Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine

Abstract

Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent.

Use of Exposure Data to Establish Causality in Drug–Adverse Event Relationships: An Example with Desvenlafaxine

“…Desvenlafaxine pharmacokinetic parameters were consistent with the information available in the literature [ 14 ] and our previous work [ 13 ], where linear pharmacokinetics was observed. Here, healthy female volunteers presented a higher C max /DW; this association was also described in our previous work with the same clinical trials but fewer volunteers [ 13 ] and may be explained by sex-specific physiological differences in drug absorption [ 19 ].…”

“…Desvenlafaxine pharmacokinetic parameters were consistent with the information available in the literature [ 14 ] and our previous work [ 13 ], where linear pharmacokinetics was observed. Here, healthy female volunteers presented a higher C max /DW; this association was also described in our previous work with the same clinical trials but fewer volunteers [ 13 ] and may be explained by sex-specific physiological differences in drug absorption [ 19 ]. Fed healthy volunteers showed a higher AUC ∞ /DW and C max /DW compared to fasting healthy volunteers; this effect in C max is well described in previous studies [ 20 ], including ours [ 13 ], where only a tendency was observed for AUC ∞ /DW, consistent with the present study.…”

“…Here, healthy female volunteers presented a higher C max /DW; this association was also described in our previous work with the same clinical trials but fewer volunteers [ 13 ] and may be explained by sex-specific physiological differences in drug absorption [ 19 ]. Fed healthy volunteers showed a higher AUC ∞ /DW and C max /DW compared to fasting healthy volunteers; this effect in C max is well described in previous studies [ 20 ], including ours [ 13 ], where only a tendency was observed for AUC ∞ /DW, consistent with the present study. Overall, the use of DW correction seems to reduce pharmacokinetic variability and increase statistical power, allowing associations with feeding conditions and sex to be established in the multivariate analysis, whereas in other models where weight is a confounding factor, these associations are not observed.…”

“…This is an extension of a previous study [ 13 ], where the impact of genetic variation of desvenlafaxine exposure and safety was investigated. Although no genetic polymorphism was related to pharmacokinetic variability or ADR incidence, a clear exposure–safety relationship was observed.…”