clinical perspective on pharmacogenetic labeling
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Clinical perspective on pharmacogenetic labeling. Some drugs have such a wide therapeutic range that individualizing the dose is not important. Predicated upon the assumption that getting the right dose of the drug for this disease is important.

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Presentation Transcript
slide2
Some drugs have such a wide therapeutic range that individualizing the dose is not important
slide3
Predicated upon the assumption that getting the right dose of the drug for this disease is important
  • Probability of response and/or adverse effects related to drug dosing
  • Titrating drug dose to response is not an optimal approach
    • Disease too serious to risk period of under-tx
    • Adverse effects too serious to risk them
    • Response or adverse effects are delayed or too difficult to monitor
phenotypes in all
Phenotypes in ALL
  • All: myelosuppression
  • VCR: peripheral neuropathy
  • Prednisone: avascular necrosis
  • MTX: Delayed neurotoxicity
  • Cyclophosphamide: sterility, obesity, growth
  • All: Cure vs relapse
  • Etoposide: 2nd tumors

onset

decision making
Decision-Making
  • What do I want to know?
  • How sure do I need to be?
  • What am I willing to assume?
what do i want to know
What do I want to know?
  • Do specific genetic polymorphisms influence the probability of response or adverse effects?
    • A general effect of genetics on drug response, without any target genes ID’d, unlikely to be of use for individual prescribing
what do i want to know1
What do I want to know?
  • How do polymorphisms affect drug response? (change absorption, metabolism, excretion, distribution, or pdy of the drug)
  • Tell me this info in the context of other info on factors that affect probability of response/adverse effects (e.g. if metabolism is subject to polymorphism plus other metabolized-drugs on board….)
what do i want to know2
What do I want to know?
  • Tell me what doses/routes were tested
    • Low doses/long exposures don’t saturate enzymes
    • Hepatic metabolism may be more relevant for oral or prolonged exposures (e.g. MTX, teniposide)
what am i willing to assume in vitro preclinical data can be helpful
What am I willing to assume? In vitro, preclinical data can be helpful….
  • Enzymes saturate: There will likely be competition, and thus possible saturation, if > 1 drug share the same gene products (e.g. low CYP3A activity might be more problematic in a pt taking > 1 CYP3A-substrate/drug than in a pt taking 1 CYP3A-substrate/drug---e.g. VCR, erythromycin, azole)
  • Effects of polymorphisms gleaned from one drug may have relevance for an independent drug that shares the same gene product (e.g. CYP2D6 PM status should be mentioned for ~all CYP2D6 substrates)
slide12
Dose recommendations in relation to P450 genotype

Drug Average PM EM UM Enzyme

dose (mg)

Propafenon 450 40% 130% CYP2D6

Amitriptyline 150 50 % 120% -”-

Tropisetron 10 30% 130% -”-

Nortriptyline 150 50% 140% 230% -”-

Metoprolol 100 30% 140% -”-

Lansoprazole 40 20% 110% CYP2C19

Omeprazole 40 20% 110% CYP2C19

S-Warfarin 3 20% 130% CYP2C9

Kirchheiner et al., Acta Psyciatr Scand 104: 173-192, 2001.

what do i want to know3
What do I want to know?
  • What is the frequency of the specific genotypes in the 3 largest ethnic/racial groups (whites, blacks, Asians)?
    • AA, homozygous common or wild-type
    • Aa, heterozygotes
    • aa, homozygous variant or defective
  • Could give allele frequencies, but most clinicians won’t be familiar with calculating genotypic frequencies
hardy weinberg
Hardy-Weinberg

P = frequency of wild-type allele(s)

Q = frequency of variant allele(s)

1 = p + q

P2 = frequency of wild-type genotype

Q2 = frequency of variant genotype

2pq = frequency of heterozygote genotype

what is the difference between phenotype and genotype
What is the difference between phenotype and genotype?
  • Phenotype is the bottom line, but phenotype can be influenced by concurrent drugs, diet etc
  • DNA is DNA is DNA (except for allogeneic BMT recipients and if source of DNA is tumor)
  • Genotype has to be studied only once (unless technology changes to capture more variants and pt was originally genotyped as < homoz. Variant)
  • Genotype more susceptible to false negatives than phenotype
genotyping tests 1
Genotyping Tests (1)
  • Multiple types of “variant” and “wild-type” alleles exist for every gene
  • False negatives: A genotyping test can’t reveal any information about areas of the gene not interrogated by the test (e.g. one can only know that the pt is “wild-type” at the loci tested)
  • Number of false negatives depends on proportion of inactivating variants accounted for by the tested variants (must be disclosed by the test)
genotyping tests 2
Genotyping Tests (2)
  • If a pt is “heterozygote” at > 1 polymorphic site in a gene, must understand whether those polymorphisms are allelic (and thus the pt is a likely “heterozygote”) or are likely on separate alleles (and thus the pts is homozygous variant)—but the genotyping test should disclose this
  • False positives: should not be a problem
some knowledge of genetics molecular biology helpful
Some knowledge of genetics/molecular biology helpful…
  • Heterozygote phenotypes are generally in between those of the 2 homozygote genotypes
  • Homozygous variant defined by presence of 2 different variant alleles in many cases
  • Gene duplications are possible and may “offset” a variant allele
slide19
Possible Drug Metabolism

