Mechanistic-static risk assessment

Mechanistic-static risk assessment

Usage

mech_stat_cyp_risk(
  perp,
  cyp_inh,
  cyp_ind,
  cyp_tdi = NULL,
  d = 1,
  include_induction = TRUE,
  substr = cyp_reference_substrates,
  cyp_kdeg = cyp_turnover,
  qh = 1.616,
  qent = 18/60
)

Arguments

perp

Precipitant object.

cyp_inh

Inhibitor object.

cyp_ind

Inducer object.

cyp_tdi

Inhibitor object.

d

Hepatocyte batch scaling factor, defaults to 1.

include_induction

Logical.

substr

The CYP probe substrates to be used as data frame, defaults to ddir::cyp_reference_substrates.

cyp_kdeg

The CYP turnover data as data frame. Defaults to the built-in reference data ddir::cyp_turnover.

qh

Hepatic blood flow in l/min, defaults to 1.616 l/min.

qent

Enteric blood flow in l/min, defaults to 0.3 l/min (18 l/h).

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 for the respective enzyme.

Examples

mech_stat_cyp_risk(
  examplinib,
  examplinib_cyp_inhibition,
  examplinib_cyp_induction,
  examplinib_cyp_tdi
 )
#> ──────── Clinical DDI risk assessment ──────── 
#> Mechanistic-static risk assessment for examplinib 
#> 
#> object    substrate     kiu    fgut   fm     fmcyp   Ag     Ah     Bg     Bh     Cg     Ch     aucr   risk    
#> CYP1A2    tizanidine    NA     1      0.95   0.98    1      1      1      1      1      1      1      FALSE   
#> CYP2B6    NA            NA     NA     NA     NA      1      1      1      1      1      1      NA     NA      
#> CYP2C8    repaglinide   11     1      1      0.61    0.63   0.98   1      1      1      1      1.01   FALSE   
#> CYP2C9    S-warfarin    0.6    1      1      0.91    0.08   0.76   1      1      1      1      1.28   TRUE    
#> CYP2C19   omeprazole    0.25   1      1      0.87    0.04   0.56   1      1      1      1      1.61   TRUE    
#> CYP2D6    desipramine   NA     1      1      0.85    1      1      1      1      1      1      1      FALSE   
#> CYP3A4    midazolam     12.5   0.57   0.96   1       0.65   0.98   0.43   0.48   6.88   1.77   0.84   FALSE