Impact of polymorphisms in transporter and metabolizing enzyme genes on olanzapine pharmacokinetics and safety in healthy volunteers

Zubiaur, Pablo; Soria‐Chacartegui, Paula; Koller, Dóra; Navares‐Gómez, Marcos; Ochoa, Dolores; Almenara, Susana; Saiz‐Rodríguez, Miriam; Mejía‐Abril, Gina; Villapalos‐García, Gonzalo; Román, Manuel; Martı́n-Vı́lchez, Samuel; Abad‐Santos, Francisco

doi:10.1016/j.biopha.2020.111087

Cited by 16 publications

(24 citation statements)

References 32 publications

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“…A polygenic risk score model was proposed for CYP1A2 , which classifies individuals into PMs, NMs and UMs ( Saiz-Rodríguez et al, 2019 ). However, associations between this risk score model and pharmacokinetic parameters were not found in other candidate gene studies ( Koller et al, 2020 ; Zubiaur et al, 2021 ) ( Table 2 ). The rs2472297 polymorphism, located between the CYP1A1 and CYP1A2 genes, was associated with variations in olanzapine plasma concentration in a GWAS, explaining 2% of the variability ( Söderberg and Dahl, 2013 ).…”

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 76%

“…A study found significantly lower AUC in individuals *3/*3 for CYP3A5 ( Cabaleiro et al, 2013 ). A different candidate gene study did not find differences in olanzapine pharmacokinetics regarding CYP3A4/5 ( Zubiaur et al, 2021 ). Therefore, results are contradictory, and additional studies are needed to evaluate its impact on olanzapine metabolism ( Table 2 ).…”

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

“…These alleles allow the classification of individuals into different phenotypes: PM, IM, NM and UM. Although this cytochrome is involved in the metabolism of olanzapine, numerous candidate gene studies did not find associations between phenotypes and plasma concentration of olanzapine ( Nozawa et al, 2008 ; Söderberg and Dahl, 2013 ; Koller et al, 2020 ; Zubiaur et al, 2021 ). This is consistent with its secondary role on the metabolism of this drug ( Table 2 ).…”

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

“…Additionally, two candidate gene studies found a higher T 1/2 and Vd in CYP2C9 PM (*2/*3 and *3/*3 carriers) compared to IM and NM, and a higher incidence of adverse drug reactions in *3 carriers ( Cabaleiro et al, 2013 ; Zubiaur et al, 2021 ) ( Table 2 ).…”

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

“…In addition, one study observed that 1236T > C (rs1128503) T allele carriers were associated with a higher serum concentration of olanzapine ( Skogh et al, 2011 ). In a different candidate gene study, ABCB1 rs3842 CC individuals showed a greater olanzapine exposure ( Zubiaur et al, 2021 ). Other polymorphisms were related to a variation of olanzapine T 1/2 ( Koller et al, 2020 ) ( Table 2 ).…”

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

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Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

et al. 2021

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Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.

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Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 76%

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

Section: Pharmacogenetics Of Olanzapine Aripiprazole and Risperidonementioning

confidence: 99%

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Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

et al. 2021

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Second-generation antipsychotic use during pregnancy and risk of congenital malformations

Ellfolk

Leinonen

Gissler

et al. 2021

Eur J Clin Pharmacol

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Purpose To study if second-generation antipsychotic (S-GA) use during the first trimester of pregnancy is associated with an increased risk of major congenital malformations (MCM). Methods A population-based birth cohort study using national register data extracted from the Drugs and Pregnancy database in Finland, years 1996–2017. The sampling frame included 1,273,987 pregnant women. We included singleton pregnancies ending in live or stillbirth or termination of pregnancy due to severe malformation. Pregnancies with exposure to known teratogens were excluded. Women were categorized into three groups: exposed to S-GAs (n = 3478), exposed to first-generation antipsychotics (F-GAs) (n = 1030), and unexposed (no purchases of S-GAs or F-GAs during pregnancy, n = 22,540). We excluded genetic conditions and compared the prevalence of MCMs in S-GA users to the two comparison groups using multiple logistic regression models. Results Use of S-GAs during early pregnancy was not associated with an increased risk of overall MCMs compared to unexposed (adjusted odds ratio, OR 0.92; 95% CI 0.72–1.19) or to F-GA users (OR 0.82; 95% CI 0.56–1.20). Of individual S-GAs, olanzapine use was associated with an increased risk of overall MCMs (OR 2.12; 95% CI 1.19–3.76), and specifically, an increased risk of musculoskeletal malformations (OR 3.71; 95% CI 1.35–10.1) when compared to unexposed, while comparisons to F-GA users did not show significant results. Conclusions Olanzapine use is associated with an increased risk of major congenital malformations and specifically, musculoskeletal malformations. Use during pregnancy should be restricted to situations where no safer alternatives exist.

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Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam

Zubiaur

Figueiredo-Tor

Villapalos‐García

et al. 2022

Biomedicine & Pharmacotherapy

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Impact of polymorphisms in transporter and metabolizing enzyme genes on olanzapine pharmacokinetics and safety in healthy volunteers

Cited by 16 publications

References 32 publications

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

Second-generation antipsychotic use during pregnancy and risk of congenital malformations

Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam

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