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ddi-and-qt.md

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1# DDI screening and concentration-QTc
2

DDI screening and concentration-QTc

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3## ICH M12 basic models
4
5Use the current [M12 guideline](https://www.pmda.go.jp/files/000268574.pdf), with measured inputs,
6units and assay binding basis recorded. A positive screen calls for further evaluation; it is not a
7predicted clinical effect size. A negative screen does not exclude unmodeled mechanisms.
8
9| Mechanism | Quantity | Screening trigger |
10| --- | --- | --- |
11| Reversible CYP | `1+Cmax,u/Ki,u` | >=1.02 |
12| Oral gut CYP | `1+(dose/0.25L)/Ki,u` | >=11 |
13| Time-dependent inhibition | `1+(kinact*I/(KI,u+I))/kdeg`, I=5*Cmax,u | >=1.25 |
14| Kinetic induction | `1/(1+Emax*I/(EC50,u+I))`, I=10*Cmax,u | <=0.8 |
15| OAT1/3, OCT2 | `Cmax,u/IC50,u` | >=0.1 |
16| MATE1/2-K; systemic P-gp/BCRP | `Cmax,u/IC50,u` | >=0.02 |
17| Intestinal P-gp/BCRP, oral | `(dose/0.25L)/IC50` | >=10 |
18| OATP1B1/1B3 | `Iin,max,u/IC50,u` | >=0.1 |
20Induction also requires interpretation of the experimental mRNA concentration-response evidence;
21the kinetic formula alone is not a complete induction assessment. For measured plasma fu<0.01,
22use 0.01 unless reliability at the low fraction has been demonstrated.

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.

MechanismQuantityScreening trigger
Reversible CYP1+Cmax,u/Ki,u>=1.02
Oral gut CYP1+(dose/0.25L)/Ki,u>=11
Time-dependent inhibition1+(kinact*I/(KI,u+I))/kdeg, I=5*Cmax,u>=1.25
Kinetic induction1/(1+Emax*I/(EC50,u+I)), I=10*Cmax,u<=0.8
OAT1/3, OCT2Cmax,u/IC50,u>=0.1
MATE1/2-K; systemic P-gp/BCRPCmax,u/IC50,u>=0.02
Intestinal P-gp/BCRP, oral(dose/0.25L)/IC50>=10
OATP1B1/1B3Iin,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.

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24## Mechanistic static model and units
26The CLI's ka is per minute and Qh=97 L/hour, so multiply ka by 60 before combining them.
27`Ih=fu*(Cmax+Fa*Fg*ka_hour*dose/(Qh*RB))`; `Ig=Fa*ka_hour*dose/Qen`, Qen=18 L/hour.
28These inlet/enterocyte values differ from basic luminal `dose/0.25L`.
29Dose must use the same amount unit as concentration times liters (micromolar -> micromoles).
30The model separates hepatic/gut reversible inhibition, inactivation and induction:
32```
33AUCR = 1/(Ag*Bg*Cg*(1-Fg)+Fg) / (Ah*Bh*Ch*fm + 1-fm)
34```
36Its full-inhibition ceiling is `1/((1-fm)*Fg)`, while `1/(1-fm)` is hepatic only. Run inhibition
37alone, induction alone and combined so cancellation cannot hide a signal. This implementation
38uses shared illustrative kinetic inputs and fixed adult flows; it does not implement every M12
39case, metabolite contribution, transporter-enzyme coupling or time-dependent dosing profile.
40Escalate to qualified PBPK/clinical evaluation when the question needs those features.

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.

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42## QT concentration-response
44The CLI regresses supplied placebo-corrected change from baseline QTc on concentration and reports
45a two-sided 90% CI at a specified exposure. Verify correction, units, timing, delayed effects,
46linearity, range coverage and influence. It assumes independent observations and is not the mixed
47model normally needed for repeated trial data. A nonzero intercept needs explanation, but is not
48an automatic model rejection rule.
50The relevant E14 exclusion threshold is an upper confidence bound **below 10 ms**, in a study with
51adequate exposure/design and model assessment. A result meeting that threshold is not proof of no
52arrhythmia risk. Integrated nonclinical evidence has additional best-practice requirements.
53[E14/S7B Q&A](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e14-and-s7b-clinical-and-nonclinical-evaluation-qtqtc-interval-prolongation-and-proarrhythmic).

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.

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