Phenotypes and Genotypes

  • Conserved aa substitutions
  • Promoter/3´-5´SNPs

Frequency

  • Heterozygous deleterious SNPs
  • Unstable protein
  • Stop codons
  • Deletions
  • Missense SNPs
  • Splice defects
  • Gene duplication
  • Induction

Low Enzyme activity/ drug clearance High

is this too much to expect
Is this too much to expect?
  • To monitor effects of imatinib, we need to follow t(9;22)
    • Can be assessed by cytogenetics or FISH or RT-PCR
  • Presence of G6PD deficiency predisposes to MetHB for several drugs;
    • Activity affected by concurrent drugs, hematocrit
  • Hepatic dosing using Child-Pugh scores
  • Cardiac output vs CVP for pressors
what do i want to know4
What do I want to know?
  • Phenotype:
    • in general how the test is done (with a blood sample, name of the test)
    • direction (e.g. low activity is associated with the variant allele and with greater risk of adverse effects)
    • what interferes with test
  • Genotype:
    • estimate of the number of inactivating variants
    • their approximate frequencies
    • proportion of phenotype accounted for by the genotypes (e.g. the *5, *19, and *22 inactive/variant alleles account for 85%, 92%, and 90% of low-activity alleles among whites, blacks, and Asians)
what do i want to know5
What do I want to know?
  • Negative results can be helpful (e.g. this drug is not a substrate for the genetically regulated CYP2D6 or CYP2C19 enzymes)
how sure do i need to be give me some real data
How sure do I need to be? Give me some real data….
  • Avg/s.d. (median +/- CI) dose in AA vs Aa vs aa pts = 30, 50, and 80 mg/m2
  • 50% (95% CI) of pts with vs 10% (95% CI) of pts without toxicity (e.g. QT widening) were AA vs Aa/aa pts
  • Given a dose of 50 mg, 10%, 30%, and 80% (95% CI) of AA, Aa, and aa pts displayed evidence of response/toxicity
slide24
Greater oral mucositis index (OMI) after low-dose MTX among BMT patients with mutant MTHFR C677T genotypes than among patients with C677C genotypes

50%

40%

10%

Ulrich et al Blood 98:231-4, 2001

slide25
Effect of the CYP2C9 genotype on the daily dose of warfarin to achieve target INR

Warfarin, mg/day

wt/mut

wt/wt

wt/var

var/var

Wadelius et al., 2002

cure rates for h pylori infections may depend upon cyp2c19 genotypes
Cure rates for H. pylori infections may depend upon CYP2C19 genotypes
  • 62 pts with duodenal or gastric ulcer
  • treated with omeprazole 20 mg and amoxicillin
  • 20% of Asian and 4% of whites are homo. variant

N = 28 25 9

Ann Intern Med 1998;129:1027-30

slide27
Polymorphism in TPMT leads to 3 distinct phenotypes,

Who differ in their 6MP dosage requirements

Evans et al, SJCRH, 2000

labeling
Labeling
  • Description
  • Clinical Pharmacology
  • Indications and Usage
  • Contraindications
  • Warnings
  • Precautions (general, info for pts, lab tests, drug interxs, carcinogenesis, pregnancy, nursing mothers, pediatrics)
  • Adverse reactions
  • Overdosage
  • Dosage and administration (general, renal, hepatic)
  • How supplied
  • References
labeling include cross references among sections
Labeling: include cross references among sections
  • Clinical Pharmacology: include mechanism of how polymorphism affects the drug and some references
  • Warnings: if indicated
  • Precautions: include lab test information
  • Adverse reactions: include frequency among different genotypes
  • Overdosage: mention if genetics likely to affect
  • Dosage and administration (general, renal, hepatic, and genetic)
terminology
Terminology
  • Use colloquial terms where relevant (EMs, PMs, ultra-rapid, fast, slow, etc)
  • Avoid “mutant” (prefer variant or defective)
  • Avoid “normal” (prefer wild-type or common or descriptive, e.g. high-activity allele)
  • Map HUGO nomenclature-designations to “wild-type/common” or “variant/defective” in the label
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