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DDI assessment

ddi-assessment.Rmd

This vignette shows how to assess the potential of a drug to act as a precipitant of drug-drug interactions with CYP and UGT enzymes and drug transporters.

Regulatory background

In May-2024, ICH published a new harmonized guidance on the assessment of enzyme- or transporter-mediated drug interactions that will be adopted by the ICH-abiding regulatory agencies, including FDA, EMA and PMDA.

Currently (Nov-2024), the following guidance documents are provided by the individual regulatory authorities:

Drug properties

As a general concept, the risk for enzyme or transporter interactions is evaluated for a given drug exposure level that corresponds to the maximal unbound clinical exposure in the relevant pharmacokinetic compartment. For interactions with hepatic enzymes, the unbound maximal plasma concentration at steady state (\(I_{max,ss,u}\)) is considered, and for intestinal enzymes as victim of orally administered drugs, the maximal clinical dose, dissolved in a volume of 250 ml (\(I_{gut}\)).

For interactions with basolateral hepatic transporters (OATP1B1, OATP1B3), the unbound hepatic inlet concentration (\(I_{max,inlet,u}\)) is considered that is composed of the \(I_{max,ss,u}\) and a portal venous term reflecting the intestinally absorbed drug escaping gut metabolism.

These concentrations can be automatically derived from the following set of drug-specific parameters:

Parameter Parameter name Default Unit
Molar weight mw NA g/mol
Clinical dose dose NA mg
Maximal total plasma concentration (\(C_max\)) imaxss NA ng/ml
Fraction unbound (\(f_u\)) fu 1
Microsomal unbound fraction (\(f_{u,mic}\)) fumic 1
Blood-to-plasma concentration ratio (\(R_b\)) rb 1
Fraction absorbed (\(f_a\)) fa 1
Fraction escapting gut metabolism (\(f_g\)) fg 1
Absorption rate constant (\(k_a\)) ka 0.1 1/min
Solubility solubility Inf mg/l

The specification of the key compound parameters is therefore the first step in the formal analysis. In the scope of this package, these key parameters are aggregated into a ‘precipitant’ object. The package contains a sample precipitant object for the ficitional drug ‘examplinib’:

examplinib
Precipitant compound parameters for examplinib
parameter value source
oral TRUE
\(MW\) (g/mol) 492.6
\(dose\) (mg) 450
\(C_{max,ss}\) (ng/ml) 3530
\(f_u\) 0.023
\(f_{u,mic}\) 1
\(R_B\) 1
\(F_a\) 0.81
\(F_g\) 1
\(k_a\) (1/min) 0.00267

The function precipitant() can be used to create custom precipitant objects:

perp <- precipitant(
  name = "test",
  dose = 100,
  imaxss = 1000,
  mw = 500,
  oral = TRUE,
  fu = 1,
  fumic = 1,
  rb = 1,
  fa = 1,
  fg = 1,
  ka = 0.1,
  solubility = Inf
)

Precipitant concentrations

The relevant precipitant concentrations for a precipitant compound can be determined using key_conc_table() - please see the documentation to this function for details about the calculations.

key_conc_table(examplinib)
Key precipitant concentrations for examplinib
parameter value (\(ng/ml\)) value (\(\mu M\))
\(I_{gut}\) 1.80e+06 3650.000
\(I_{max,ss,u}\) 8.12e+01 0.165
\(I_{max,inlet,u}\) 9.50e+01 0.193
\(I_{max,intestinal}\) 3.24e+03 6.590

Direct enzyme inhibition

CYP enzymes

In vitro CYP inhibition data is expected as inhibition_data object that can be constructed like so:

cyp_inh <- inhibition_data(
  tibble::tribble(
    ~object,  ~ki,     ~source,
   "CYP1A2",   NA,          NA,
   "CYP2B6",   NA,          NA,
   "CYP2C8",   11, "study 001",
   "CYP2C9",  0.6, "study 001",
  "CYP2C19", 0.25, "study 001",
   "CYP2D6",   NA,          NA,
   "CYP3A4", 12.5, "study 001"
  ),
  precipitant = "examplinib"
)

Printing this object yields a convenient table view:

print(cyp_inh)
In vitro inhibition data for precipitant examplinib
object ki source
CYP1A2 NA
CYP2B6 NA
CYP2C8 11.00 study 001
CYP2C9 0.60 study 001
CYP2C19 0.25 study 001
CYP2D6 NA
CYP3A4 12.50 study 001

The function to assess the clinical risk for direct CYP inhibition, ddir::basic_cyp_inhibition_risk(), takes a precipitant object and a CYP inhibition data object:

print(basic_cyp_inhibition_risk(examplinib, cyp_inh))
Direct CYP inhibition risk for examplinib
object ki kiu source r risk_hep r_gut risk_intest
CYP1A2 NA NA NA NA NA - -
CYP2B6 NA NA NA NA NA - -
CYP2C8 11.00 11.00 study 001 0.0150 FALSE - -
CYP2C9 0.60 0.60 study 001 0.2750 TRUE - -
CYP2C19 0.25 0.25 study 001 0.6590 TRUE - -
CYP2D6 NA NA NA NA NA - -
CYP3A4 12.50 12.50 study 001 0.0132 FALSE 292 TRUE

