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1.
Clin Ther ; 35(6): 782-94, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23623756

ABSTRACT

BACKGROUND: Many antidepressants are extensively metabolized in the liver, requiring dose adjustments in individuals with hepatic impairment. Clinical studies indicate that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine is metabolized primarily via glucuronidation, and ∼45% is eliminated unchanged in urine. OBJECTIVE: The objectives of this study were to assess the pharmacokinetic profile, safety, and tolerability of desvenlafaxine in adults with chronic Child-Pugh class A, B, and C hepatic impairment. METHODS: Subjects (aged 18-65 years) with mild (Child-Pugh class A, n = 8), moderate (Child-Pugh class B, n = 8), and severe (Child-Pugh class C, n = 8) hepatic impairment and 12 healthy matched subjects received a single 100-mg oral dose of desvenlafaxine. Disposition of (R)-, (S)-, and (R+S)-enantiomers of desvenlafaxine were examined in plasma and urine. Geometric least squares (GLS) mean ratios and 90% CIs for AUC, AUC0-τ, Cmax, and Cl/F were calculated; comparisons were made by using a 1-factor ANOVA. Safety was evaluated according to adverse events, physical examination, vital signs, and laboratory assessments. RESULTS: Healthy participants had a mean age of 51 years (range, 36-62 years) and weight of 79.1 kg (range, 52.5-105.0 kg); hepatically impaired participants had a mean age of 52 years (range, 31-65 years) and weight of 80.9 kg (range, 50.2-119.5 kg). In both groups, 67% of participants were male. No statistically significant differences (≥50%) in the disposition of desvenlafaxine were detected between hepatically impaired patients and healthy subjects based on GLS mean ratios for Cmax, AUC0-τ, AUC, or Cl/F (P > 0.05 for each comparison). Median Tmax was similar for all groups (range, 6-9 hours). A nonsignificant increase was observed for desvenlafaxine exposure in patients with moderate or severe hepatic impairment (GLS mean ratios [90% CIs] for AUC, 31% [93.2-184], 35% [96.5-190], respectively). The most common adverse events were nausea (n = 2, healthy subjects; n = 3, hepatically impaired subjects) and vomiting (n = 1, healthy subjects; n = 2, hepatically impaired subjects). CONCLUSIONS: A single 100-mg dose of desvenlafaxine was well tolerated in healthy subjects and hepatically impaired patients. A mild increase in exposure was observed for moderate and severe hepatically impaired subjects (Child-Pugh class B and C).


Subject(s)
Antidepressive Agents/administration & dosage , Cyclohexanols/administration & dosage , Liver Diseases/metabolism , Liver/drug effects , Neurotransmitter Uptake Inhibitors/administration & dosage , Adolescent , Adult , Aged , Antidepressive Agents/adverse effects , Antidepressive Agents/pharmacokinetics , Cyclohexanols/adverse effects , Cyclohexanols/pharmacokinetics , Desvenlafaxine Succinate , Female , Humans , Liver/metabolism , Male , Middle Aged , Neurotransmitter Uptake Inhibitors/adverse effects , Neurotransmitter Uptake Inhibitors/pharmacokinetics , Young Adult
2.
Int Clin Psychopharmacol ; 28(2): 99-105, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23221858

ABSTRACT

The results of two single-center, two-period, open-label trials that evaluated the effects of multiple doses of desvenlafaxine on the pharmacokinetics of desipramine, a cytochrome P450 (CYP) 2D6 enzyme substrate, are presented. Healthy individuals aged 18-45 years were administered a single oral dose of 50 mg desipramine with and without 100 mg daily (n=34) or 400 mg daily (n=23) desvenlafaxine for 5 days. After coadministration of 100 mg desvenlafaxine, desipramine exposure, measured by peak plasma concentration (C(max)) and total area under the plasma concentration-versus-time curve (AUC), showed minimal increases of 25 and 17%, respectively; coadministration of 400 mg desvenlafaxine resulted in a 52% increase in desipramine C(max) and a 90% increase in AUC. For the 100 mg dose, the geometric least squares mean ratios and 90% confidence intervals (CIs) for desipramine AUC (117%; 90% CI 110-125%), 2-hydroxydesipramine AUC (114%; 90% CI 110-119%), and C(max) (110%; 90% CI 104-116%) were all within the 80-125% interval, showing the bioequivalence for AUC between desipramine administered alone and in combination with 100 mg desvenlafaxine. These results indicate that desvenlafaxine is a relatively weak inhibitor of CYP2D6 and that desvenlafaxine 100 mg, twice the recommended therapeutic dose of 50 mg, is unlikely to cause drug-drug interactions with CYP2D6 substrates.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacokinetics , Antidepressive Agents/adverse effects , Cyclohexanols/adverse effects , Desipramine/pharmacokinetics , Neurotransmitter Uptake Inhibitors/adverse effects , Adolescent , Adult , Antidepressive Agents/administration & dosage , Antidepressive Agents, Tricyclic/adverse effects , Antidepressive Agents, Tricyclic/blood , Antidepressive Agents, Tricyclic/urine , Biological Availability , Cyclohexanols/administration & dosage , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Desipramine/adverse effects , Desipramine/analogs & derivatives , Desipramine/blood , Desipramine/urine , Desvenlafaxine Succinate , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Female , Half-Life , Humans , Male , Metabolic Clearance Rate , Metabolic Detoxication, Phase I , Middle Aged , Neurotransmitter Uptake Inhibitors/administration & dosage , Polymorphism, Genetic , Young Adult
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