Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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204 Applying Pharmacogenomics in TherapeuticsTABLE 8.1 (Continued)FDA Product Labeling for CNS MedicationsDrug NamePharmacogeneticBiomarkerLabel InformationDesipramine CYP2D6 • PMs: Higher than expected plasma concentrations of TCAswhen given usual doses, the increase in plasmaconcentration may be small or quite large (eightfoldincrease in plasma AUC of the TCAs).Diazepam(rectal gelformulationonly, not theoral tablet)CYP2C19• Marked interindividual variability in the clearance ofdiazepam reported, likely attributable to variability ofCYP2C19.Doxepin CYP2D6 • PMs: 2D6 may have higher plasma levels than normalsubjects.Fluoxetine CYP2D6 • PMs: Metabolized S-fluoxetine at a slower rate andachieved higher concentrations of S-fluoxetine. Comparedto normal metabolizers, the total sum at steady state of theplasma concentrations of the 4 active enantiomers was notsignificantly greater among poor metabolizers. The netpharmacodynamic activities were essentially the same forPMs and normal metabolizers.Fluoxetine and CYP2D6 • Same as fluoxetine.olanzapinecombinationFluvoxamine CYP2D6 • In vivo study of fluvoxamine single-dose pharmacokineticsin 13 PMs demonstrated altered pharmacokinetic propertiescompared to 16 EMs: mean C max , AUC, and t ½ wereincreased by 52%, 200%, and 62%, respectivelyIloperidone CYP2D6 • PMs: Dose should be reduced by ½.• Observed mean elimination half-lives for iloperidone, P88,and P95 in EMs are 18, 26, and 23 h, respectively; and inPMs are 33, 37, and 31 h, respectively.Imipramine CYP2D6 • PMs: Higher than expected plasma concentrations of TCAswhen given usual doses. Depending on the fraction of drugmetabolized by CYP2D6, the increase in plasmaconcentration may be small, or quite large (eightfoldincrease in plasma AUC of the TCAs).Modafinil CYP2D6 • PMs: Levels of CYP2D6 substrates may be increased bycoadministration of modafinil.• Dose adjustments may be necessary for patients beingtreated with CYP2D6 substrates or inhibitors.Nortriptyline CYP2D6 • PMs: Higher than expected plasma concentrations of TCAswhen given usual doses. Depending on the fraction of drugmetabolized by CYP2D6, the increase in plasmaconcentration may be small or quite large (eightfoldincrease in plasma AUC of the TCAs).(Continued)
Pharmacogenomics of CNS Disorder Treatments205TABLE 8.1 (Continued)FDA Product Labeling for CNS MedicationsDrug NamePharmacogeneticBiomarkerLabel InformationParoxetine CYP2D6 • Only information about inhibition of CYP2D6.Perphenazine CYP2D6 • PMs: Will metabolize perphenazine more slowly andwill experience higher concentrations comparedwith EMs.Phenytoin HLA-B*1502 • Chinese ancestry: Strong association between the risk ofdeveloping SJS/TEN and the presence of HLA-B*1502 inpatients using carbamazepine.• Limited evidence suggests the polymorphism is also a riskfor the development of SJS/TEN in patients of Asianancestry taking other antiepileptic drugs associated withSJS/TEN, including phenytoin.• Phenytoin should be avoided as an alternative forcarbamazepine in patients positive for HLA-B*1502Pimozide CYP2D6 • PMs: Exhibit higher pimozide concentrations thanEMs. Time to achieve steady-state concentrationsis expected to be longer in PMs because of theprolonged t ½ . Alternate dosing strategies arerecommended in PMs.• Children: At doses >0.05 mg/kg/day, CYP2D6 genotypingshould be performed.• In PMs, doses should not exceed 0.05 mg/kg/day, and dosesshould not be increased earlier than 14 days. Adult dosing:doses above 4 mg/day, CYP2D6 genotyping should beperformed. In PMs, doses should not exceed 4 mg/day, anddoses should not be increased earlier than 14 days.Protriptyline CYP2D6 • PMs: Higher than expected plasma concentrations of TCAswhen given usual doses; the increase in plasmaconcentration may be small or quite large (eightfoldincrease in plasma AUC of the TCAs).Risperidone CYP2D6 • EMs: Convert risperidone rapidly to 9-hydroxyrisperidone,whereas PMs convert it much more slowly.• After single and multiple dose studies, thepharmacokinetics are similar in EMs and PMs.Tetrabenazine CYP2D6 • Doses above 50 mg should not be given without CYP2D6genotyping.• PMs: Will have substantially higher levels of the primarydrug metabolites than EMs.• PMs: Maximum recommended total daily dose is 50 mgand the maximum recommended single dose is 25 mg.• EMs: Maximum recommended total daily dose is100 mg and the maximum recommended singledose is 37.5 mg.(Continued)
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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1Concepts inPharmacogenomics andPer
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11 PharmacoeconogenomicsA Good Marr
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Pharmacoeconomics of Pharmacogenomi
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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