Basic CYP inhibition risk

Evaluate the clinical risk for direct (reversible) CYP inhibition according to the basic model defined in the ICH M12 guideline.

Usage

basic_cyp_inhibition_risk(perp, cyp_inh)

Arguments

perp

The precipitant object.

cyp_inh

CYP inhibition data object.

Value

DDI risk object.

Details

For the basic modeling of direct (reversible) CYP enzyme inhibition, the ratio of the relevant inhibitor concentration to the \(K_i\) of the respective CYP enzyme is considered, i.e., \(R\) for hepatic enzymes and \(R_{gut}\) for intestinal enzymes (refer to Section 2.1.2.1 of the ICH M12 guidance document).

Liver

$$R=\frac{C_{max,ss,u}}{K_{i,u}}$$

\(R\) values > 0.02, i.e., maximal unbound precipitant concentrations 50-fold over \(K_i\) are considered to indicate a potential clinical CYP inhibition risk using this method.

Intestine

$$R_{gut}=\frac{I_{gut}}{K_{i,u}}$$

where

$$I_{gut}=\frac{Dose}{250\ ml}$$

\(R\) values > 10 are considered to indicate a clinical risk for intestinal CYP3A inhibition.

In the output, the columns risk_hep and risk_intest indicate whether the regulatory threshold is reached.

Examples

basic_cyp_inhibition_risk(examplinib, examplinib_cyp_inhibition)
#> ──────── Clinical DDI risk assessment ──────── 
#> Direct CYP inhibition risk for examplinib 
#> 
#> object    ki     kiu    source      r        risk_hep   r_gut   risk_intest   
#> CYP1A2    NA     NA     NA          NA       NA         NA      NA            
#> CYP2B6    NA     NA     NA          NA       NA         NA      NA            
#> CYP2C8    11     11     study 001   0.015    FALSE      NA      NA            
#> CYP2C9    0.6    0.6    study 001   0.275    TRUE       NA      NA            
#> CYP2C19   0.25   0.25   study 001   0.659    TRUE       NA      NA            
#> CYP2D6    NA     NA     NA          NA       NA         NA      NA            
#> CYP3A4    12.5   12.5   study 001   0.0132   FALSE      292     TRUE