Interferon-beta treatment in patients with multiple sclerosis does not alter CYP2C19 or CYP2D6 activity

Abstract

Aims: To determine CYP2C19 and CYP2D6 activity in patients with multiple sclerosis (MS) before and during interferon (IFN)-beta treatment.

Methods: CYP2C19 and CYP2D6 activities were assessed using the probe drugs mephenytoin and debrisoquine, respectively. Urinary mephenytoin (S/R) and debrisoquine (debrisoquine/hydroxy-debrisoquine) metabolic ratios (MR) were determined in 10 otherwise healthy Caucasian multiple sclerosis (MS) patients in the initial stage of the disease, prior to and 1 month after commencing treatment with IFN-beta (Avonex, Rebif or Betaferon). In addition, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, and CYP2D6*5 genotyping was performed.

Results: There was no significant difference in the (S)/(R) mephenytoin ratio (mean difference 0.04; 95% CI -0.03, 0.11) or the debrisoquine MR (mean difference 0.29; 95% CI -0.44, 1.02) before and during regular IFN-beta treatment in extensive metabolizers (EM) (P = 0.5 and P = 0.4 for the respective probe drugs; n = 9 subjects). There were also no differences between the different IFN-beta treatments (P = 0.6 for the (S)/(R) mephenytoin ratio and P = 0.7 for the debrisoquine MR; anova; n = 10).

Conclusions: IFN-beta treatment did not affect the activity of CYP2C19 or CYP2D6. The results suggest that it is safe to administer CYP2C19 or CYP2D6 substrates, without dose adjustment, to patients treated with IFN-beta.

Figure 1

(S)/(R) mephenytoin ratio (upper panel) and debrisoquine metabolic ratio (MR) (lower panel) before and during administration of interferon (IFN)-β in patients with MS with two, one, or zero wild-type (wt) or mutated (mut) alleles, respectively. The different CYP2C19 and CYP2D6 genotypes are indicated as filled, semi or unfilled squares and refer to the CYP2C19*2 (upper panel) and the CYP2D6*3 or CYP2D6*4 (lower panel) mutations, respectively. The dotted lines indicate the antimodes of the two ratios. There was no significant difference in the (S)/(R) mephenytoin ratio (mean difference 0.04; 95% CI −0.03, 0.11) or the debrisoquine MR (0.29; 95% CI −0.44, 1.02) before and during regular IFN-β treatment in EM (P = 0.5 and P = 0.4 for the respective probe drugs; n = 9 subjects). There was a complete concordance between geno- and phenotype for both enzymes. Mut/mut (▪); wt/mut (); and wt/wt (□).