K Number
K043576
Device Name
ROCHE AMPLICHIP CYP450 TEST
Date Cleared
2005-01-10

(14 days)

Product Code
Regulation Number
862.3360
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP Authorized
Intended Use
The AmpliChip CYP450 test is intended to identify a patient's CYP2C19 genotype from genomic DNA extracted from a whole blood sample. Information about CYP2C19 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics that are metabolized by the CYP2C19 gene product.
Device Description
The AmpliChip CYP450 Test is based on five major processes: PCR amplification of purified DNA: fragmentation and labeling of the amplified products; hybridization of the amplified products to a microarray and staining of the bound products; scanning of the microarray; and determination of the CYP450 genotype and predicted phenotype. The AmpliChip CYP450 Test is designed to identify specific nucleic acid sequences and query for the presence of known sequence polymorphisms through analysis of the pattern of hybridization to a series of probes that are specifically complementary either to wildtype or mutant sequences. Microarrays of oligonucleotide probes synthesized on a glass substrate are utilized for the analysis.
More Information

Not Found

No
The device description outlines a process based on PCR, hybridization to microarrays, scanning, and analysis of hybridization patterns to determine genotype. There is no mention of AI or ML algorithms being used for data analysis or interpretation. The performance studies focus on traditional metrics like specificity, agreement, and call rate, without referencing AI/ML-specific evaluation methods.

No.
The device is an in vitro diagnostic test that provides genetic information to aid clinicians in determining therapeutic strategy and treatment dose; it does not directly treat or diagnose a condition.

Yes

The device aids clinicians in determining therapeutic strategy and treatment dose by identifying a patient's CYP2C19 genotype, which is a diagnostic purpose.

No

The device description explicitly details hardware components and processes like PCR amplification, fragmentation, labeling, hybridization to a microarray, staining, and scanning. This indicates it is a system involving physical reagents and hardware, not solely software.

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

  • Intended Use: The intended use explicitly states that the test is "intended to identify a patient's CYP2C19 genotype from genomic DNA extracted from a whole blood sample." This involves examining a sample taken from the human body (whole blood) to provide information about a patient's health status (genotype).
  • Purpose: The information about the genotype is intended to be used "as an aid to clinicians in determining therapeutic strategy and treatment dose." This indicates the test is used for medical purposes related to diagnosis, treatment, or prevention of disease.
  • Sample Type: The test uses "genomic DNA extracted from a whole blood sample," which is a biological specimen taken from the human body.
  • Device Description: The description details the process of analyzing biological material (DNA) using techniques like PCR, hybridization to a microarray, and scanning to determine a genotype.

These characteristics align with the definition of an In Vitro Diagnostic device, which is used to examine specimens derived from the human body to provide information for the diagnosis, treatment, or prevention of disease.

N/A

Intended Use / Indications for Use

The AmpliChip CYP450 test is intended to identify a patient's CYP2C19 genotype from genomic DNA extracted from a whole blood sample. Information about CYP2C19 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics that are metabolized by the CYP2C19 gene product.

Product codes (comma separated list FDA assigned to the subject device)

NTI

Device Description

The AmpliChip CYP450 Test is based on five major processes: PCR amplification of purified DNA: fragmentation and labeling of the amplified products; hybridization of the amplified products to a microarray and staining of the bound products; scanning of the microarray; and determination of the CYP450 genotype and predicted phenotype.

The AmpliChip CYP450 Test is designed to identify specific nucleic acid sequences and query for the presence of known sequence polymorphisms through analysis of the pattern of hybridization to a series of probes that are specifically complementary either to wildtype or mutant sequences. Microarrays of oligonucleotide probes synthesized on a glass substrate are utilized for the analysis.

Mentions image processing

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Mentions AI, DNN, or ML

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Input Imaging Modality

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Anatomical Site

Not Found

Indicated Patient Age Range

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Intended User / Care Setting

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Description of the training set, sample size, data source, and annotation protocol

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Description of the test set, sample size, data source, and annotation protocol

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Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

6.1. Limit of Detection
The limit of detection of the AmpliChip CYP450 Test was determined by analysis of dilutions of two genomic DNA samples to 0.1, 1 and 2 ng DNA/mL. The concentration of the DNA samples was determined by use of a PicoGreen double stranded DNA Quantitation kit. The DNA samples were * 2/* 2 and * 1/* 1 for the CYP2C19 gene. The % positivity rate was determined from the number of correct genotype calls. The lowest level of genomic DNA at which a ≥ 95% positivity rate was obtained for correct detection of the CYP2C19 gene was 25 and 2.5 ng. (Sample sizes: 144 for each DNA amount of 50ng, 25ng, and 2.5ng).

