Table 3.

Summary pharmacokinetic metrics from clinically approved doses and corresponding mouse CRD

ErlotinibDasatinibaVismodegibaTrastuzumabaIrinotecan (SN38)Capecitabine (5-FU)
Clinical information
Clinical dose and regimen150 mg QD p.o.100 mg QD p.o.150 mg QD p.o.4 mg/kg i.v. week 1 and 2 mg/kg i.v. QW after week 1125 mg/m2 QWx3350 mg/m2 Q3W850 – 1,250 mg/m2 BID p.o. on days 1–14 of a 3-week cycle
Human Fu0.0830.06< – 0.060.9
Cmax,ss (ng/mL)165.6 (75.2)7.7 [57%]14,300 (5,100)123,00026.3 (11.9)56.0 (28.2)n.r.
Cmin,ss (ng/mL)102.8 (68.6)n.r.n.r.79,000n.r.n.r.n.r.
AUCtau,ss (ng*hr/mL)3,400 (1,800)28.7 [43%]n.r.14,900 μg/h*mL229 (108)474 (245)n.r.
Tau (h)2424n.r.1682424n.r.
Cav,ss (ng/mL)142.8 (76.1)1.2 [43%]11,800 (4800)89,000n.r.n.r.400 ng/g
Metric matchedUnbound plasma Cav,ssUnbound plasma Cav,ssTotal plasma Cav,ssTotal plasma Cav,ssTotal plasma SN38 AUC5-FU tumor concentrations
Nonclinical information
Mouse CRD and regimen25 mg/kg BID p.o.50 mg/kg QD p.o.4.5 mg/kg QD p.o.75 mg/kg QD p.o.13 mg/kg i.v. W1 & 4.5 mg/kg i.v. QW2–5.5 mg/kg i.v., QDx34–12 mg/kg i.v.,Q4D120 – 250 mg/kg QD p.o. (dependent upon xenograft model)
Mouse Fu0.0350.080.0134 (0.0017)1.000.012–0.0340.89
Cmax,ss (ng/mL)2784843.5720,700133,00080–220160–480n.c.
Cmin,ss (ng/mL)44.711.40.064,85072,700< 1 × 10−3< 1 × 10−3n.c.
AUCtau,ss (ng*h/mL)3,2003,20028.16.1 × 10615,300 μg/h*mL117–321233 – 700n.c.
Tau (h)2424245041682424n.c.
Cav,ss (ng/mL)1331331.1712,10095,0004.9–13.49.7–29.2∼ 400 ng/g
  • NOTE: Values reported as mean (SD) or mean [CV%]. Matching metrics in humans and mice are bolded to ease comparisons.

  • aDasatinib, vismodegib, and trastuzumab analyses are included in Supplementary materials.

  • Abbreviations: BID, twice daily; n.r., not reported; n.c., not calculated; p.o., orally; QD, once a day; QW, once a week; QWx3, once weekly for 3 weeks; W1, week 1; QDx3, once daily for 3 consecutive days; Q4D, once every 4 days.