UGT enzymes 

print(basic_ugt_inhibition_risk(examplinib, examplinib_ugt_inhibition))
UGT inhibition risk for examplinib
object ki kiu source r risk
UGT1A1 15.0 15.0 study 009 0.0110 FALSE
UGT1A3 15.0 15.0 study 009 0.0110 FALSE
UGT1A4 15.0 15.0 study 009 0.0110 FALSE
UGT1A6 15.0 15.0 study 009 0.0110 FALSE
UGT1A9 3.8 3.8 study 009 0.0434 TRUE
UGT2B7 15.0 15.0 study 009 0.0110 FALSE
UGT2B15 15.0 15.0 study 009 0.0110 FALSE
UGT2B17 6.1 6.1 study 009 0.0270 TRUE

Time-dependent enzyme inhibition 

print(basic_cyp_tdi_risk(examplinib, examplinib_cyp_tdi))
Time-dependent CYP inhibition risk for examplinib
object ki fu kinact kdeg source r risk
CYP3A4 0.17 0.023 0.04 0.0193 study 001 2.72 TRUE

CYP induction

Fold-change method 

print(static_cyp_induction_risk(examplinib, examplinib_cyp_induction))
Static CYP induction risk for examplinib
object emax max_c source risk note
CYP1A2 1.00 5 study 007 FALSE Not tested up to 50-fold Cmax,u
CYP2B6 1.00 5 study 007 FALSE Not tested up to 50-fold Cmax,u
CYP2C8 NA NA NA NA
CYP2C9 NA NA NA NA
CYP2C19 NA NA NA NA
CYP2D6 NA NA NA NA
CYP3A4 7.35 3 study 007 TRUE Not tested up to 50-fold Cmax,u

Basic kinetic model 

print(kinetic_cyp_induction_risk(examplinib, examplinib_cyp_induction))
Kinetic CYP induction risk for examplinib
object emax ec50 max_c source r risk
CYP1A2 1.00 NA 5 study 007 NA NA
CYP2B6 1.00 NA 5 study 007 NA NA
CYP2C8 NA NA NA NA NA NA
CYP2C9 NA NA NA NA NA NA
CYP2C19 NA NA NA NA NA NA
CYP2D6 NA NA NA NA NA NA
CYP3A4 7.35 1.64 3 study 007 0.213 TRUE 
print(mech_stat_cyp_risk(examplinib, examplinib_cyp_inhibition, examplinib_cyp_induction, examplinib_cyp_tdi))
Mechanistic-static risk assessment for examplinib
object substrate kiu fgut fm fmcyp Ag Ah Bg Bh Cg Ch aucr risk
CYP1A2 tizanidine NA 1.00 0.95 0.98 1.00 1.00 1.00 1.00 1.00 1.00 1.00 FALSE
CYP2B6 NA NA NA NA NA 1.00 1.00 1.00 1.00 1.00 1.00 NA NA
CYP2C8 repaglinide 11.00 1.00 1.00 0.61 0.63 0.98 1.00 1.00 1.00 1.00 1.01 FALSE
CYP2C9 S-warfarin 0.60 1.00 1.00 0.91 0.08 0.76 1.00 1.00 1.00 1.00 1.28 TRUE
CYP2C19 omeprazole 0.25 1.00 1.00 0.87 0.04 0.56 1.00 1.00 1.00 1.00 1.61 TRUE
CYP2D6 desipramine NA 1.00 1.00 0.85 1.00 1.00 1.00 1.00 1.00 1.00 1.00 FALSE
CYP3A4 midazolam 12.50 0.57 0.96 1.00 0.65 0.98 0.43 0.48 6.88 1.77 0.84 FALSE

Transporter inhibition 

print(transporter_inhibition_risk(examplinib, examplinib_transporter_inhibition))
Transporter inhibition risk for examplinib
object ic50 source i r threshold risk
Pgp_int 0.41 study 005 igut 8.91e+03 10.00 TRUE
Pgp_sys 0.41 study 005 imaxssu 4.02e-01 0.02 TRUE
BCRP_int 1.90 study 005 igut 1.92e+03 10.00 TRUE
BCRP_sys 1.90 study 005 imaxssu 8.67e-02 0.02 TRUE
OATP1B1 177.00 study 006 imaxinletu 1.09e-03 0.10 FALSE
OATP1B3 35.00 study 006 imaxinletu 5.51e-03 0.10 FALSE
OAT1 271.00 NA imaxssu 6.08e-04 0.10 FALSE
OAT3 300.00 NA imaxssu 5.49e-04 0.10 FALSE
BSEP 12.80 NA imaxssu 1.29e-02 0.10 FALSE
OCT1 2.30 study 006 imaxssu 7.17e-02 0.10 FALSE
OCT2 67.00 study 006 imaxssu 2.46e-03 0.10 FALSE
MATE1 3.60 study 006 imaxssu 4.58e-02 0.02 TRUE
MATE2k 1.10 study 006 imaxssu 1.50e-01 0.02 TRUE