6.2. Specificity
Specificity of the AmpliChip CYP450 Test was evaluated using genomic DNA samples at approximately 2 ng/mL. Results were recorded as correct genotype calls, or miscalls. Established methods including allele-specific PCR, PCR-RFLP, and DNA sequence analysis were used to establish the reference CYPC19 genotype for the samples. (Sample size: 270 samples containing one CYP2C19 allele with normal predicted enzymatic activity (*1 allele)). The specificity of the AmpliChip CYP450 Test for detection of wild-type samples was 100% for the CYP2C19 gene.

6.3. Genotype Detection
Method comparison studies were performed using bi-directional DNA sequencing as the comparator for the AmpliChip CYP450 test. DNA sequence analysis for genotype confirmation was performed for 123 samples with CYP2C19 genotype that had been previously analyzed by the AmpliChip CYP450 Test. One sample that was identified as CYP2C19 *2/*2 genotype by RFLP and by the AmpliChip CYP450 Test was shown by sequencing to be a CYP2C19 *2/*10 genotype. With this single miscall, the agreement between the AmpliChip CYP450 Test and sequencing for CYP2C19 alleles was 99.6%.
Genotype detection was evaluated using genomic DNA samples at approximately 50 ng/PCR. Additional samples were evaluated by established methods including allele-specific PCR and PCR-RFLP to determine the reference CYP2C19 genotype. The percent agreement for genotype detection of the AmpliChip CYP450 Test was calculated by determining the percentage of tested samples with the correct genotype assigned as compared to the total number of samples tested of that genotype. The overall genotype call rate and percent agreement for CYP2C19 were both 99.7% for all 399 tested samples.

6.3.1. Performance Compared to Other CYP450 Genotyping Methods
The sensitivity and specificity of the identification of the CYP2C19 alleles was determined as compared to PCR-RFLP and DNA sequencing. (Sample sizes: 276 for PCR-RFLP; 123 for DNA Sequencing and PCR-RFLP).

6.4. Whole System Failure
The robustness of the AmpliChip CYP450 Test was evaluated by testing 100 replicates of genomic DNA purified from a whole blood specimen using the QIAamp DNA Blood kit. There was one System Failure event where no result was obtained due to inability to scan the stained AmpliChip CYP450 Microarray resulting in a Whole System Failure rate of 1% with a 95% confidence interval from 94.55 - 99.97%. There was a 0% Whole System Failure rate due to the AmpliChip CYP450 Test amplification and detection reagents.

6.5. Cross Contamination
Potential carryover contamination was assessed with five runs of alternating two specimens of distinct genotype, along with the appropriate controls. No carryover contamination was observed; the appropriate CYP2C19 genotype was obtained for all specimens.

6.6. Reproducibility
To evaluate the reproducibility of the AmpliChip CYP450 Test a six-member panel was constructed from cell lines that represent all known 2C19 alleles. The Reproducibility Panel samples were tested at a concentration of 50 ng DNA/PCR. Testing was conducted at three sites; including two external sites and a laboratory at Roche Molecular Systems. The Reproducibility Panel was tested in triplicate for five runs by one operator at each of the three sites, using three lots of reagents. (Sample size: 809 results). Genotype calls for CYP2C19 were made for 807/809 (99.8%) samples. Two results did not provide a genotype call. There was one incorrect call for CYP2C19 *1/*1 (99.9% [806/807] correct).

6.7. Interference Studies
Ten random specimens of whole blood collected in EDTA, adjusted to a level approximating or exceeding 50 ng DNA/PCR were tested in the absence of, and with, elevated levels of one of three potential endogenous interfering substances (albumin, bilirubin or lipids). Results from this study demonstrated that elevated levels of lipids, bilirubin and albumin in specimens do not to interfere with the performance of the AmpliChip CYP450 Test.

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

  • Limit of Detection: ≥ 95% positivity rate for correct detection of the CYP2C19 gene.
  • Specificity: 100% for the CYP2C19 gene.
  • Genotype Detection: 99.6% agreement between AmpliChip CYP450 Test and sequencing for CYP2C19 alleles. Overall genotype call rate and percent agreement for CYP2C19 both 99.7% for all 399 tested samples.
  • Whole System Failure rate: 1% with a 95% confidence interval from 94.55 - 99.97%.
  • Cross Contamination: No carryover contamination observed.
  • Reproducibility: Genotype calls for CYP2C19 were made for 99.8% of samples (807/809). Correct call rate for CYP2C19 *1/*1 was 99.9% (806/807).

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

K042259

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

§ 862.3360 Drug metabolizing enzyme genotyping system.

