Details

Autor(en) / Beteiligte

• Zhang, Lusi
• Brown, Sarah Jane
• Shan, Yuting
• Lee, Adam M.
• Allen, Josiah D.
• Eum, Seenae
• Leon, Jose
• Bishop, Jeffrey R.

Titel

CYP2D6 Genetic Polymorphisms and Risperidone Pharmacokinetics: A Systematic Review and Meta‐analysis

Ist Teil von

• Pharmacotherapy, 2020-07, Vol.40 (7), p.632-647

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Background Risperidone is a second‐generation antipsychotic drug metabolized to an active metabolite, 9‐hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9‐hydroxyrisperidone exposure has not been clarified. Objective A systematic review and meta‐analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype–phenotype translation system. Methods A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9‐hydroxyrisperidone) was measured by dose‐adjusted steady‐state serum or plasma concentration or area under the concentration‐time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype–phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens. Results A total of 15 studies involving 2125 adult subjects were included in the meta‐analysis. Following multiple‐dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose‐adjusted steady‐state serum/plasma concentration was 2.35‐fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77–3.13, p<0.0001) and 6.20‐fold higher in poor metabolizers (95% CI 5.05–7.62, p<0.0001); the active moiety dose‐adjusted steady‐state concentration was 1.18‐fold higher in intermediate metabolizers (95% CI 1.11–1.25, p<0.0001) and 1.44‐fold higher in poor metabolizers (95% CI 1.23–1.69, p<0.0001). Higher area under the concentration‐time curve of risperidone and active moiety was also found in single‐dose studies. Conclusion Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9‐hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.