正文
获取原文件references/ddi-and-qt.md
ICH M12 basic models
Use the current M12 guideline, with measured inputs, units and assay binding basis recorded. A positive screen calls for further evaluation; it is not a predicted clinical effect size. A negative screen does not exclude unmodeled mechanisms.
| Mechanism | Quantity | Screening trigger |
|---|---|---|
| Reversible CYP | 1+Cmax,u/Ki,u |
>=1.02 |
| Oral gut CYP | 1+(dose/0.25L)/Ki,u |
>=11 |
| Time-dependent inhibition | 1+(kinact*I/(KI,u+I))/kdeg, I=5*Cmax,u |
>=1.25 |
| Kinetic induction | 1/(1+Emax*I/(EC50,u+I)), I=10*Cmax,u |
<=0.8 |
| OAT1/3, OCT2 | Cmax,u/IC50,u |
>=0.1 |
| MATE1/2-K; systemic P-gp/BCRP | Cmax,u/IC50,u |
>=0.02 |
| Intestinal P-gp/BCRP, oral | (dose/0.25L)/IC50 |
>=10 |
| OATP1B1/1B3 | Iin,max,u/IC50,u |
>=0.1 |
Induction also requires interpretation of the experimental mRNA concentration-response evidence; the kinetic formula alone is not a complete induction assessment. For measured plasma fu<0.01, use 0.01 unless reliability at the low fraction has been demonstrated.
Mechanistic static model and units
The CLI's ka is per minute and Qh=97 L/hour, so multiply ka by 60 before combining them.
Ih=fu*(Cmax+Fa*Fg*ka_hour*dose/(Qh*RB)); Ig=Fa*ka_hour*dose/Qen, Qen=18 L/hour.
These inlet/enterocyte values differ from basic luminal dose/0.25L.
Dose must use the same amount unit as concentration times liters (micromolar -> micromoles).
The model separates hepatic/gut reversible inhibition, inactivation and induction:
AUCR = 1/(Ag*Bg*Cg*(1-Fg)+Fg) / (Ah*Bh*Ch*fm + 1-fm)
Its full-inhibition ceiling is 1/((1-fm)*Fg), while 1/(1-fm) is hepatic only. Run inhibition
alone, induction alone and combined so cancellation cannot hide a signal. This implementation
uses shared illustrative kinetic inputs and fixed adult flows; it does not implement every M12
case, metabolite contribution, transporter-enzyme coupling or time-dependent dosing profile.
Escalate to qualified PBPK/clinical evaluation when the question needs those features.
QT concentration-response
The CLI regresses supplied placebo-corrected change from baseline QTc on concentration and reports a two-sided 90% CI at a specified exposure. Verify correction, units, timing, delayed effects, linearity, range coverage and influence. It assumes independent observations and is not the mixed model normally needed for repeated trial data. A nonzero intercept needs explanation, but is not an automatic model rejection rule.
The relevant E14 exclusion threshold is an upper confidence bound below 10 ms, in a study with adequate exposure/design and model assessment. A result meeting that threshold is not proof of no arrhythmia risk. Integrated nonclinical evidence has additional best-practice requirements. E14/S7B Q&A.