Table 1 Summary of in vitro pharmacologic activity and nonclinical and clinical pharmacokinetic properties of PF-06427878.

Summary of in vitro pharmacologic activity and nonclinical and clinical pharmacokinetic properties of PF-06427878.. Fa determined after 10 mg/kg of oral dose in 0.5% methylcellulose. CYP, cytochrome P450; DGAT1, diacylglycerol acyltransferase 1; DGAT2, diacylglycerol acyltransferase 2; IC50, half maximal inhibitory concentration; MGAT1, monoacylglycerol acyltransferase 1; MGAT2, monoacylglycerol acyltransferase 2; MGAT3, monoacylglycerol acyltransferase 3; AUCinf, area under the plasma concentration time profile from 0 extrapolated to infinity; AUClast, area under the plasma concentration time profile from 0 to the last quantifiable concentration; AUCtau, area under the plasma concentration time profile from time 0 to time tau (τ), where τ equals 8 hours; Cmax, maximum plasma concentration; CV, coefficient of variation; n, number of participants in the treatment group and contributing to the summary statistics; n1, number of participants for AUCinf and t1/2; NA, not applicable; NR, not reported; PK, pharmacokinetics; Q8H, every 8 hours; t1/2, terminal elimination half-life; Tmax, time for Cmax.

AssayPharmacodynamic activity
Recombinant enzyme inhibition assays: DGAT2
Human DGAT2, IC50 (nM)99.9 ± 3.2*
Rat DGAT2, IC50 (nM)202 ± 4.4*
Recombinant enzyme inhibition assays: Selectivity
Human DGAT1, IC50 (μM)>50
Mouse MGAT1, IC50 (μM)>50
Human MGAT2, IC50 (μM)>45
Human MGAT3, IC50 (μM)>50
Primary hepatocyte assays
Human DGAT2, IC50 (nM)11.6 ± 1.3*
Nonclinical pharmacokinetic properties
Fraction unbound (Fu), human/rat plasma0.046/0.038
Fraction absorbed in rat, Fa (%)78.0
Total plasma clearance, rat, CLp (ml/min per kg)31.4
Human CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 inhibition, IC50 (μM)>100
*Means ± SEM
Clinical pharmacokinetic properties
n, n1Cmax (ng/ml)Tmax (hours)t1/2 (hours)AUCinf (ng·hour/ml)AUCtau (ng·hour/ml)
Single ascending doses of PF-06427878*
3 mg6, 16.3 (48)2.0 (0.5–3.0)NRNRNA
10 mg6, 425.5 (74)1.5 (0.5–3.0)1.6 ± 0.381.4 (49)NA
30 mg6, 672.0 (30)2.0 (0.5–4.0)1.7 ± 0.2242.0 (20)NA
100 mg6, 6244.1 (26)3.1 (0.5–4.0)3.0 ± 0.9870.2 (57)NA
300 mg6, 31092 (28)1.5 (1.0–4.0)5.2 ± 1.73046 (37)NA
600 mg6, 51728 (41)2.0 (1.0–2.0)4.4 ± 2.25867 (33)NA
1200 mg6, 54072 (34)2.0 (0.5–4.0)5.3 ± 2.217940 (21)NA
2000 mg6, 59302 (63)4.0 (3.0–6.0)5.0 ± 1.043830 (41)NA
Multiple doses of PF-06427878 with plasma PK assessed on day 14*,
15 mg/day6, 111.2 (43)1.0 (1.0–1.0)NRNR21.5 (67)
45 mg/day8, 439.0 (44)1.0 (1.0–2.1)7.6 ± 3.7NR109.0 (40)
150 mg/day8, 2127.5 (51)1.0 (1.0–3.0)NRNR299.8 (54)
450 mg/day8, 5476.4 (72)1.0 (1.0–2.0)10.3 ± 3.4NR1208 (63)
1500 mg/day12, 101254 (69)1.0 (0.5–3.9)6.2 ± 2.4NR4403 (54)

*Geometric mean (%CV) for all PK parameters except: median (range) from Tmax; arithmetic means ± SD for t1/2.

†The mean value of AUClast was higher than AUCinf when AUCinf was not reportable in individual participant(s) with high AUClast value(s).

‡Daily administration divided Q8H with a meal.