Download 37 - Clinical Cancer Research

Supplemental Material
Vismodegib CRD Calculation
1. Human Pharmacokinetics
Vismodegib is a small molecule inhibitor of the smoothened receptor in the Hedgehog signaling
pathway. Its clinical dose is 150 mg PO QD. The drug is reported to be highly bound to plasma
proteins (>99%) and furthermore demonstrates saturable binding to serum alpha-1-acid
glycoprotein, which complicates the in vivo pharmacokinetics. This may be reflected in the halflife differences observed following single or multiple days of dosing (12 versus 4 days,
respectively) (vismodegib label, Table 1). Given the differences in PK following single and
multiple dosing regimens, only information from the multiple dose regimens was used in the
back-extrapolation. At steady state, the average total drug concentration following 42 days of
treatment is 11.8 µg/mL (vismodegib Clinical Pharmacology and Biopharmaceutics Review,
Table 1), which is consistent with another reported value (9.5 µg/mL)[37].
2. Scaling Method
Vismodegib is reported to be highly bound in all species tested (vismodegib FDA Briefing
Package, Table 1), with an unbound fraction in mouse plasma of 1.34 ± 0.17% [38]. Since both
humans and mice show high protein binding, it was decided to match total drug levels so that
small errors in the plasma protein binding estimates would not introduce large errors in the back
translation.
3. Mouse Pharmacokinetics at the Mouse Dose Adjusted to Match Human Metric
A mathematical model for the mouse PK [38] was implemented and subsequently used to
simulate various dosing paradigms in order to match the clinical PK metric. The average drug
concentrations observed in humans could be approximated with doses of 38 mg/kg BID (Cave =
11.2 µg/mL, total) or 75 mg/kg QD (Cave = 12.0 µg/mL). Either dosing regimen will match the
clinical Cav,ss. However, as was observed with erlotinib, the BID dosing protocol will mitigate
the larger concentration swings in Cmax and Cmin values present following QD dosing (Fig. 4C)
and in the case of vismodegib, will result in concentrations at steady state that fall within one
standard deviation of the reported human mean concentration value.
2