Note for: Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies

Note for: Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies

Doi: 10.1158/1078-0432.CCR-16-3083

Aim of this paper;

Giving a guideline for setting up the in vitro experiment on cell line, esp. concentrations by which it makes some sense when translated back to clinical level.

Extraction;

For doing experiment with FDA-approved drug – it is better to search for pharmacokinetics as well as toxicity of particular drug. Thus, we can design the experiment which will be more clinically relevant. 

Guiding dose and concentration selection – providing comprehensive compilation of human plasma exposures for drug-approved by the FDA for used in oncology.

Sources of FDA-approved drug

• NCI – cross-checked with MediLexicon and Centerwatch

Pharmacokinetic search through databases – original literature or conference abstract

• Using Cmax (maximum plasma concentration) and the integrated area under the plasma concentration–time curve (AUC) associated with the highest recommended dose of the drugs

Results

• 145 unique small-molecule drugs approved to treat cancer

• 10 – prodrugs

• Active drugs (table1)

• IV route – duration of injection is included

• Cmax – normally reported as ng/mL but convert to umol/L

• Fraction bound to plasma protein – important parameter to translate from in vivo to in vitro setting with varied protein composition

• Cmax and AUC presented here – average values and interindividual variability can be large due to genetic polymorphism in clearance and other factors

• Attempt to translate doses or plasma exposures from nonclinical models to human – most utilize 

• allometric scaling/empirical measurement

• based on body surface area

• in vivo pharmacokinetics

• pharmacokinetics/pharmacodynamics and physiologically based pharmacokinetic models

• Plasma Cmax – highly dependent on 

• route of administration, 

• formulation and 

• physical properties

• Cmax

• May consider as an upper limit for drug concentration during in vitro studies

• May consider as the highest plasma exposure for in vivo studies

• This will help the off-target effects during study in vivo

• 10 or 100 times greater than IC50 or Ki for the molecular target – increase the possibility of introducing off-target activity – it will be unrelated to clinical benefit

• Cmax – (free + protein bound); free form is the form which interacts with molecular target – it is important to consider protein binding percentage before setting up the experiment

• Each drug has different serum protein binding capability – thus the mode of action will be affected

• Species different in plasma protein binding – effect the binding capability to each drug

• For example, vismodegib primarily bound to alpha-1-acid glycoprotein (AAG) with much lower affinity for albumin

• Kd between rat and human albumin-AAG yields 100-fold differences

• AUC

• Integration of plasma drug exposure over time – things need to be considered

• Bioavailability

• Different absorption rates

• Elimination rates

• Particularly important when comparing exposures between species or routes of administration

• Things to be considered

• Cytochrome-P450 isoform – produce different metabolites might be more potent than the parental

• Route to introduce drugs in animal – ip in mouse, mostly, being absorbed through the visceral peritoneum

• Route to introduce drug – must consider first-pass hepatic clearance