A population analysis on the effects of the CYP2D6 deficiency on pharmacokinetics and exposure of esmirtazapine in healthy volunteers.
O. Lillin-de Vries, T. Kerbusch, P-J. de Kam, N. Ivgy-May, R. Bursi
Organon, a part of Schering – Plough Corporation
Objectives: Esmirtazepine is a novel agent under development for insomnia. This is a pooled population analysis of the PK of esmirtazapine using data from three HV studies. The effect of CYP2D6 polymorphism was evaluated .
Methods: A 2-compartment 1st-order absorption model (NONMEM VI) was fitted to PK data of 17 postmenopausal women receiving SD and MD of esmirtazapine 1.5 mg, 7.5 mg and 18 mg (4-period cross-over), 78 adult HV (45 - 65 years) receiving 18 mg SD and 18 mg titrated up to 54 mg MD (parallel groups) and 20 adult HV receiving 4.5 mg SD esmirtazapine with or without paroxetine for inhibition of CYP2D6 (coded as genedose).
Results: 104 HV contributed to 2910 esmirtazapine samples. The dataset contained 24 poor metabolizers (PM, both alleles deficient by either genotype (4 subjects) or phenotype (20 subjects)), 34 intermediate metabolizers (IM, one allele deficient), 64 extensive metabolizers (EM, two working alleles) and 2 ultra-rapid metabolizers (UM, three working alleles). The data for all 4 genotypes were combined in a linear relationship. Oral clearance for male EM was 83.6 L/h, Vc was 59.2 L, Q was 72 L/h, Vp was 1150 L, Ka was 0.33 h-1 and lag time was 0.5 h. Of the covariates evaluated (CYP2D6, sex, age, body weight and study), CYP2D6 had a statistically significant influence on esmirtazapine PK. Oral CL increased with 13.7 L/h per functional CYP2D6 allele. The rel. bioF for PM and IM was estimated 22% higher than for EM and UM (fixed to 1). No significant difference could be detected between EM and UM, nor between IM and PM. The rel. bioF was characterized by modest IIV (Rel Std. Err. 22%). Model performance was adequate with a residual variability of 34.3 % and robust as indicated by bootstrapping.
Conclusions: A pooled population PK model successfully described the data of 3 phase 1 trials. CYP2D6 polymorphism (PM exposure 2-fold higher than EM) was identified as relevant covariate. This model provides a sound basis to explore the exposure-response relationship with efficacy data obtained in phase 3.
 J. Brockmöller et al, Clin. Pharm. And Therapeutics 81: 699-707 (2007)