CYP2D6 genotype information to guide pimozide treatment in adult and pediatric patients: basis for the U.S. Food and Drug Administration's new dosing recommendations.
OBJECTIVE
The occurrence of pimozide-induced arrhythmias is concentration dependent. Hence, it is important for prescribers to consider causes of increased pimozide exposure. This article summarizes the U.S. Food and Drug Administration's (FDA's) review of drug interaction and pharmacogenomic studies and discusses pharmacokinetic simulations we performed to develop new cytochrome P450 2D6 (CYP2D6) genotype-guided dosing recommendations for pimozide.


METHODS
Pharmacokinetic parameters by CYP2D6 genotype were derived from a published single-dose pharmacogenomic study of pimozide. We simulated what pimozide exposures would result from a multiple-dose scenario in different CYP2D6 genotype groups: extensive, intermediate, and poor metabolizers. The maximum dose for poor metabolizers was defined as the dose that would not exceed pimozide concentrations following 10 mg daily in extensive metabolizers and intermediate metabolizers (the current maximum dose in an unselected population).


RESULTS
Dose-ranging analyses revealed that 4 mg daily in CYP2D6 poor metabolizers was the maximum dose that would not result in plasma concentrations in excess of those observed in extensive metabolizer and intermediate metabolizer patients receiving 10 mg daily. CYP2D6 genotyping is now consequently recommended in the pimozide product label before exceeding 4 mg of pimozide daily in adults or 0.05 mg/kg/d in children. Previously, dose adjustment was recommended every 3 days to achieve the desired clinical response for all patients. The label was modified to subsequently reflect that pimozide doses should not be increased earlier than 14 days in patients who are known CYP2D6 poor metabolizers.


CONCLUSIONS
Given the risk of increased pimozide concentrations and longer time to steady state in CYP2D6 poor metabolizers, the FDA has revised the pimozide label to provide clinicians with clearer dosing, titration, and genotype testing recommendations. The new information is intended to enhance therapeutic individualization of pimozide in pediatric and adult patients.
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, White Oak Bldg 51, Room 3175, Silver Spring, MD 20993, USA. Hobart.Rogers@fda.hhs.gov
Hobart L
HL
Rogers
Atul
A
Bhattaram
Issam
I
Zineh
Jogarao
J
Gobburu
Mitchell
M
Mathis
Thomas P
TP
Laughren
Michael
M
Pacanowski
D000328:Adult; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D018492:Dopamine Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004348:Drug Labeling; D016903:Drug Monitoring; D005820:Genetic Testing; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D010868:Pimozide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D017410:Practice Guidelines as Topic; D057285:Precision Medicine; D005879:Tourette Syndrome / Q000188:drug therapy* / Q000235:genetics*; D014481:United States
D018492:Dopamine Antagonists; D010868:Pimozide; D019389:Cytochrome P-450 CYP2D6