A Phase 1 Single/Multiple Dose Study Of PF-06293620 To Assess Safety, Tolerability And Pharmacokinetics In Subjects With Type 2 Diabetes Mellitus

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of its causal relationship with study treatment. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; was life-threatening (immediate risk of death); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs are events between first dose of study drug and up to Day 85 (for SAD cohorts) or Day 169 (for MAD cohorts) that were absent before treatment or that worsened after treatment. AEs included both serious and non-serious AEs. Causality with the study treatment was determined by the investigator.

Dose limiting or intolerable AEs were originally planned to be collected. However, this outcome measure was not actually summarized, since collection and monitoring of treatment-emergent AEs was performed during the study, and deemed sufficient to ensure the participants safety.

ADA against PF-06293620 in human serum samples was determined following a tiered approach using screening, confirmation, and titer/quantification by semi-quantitative enzyme linked immunosorbent assay (ELISA). Endpoint titer >=1.88 was considered positive.

AUCinf was calculated as AUClast +(Clast*/kel), where AUClast is area under the serum concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* is the predicted serum concentration at the last quantifiable time point estimated from the log-linear regression analysis, kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.

AUCinf(dn) was calculated as AUCinf/dose, where AUCinf is area under the serum concentration-time profile from time 0 extrapolated to infinite time.

Area under the serum concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of PF-06293620 was determined using linear/log trapezoidal method.

AUClast(dn) of PF-06293620 was calculated as AUClast/dose, where AUClast was area under the serum concentration-time profile from time 0 to the time of the last quantifiable concentration.

Clearance (CL) was calculated as dose/AUCinf, where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time. This outcome measure only applies to IV arms.

Apparent Clearance (CL/F) of PF-06293620 was calculated as dose/AUCinf, where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time. This outcome measure only applies to SC arms.

Maximum serum concentration (Cmax) of PF-06293620 was observed directly from data.

Time for Maximum serum concentration (Tmax) of PF-06293620 was observed directly from data as time of first occurrence.

Steady-state volume of distribution (Vss) of PF-06293620 was calculated as CL*MRT, where MRT was the mean residence time calculated as (AUMCinf/AUCinf - infusion duration/2), AUMCinf was area under the moment curve from time 0 extrapolated to infinity; CL was the clearance. This outcome measure only applies to IV arms.

Apparent Volume of Distribution (Vz/F) of PF-06293620 was calculated as dose/(AUCinf*kel), where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time, kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. This outcome measure only applies to SC arms.

Terminal elimination half-life (Thalf) of PF-06293620 was calculated as ln(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.

Tau refers to the dosing interval, which was 4 weeks (672 hours). Area under the concentration-time profile from time 0 to time tau (AUCtau) was determined using linear/log trapezoidal method.

Average Concentration (Cav) of PF-06293620 was calculated as AUCtau/tau, where AUCtau was area under the concentration-time profile from time 0 to time tau, and tau was the dosing interval, 4 weeks (672 hours).

Time for maximum serum concentration (Tmax) of PF-06293620 was observed directly from data as time of first occurrence.

Apparent clearance (CL/F) of PF-06293620 was calculated as dose/AUCtau, where AUCtau was area under the concentration-time profile from time 0 to time tau, and tau was the dosing interval, 4 weeks (672 hours).

Apparent volume of distribution (Vz/F) of PF-06293620 was calculated as dose/(AUCtau/kel), where AUCtau was area under the concentration-time profile from time 0 to time tau, and tau was the dosing interval, 4 weeks (672 hours); and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.

Terminal elimination half-life (Thalf) of PF-06293620 was calculated as ln(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.

Observed accumulation ratio based on AUC (Rac) of PF-06293620 was calculated as AUCtau(Day57)/AUCtau(Day1).

Observed accumulation ratio based on Cmax (Rac,Cmax) of PF-06293620 was calculated as Cmax(Day57)/Cmax(Day1).