Pharmacogenetics of Drug : Part 3 Reginald F. Frye, Pharm.D., Ph.D. Professor, Department of Pharmacotherapy and Translational Research, UF College of Pharmacy [email protected]

Precision Medicine Conference Disclosure • I declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.

The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. CYP2 FAMILY CYP2C19 CYP2C Subfamily CYP2C19

Substrates (CPIC*) Inhibitors Inducers Clopidogrel (A) Fluvoxamine Rifampin Proton pump Fluconazole inhibitors (PPIs) SSRIs (A) PPIs CPIC Guideline TCAs (A) Voriconazole (A) CYP2C Gene Subfamily CYP2C19 • Most common allelic variants are – Loss‐of‐function • CYP2C19*2 • CYP2C19*3 – Gain‐of‐function • CYP2C19*17 CYP2C19 Phenotype Frequency (%)

South/ African East Phenotype Caucasian Central American Asian Asian Ultrarapid Metabolizer 4503 Rapid Metabolizer 24 27 2 16 Normal Metabolizer 36 39 36 23 Intermediate Metabolizer 32 27 47 46 Poor Metabolizer 4 3 15 12 CYP2C19 Genotype and Omeprazole Pharmacokinetics

Day 8 Pharmacokinetic Parameters Omeprazole EM IM PM AUC (nM*hr) 1130 ± 513 5984 ± 2305 14842 ± 3513

T1/2 (hr) 0.70 ± 0.15 1.31 ± 0.21 2.44 ± 0.35 Concentration CL (L/hr*kg) 0.81 ± 0.29 0.15 ± 0.04 0.06 ± 0.01

Time (hr) Cmax (µM) 0.68 ± 0.43 1.96 ± 0.73 3.54 ± 1.36

Chang et al., Br J Clin Pharmacol 39:511‐8, 1995 H. pylori Cure Rate Based on CYP2C19 Genotype Total cure rate = 52% (n=62) (n=9) 100 90 80

rate 70

(n=25) 60 cure

50

Percent 40 (n=28) 30 20 10 0 *1/*1 *1/*2 *2/*3 *1/*3 *2/*2 Omeprazole 20 mg/day for 6‐8 weeks Amoxicillin 2000 mg/day for 2 weeks T. Furuta et al., Ann. Int. Med., 129: 1027‐1030, 1998 CYP2C19 Genotype and Pantoprazole Pharmacokinetics h/L AUC, mg AUC,

*1 *2 7 / / *1 *1 *1/*2 *2 / *1/*17 *2/*17 *17

Eur J Clin Pharmacol. 2012 Sep;68(9):1267‐74. CYP2C19 Genotype and Voriconazole Pharmacokinetics

J Clin Pharmacol 2012;52:195‐203 Genotype Dependent Interaction Voriconazole and Ritonavir

Clin PharmacolTher. 2006 Aug;80(2):126‐35. CYP2C19 – Voriconazole

CPIC guideline recommends: • Alternative agent that is not dependent on CYP2C19 metabolism in adults who are CYP2C19 ultrarapid metabolizers, rapid metabolizers or poor metabolizers • Therapeutic drug monitoring is recommended to titrate dose to therapeutic trough concentrations CYP2 FAMILY CYP2D6 CYP2D6 Pharmacogenetics

• Polymorphic hydroxylation of debrisoquine was first reported over 40 years ago • CYP2D6 has a high degree of genetic variability with more than 100 allelic variants identified to date. • Multiple non‐functional alleles have been identified • Four alleles, CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D*6, are predominately responsible for the “poor metabolizer” phenotype • CYP2D6*4 is the most common variant CYP2D6 Pharmacogenetics

• Poor metabolizer phenotype: – homozygous for one particular loss‐of‐function allele (e.g., CYP2D6*4/*4) – heterozygous for different defective alleles (e.g., CYP2D6*4/*6), which is termed compound heterozygosity. • Up to 10% of the Caucasians are classified as “ultra‐rapid metabolizers,” which is associated with duplication of the CYP2D6 gene and greatly enhanced capacity for metabolism. Frequency of PMs and UMs in Different Populations PMs UMs Caucasians 8.0% 2‐8% Japanese 0.5% Chinese 0.7% African‐Americans 6.1% Ethiopians 1‐3% 29% CYP2D6

Substrates (CPIC*) Inhibitors Inducers Antidepressants (A) Cimetidine Codeine (A) Fluvoxamine Ondansetron (A) Quinidine Tamoxifen Tramadol (A) CPIC Guideline Relationship between CYP2D6 genetic status and nortriptyline pharmacokinetics

Dalen P. Clin PharmacolTher 1998:63:444‐52. CYP2D6 and Codeine 8/15/2012

http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm CYP2D6 and Codeine

PM

CYP2D6

Codeine Morphine CYP2D6 and Codeine

UM

CYP2D6

Codeine Morphine CYP2D6 and Codeine

EM

10 EM + Q

5

0 012 Pain Threshold (mA) Pain Threshold Time (hr)

Eur J Clin Pharmacol 41:23:26, 1991 CYP3A SUBFAMILY CYP3A Gene Subfamily Substrates Inhibitors Inducers CCBs Ketoconazole Rifampin Clarithromycin Ritonavir St. John’s wort Erythromycin Verapamil Midazolam Protease inhibitors CPIC Guideline Tacrolimus (A) CYP3A Gene Subfamily • Contains four – CYP3A4, CYP3A5, CYP3A7, and CYP3A43 – > than 80% cDNA • CYP3A – constitute 40% and 82% of the CYP content in human liver and intestine, respectively – are responsible for the metabolism of more than 50% of currently marketed drugs CYP3A4 Pharmacogenetics • Several allelic variants (>30) of CYP3A4 have been identified • NONE are loss‐of‐function alleles • Polymorphisms in coding region rare • The most common variant that appears to have a modest functional consequence is CYP3A4*1B, which is a ‐392A>G transition in the 5‐flanking region • CYP3A4*1B found mainly in Blacks CYP3A5 • Polymorphically expressed – 1/5 Caucasians but 3/4 African‐Americans – CYP3A5*3: splicing defect, truncated • If a CYP3A5*1 allele (functional) present, then CYP3A5 can be major contributor to CYP3A activity in liver & intestine – CYP3A5 can contribute to 50% of total CYP3A content CYP3A5 Expression CYP3A5 Pharmacogenetics

Transplantation. 2005 Feb 27;79(4):499-502. CYP3A5 Pharmacogenetics CYP3A5 Therapeutic Evidence phenotype recommendations Increase starting dose 1.5–2 Normal metabolizer times recommended Strong (CYP3A5 expresser) starting dose.

Intermediate Increase starting dose 1.5–2 metabolizer times recommended Strong (CYP3A5 expresser) starting dose.

Poor metabolizer Initiate therapy with (CYP3A5 standard recommended Strong nonexpresser) dose. Tacrolimus Pgx-TDM • CYP3A5 genotype informs starting dose • Subsequent maintenance doses adjusted according to therapeutic drug monitoring (TDM) and response

*1/*1 or 1.5‐2x *1/*3 Starting Dose TDM Yes Standard CYP3A5 *3/*3 Starting Dose TDM Genotype Standard No Starting Dose TDM END – PART 3