab for longer than 3?weeks. Individuals received a median of three doses and nearly 92% of individuals had a relative dose intensity greater than 90% (Table?2). Table 2. Summary of TRAEs during weight-based nivolumab treatment across CheckMate 066, 025, 057, and 017, and the pooled individual cohort that transitioned to nivolumab 480?mg Q4Wa (%)on-line). The incidence of serious adverse events (SAEs) was similar between BW organizations (supplementary Table S3, available at on-line), indicating that the higher exposure of individuals in the lower BW group was not associated with improved risk of SAEs. One individual (1.6%) in the 70 and 90?kg BW group experienced an SAE related to nivolumab (grade 3 immune-mediated renal failure) (Table?2), which was treated with immune-modulating therapy. No infusion reactions were reported. No AEs led to treatment discontinuation and no deaths were attributed to study-drug toxicity. No fresh safety concerns were identified. Conversation This analysis evaluated PK exposure and clinical security of nivolumab 480?mg Q4W compared with 240?mg Q2W and 3?mg/kg Q2W dosing schedules using quantitative clinical pharmacology methods and pooled safety data from four phase III clinical tests. A flat dose of 240?mg Q2W was previously approved by the FDA based on modeled comparisons of exposure, and bridging of effectiveness and security.
