* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download 37 - Clinical Cancer Research
Survey
Document related concepts
Discovery and development of cyclooxygenase 2 inhibitors wikipedia , lookup
Nicotinic agonist wikipedia , lookup
Discovery and development of antiandrogens wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Prescription costs wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Pharmacognosy wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Neuropharmacology wikipedia , lookup
Drug discovery wikipedia , lookup
Dydrogesterone wikipedia , lookup
Plateau principle wikipedia , lookup
Drug design wikipedia , lookup
Transcript
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