(a)
Identification. A drug metabolizing enzyme genotyping system is a device intended for use in testing deoxyribonucleic acid (DNA) extracted from clinical samples to identify the presence or absence of human genotypic markers encoding a drug metabolizing enzyme. This device is used as an aid in determining treatment choice and individualizing treatment dose for therapeutics that are metabolized primarily by the specific enzyme about which the system provides genotypic information.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Drug Metabolizing Enzyme Genotyping Test System.” See § 862.1(d) for the availability of this guidance document.

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AmpliChip CYP450 Test Section 4: Summary 510(k) Summary Report

K043576

AmpliChip CYP450 Test for CYP2C19 510(k) Summary

1

TABLE OF CONTENTS

1.Device Name1
2.Identification of the Legally Marketed Device to Which Is Claimed Equivalence1
3.Description of the Device1
4.Intended Use of the Device1
5.Summary of the Technological Characteristics of the Device Compared to the
Predicate Device2
6.Performance Data from the Non-Clinical Studies2
6.1. Limit of Detection2
6.2. Specificity2
6.3. Genotype Detection3
6.3.1. Performance Compared to Other CYP450 Genotyping
Methods5
6.4. Whole System Failure5
6.5. Cross Contamination6
6.6. Reproducibility6
6.7. Interference Studies7
6.8. Conclusions7
7.Clinical Validity8
7.1. Geographic Distribution of Allele Frequencies9

List of Tables

Table 1: Limit of Detection for the CYPC19 Gene2
Table 2: Specificity for the CYPC19 Gene3
Table 3: Sequencing Concordance for CYP2C19 Alleles4
Table 4: Detection of CYP2C19 Alleles4
Table 5: Detection of Samples by CYP2C19 Genotype5
Table 6: Reference Method for CYP2C19 Allele Identification5

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Table 7: AmpliChip CYP450 Test Panel6
Table 8: Reproducibility Panel Results for CYPC19 Genotype7
Table 9: Clinically Relevant Drug Substrates for Metabolism by
CYP2C19 Enzymes8
Table 10: Geographic Differences in CYP2C19 Allelic Frequencies9

3

DEVICE NAME 1.

Trade or Proprietary Name: AmpliChip CYP450 Test

Common or Usual Name: Cytochrome P450 CYP2C19 Test

Classification Name: 21 CRF 862.3360 - Drug Metabolizing Enzyme Genotyping System

IDENTIFICATION OF THE LEGALLY MARKETED DEVICE TO WHICH IS 2. CLAIMED EQUIVALENCE

The AmpliChip CYP450 Test for CYP2C19 is equivalent to the AmpliChip CYP450 Test for CYP2D6 (510(k) Premarket Notification K042259, submitted August 20, 2004).

3. DESCRIPTION OF THE DEVICE

The AmpliChip CYP450 Test is based on five major processes: PCR amplification of purified DNA: fragmentation and labeling of the amplified products; hybridization of the amplified products to a microarray and staining of the bound products; scanning of the microarray; and determination of the CYP450 genotype and predicted phenotype.

The AmpliChip CYP450 Test is designed to identify specific nucleic acid sequences and query for the presence of known sequence polymorphisms through analysis of the pattern of hybridization to a series of probes that are specifically complementary either to wildtype or mutant sequences. Microarrays of oligonucleotide probes synthesized on a glass substrate are utilized for the analysis.

4. INTENDED USE OF THE DEVICE

The AmpliChip CYP450 test is intended to identify a patient's CYP2C19 genotype from genomic DNA extracted from a whole blood sample. Information about CYP2C19 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics that are metabolized by the CYP2C19 gene product.

4

SUMMARY OF THE TECHNOLOGICAL CHARACTERISTICS OF THE 5. DEVICE COMPARED TO THE PREDICATE DEVICE

The technological characteristics of the AmpliChip CYP450 Test for CYP2C19 are identical to those of the AmpliChip CYP450 Test for CYP2D6 (K042259).

6. PERFORMANCE DATA FROM THE NON-CLINICAL STUDIES

6.1. Limit of Detection

The limit of detection of the AmpliChip CYP450 Test was determined by analysis of dilutions of two genomic DNA samples to 0.1, 1 and 2 ng DNA/mL. The concentration of the DNA samples was determined by use of a PicoGreen double stranded DNA Quantitation kit. The DNA samples were * 2/* 2 and * 1/* 1 for the CYP2C19 gene. The % positivity rate was determined from the number of correct genotype calls. The lowest level of genomic DNA at which a ≥ 95% positivity rate was obtained for correct detection of the CYP2C19 gene was 25 and 2.5 ng.

| DNA Amount
(ng) | Number of
Arrays | Number of
Correct Calls | Positivity Rate | 95% Confidence
Limit |
|--------------------|---------------------|----------------------------|-----------------|-------------------------|
| 50 | 144 | 144 | 100% | 97.5 – 100% |
| 25 | 144 | 144 | 100% | 97.5 – 100% |
| 2.5 | 144 | 134 | 93.1% | 87.6 – 96.6% |

Table 1: Limit of Detection for the CYPC19 Gene

6.2. Specificity

Specificity of the AmpliChip CYP450 Test was evaluated using genomic DNA samples at approximately 2 ng/mL. Results were recorded as correct genotype calls, or miscalls. Established methods including allele-specific PCR, PCR-RFLP, and DNA sequence analysis were used to establish the reference CYPC19 genotype for the samples.

