Demonstration of Equation 1 and 3

Supplementary appendix 1

Demonstration of equation 1 and 3

The metabolic clearance of the substrate drug is assumed to be close to total clearance. Metabolism is assumed to occur in the gut wall (with gastrointestinal availability Fg) and in the liver (with hepatic availability Fh). The drug is metabolized by CYP2C19 and possibly by other pathways. Then, under the well-stirred clearance model, the oral clearance is:

(Eq. A1)

where fu is the unbound fraction of drug in the blood, and CLi the intrinsic clearance in the liver. In subjects with mutated CYP2C19 alleles, whose genotype is denoted XM (XM may be PM, IM or UM), the metabolism is altered and the oral clearance of the drug becomes:

(Eq. A2)

Therefore, the ratio of the drug AUCin subjects with XM genotype to the AUC in a wild type, extensive metabolizer individuals (EM)is as follows:

(Eq.A3)

Then, a simplification is made by assuming that the FgXM/FgEM is equal to one. This does not necessarily mean that CYP2C19-mediated metabolism is negligible, but rather that such metabolism is considered as part of hepatic metabolism and that it is altered in the same proportion than intrinsic clearance in XM subjects.

The intrinsic clearance in EM individuals may be written as the sum of two terms, the intrinsic clearance mediated by CYP2C19 plus the intrinsic clearance independent of CYP2C19, as follows:

(Eq.A4)

The intrinsic clearance in a CYP2D6-mutant individual is:

(Eq.A5)

In equations A4 and A5, CREM (contribution ratio) is the fraction of drug clearance due to CYP2C19 in extensive metabolizers, and FA (fractional activity) is the fraction of activity of CYP2C19 resulting from the combination of mutated alleles, with respect to the reference genotype (wild-type). FA is a positive number, lower than 1 in IMs and PMs, greater than 1 in UMs.

The ratio of AUCXMto AUCEM is then:

(Eq.A6)

When an inhibitor of CYP2C19 is co-administered, the intrinsic clearance of the drug in individuals with CYP2C19-mutant allelesis altered as follows:

(Eq.A7)

In equation A7, IR is the inhibition ratio of the inhibitor drug defined as:

(Eq.A8)

where I is the time-averaged apparent unbound concentration of the inhibitor in the liver, and Ki is the inhibition constant of the inhibitor. The range of IR values is [0, 1].

Finally, the ratio of AUCXM*to AUCXM is given by:

(Eq. A9)

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