5

Two hundred seventy (270) samples containing one CYP2C19 allele with normal predicted enzymatic activity (*1 allele) were tested.

The specificity of the AmpliChip CYP450 Test was calculated by determining the percentage of tested wild-type samples with the correct wild-type genotype identified, as compared to the total number of wild-type samples tested. The specificity of the AmpliChip CYP450 Test for detection of wild-type samples was 100% for the CYP2C19 gene.

| CYP2C196 Genotype | Number of Samples
Tested | Number of
Correct Calls | Number of Miscalls |
|-------------------|-----------------------------|----------------------------|--------------------|
| *1/*1 | 270 | 270 | 0 |

Table 2: Specificity for the CYPC19 Gene

6.3. Genotype Detection

Method comparison studies were performed using bi-directional DNA sequencing as the comparator for the AmpliChip CYP450 test. DNA sequence analysis for genotype confirmation was performed for 123 samples with CYP2C19 genotype that had been previously analyzed by the AmpliChip CYP450 Test. One sample that was identified as CYP2C19 *2/*2 genotype by RFLP and by the AmpliChip CYP450 Test was shown by sequencing to be a CYP2C19 *2/*10 genotype. With this single miscall, the agreement between the AmpliChip CYP450 Test and sequencing for CYP2C19 alleles was 99.6%.

The results for each allele analyzed in this manner are presented below in Table 3 for CYP2C19 alleles.

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| CYP2C19
Allele | Number of
Alleles
Sequenced | AmpliChip Results | | | Percent
Agreement |
|-------------------|-----------------------------------|-------------------|----------|-------------|----------------------|
| | | Correct Calls | Miscalls | No
Calls | |
| *1 | 153 | 153 | 0 | 0 | 100.0% |
| *2 | 79 | 78 | 11 | 0 | 98.7% |
| *3 | 14 | 14 | 0 | 0 | 100.0% |
| Total | 246 | 245 | 0 | 0 | 99.6% |

Table 3: Sequencing Concordance for CYP2C19 Alleles

\ One sample, identified as CYP2C19 *2/*2 by RFLP and the AmpliChip CYP450 Test, was shown by sequencing to be a CYP2C19 *2/10 genotype.

Genotype detection was evaluated using genomic DNA samples at approximately 50 ng/PCR. In addition to the sequencing confirmation presented above, additional samples were evaluated by established methods including allele-specific PCR and PCR-RFLP in order to determine the reference CYP2C19 genotype for the samples. The percent agreement for genotype detection of the AmpliChip CYP450 Test was calculated by determining the percentage of tested samples with the correct genotype assigned as compared to the total number of samples tested of that genotype.

Genotype detection results for CYP2C19 were calculated for the individual alleles (Table 4) and by sample (Table 5). The overall genotype call rate and percent agreement for CYP2C19 were both 99.7% for all 399 tested samples.

| CYP2C19
Allele | Number of Unique
Alleles Tested | Number of
Correct Calls | Number of
Miscalls | Number of
No Calls | Percent
Agreement | Number of
Replicates |
|-------------------|------------------------------------|----------------------------|-----------------------|-----------------------|----------------------|-------------------------|
| *1 | 647 | 647 | 0 | 0 | 100% | 842 |
| *2 | 137 | 136 | 1 | 0 | 99.3% | 176 |
| *3 | 14 | 14 | 0 | 0 | 100% | 32 |
| Total | 796 | 796 | 0 | 0 | 99.9% | 1050 |

Table 4: Detection of CYP2C19 Alleles

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| CYP2C19
Genotype | Total Unique
Samples | Number of
Correct calls | Number of
Miscalls | Number of
No Calls | Percent
Agreement | Genotype
Call Rate |
|---------------------|-------------------------|----------------------------|-----------------------|-----------------------|----------------------|-----------------------|
| *1/*1 | 270 | 270 | 0 | 0 | 100.0% | 100.0% |
| *1/*2 | 101 | 101 | 0 | 0 | 100.0% | 100.0% |
| *1/*3 | 6 | 6 | 0 | 0 | 100.0% | 100.0% |
| *2/*2 | 15 | 14 | 11 | 0 | 93.3% | 93.3% |
| *2/*3 | 6 | 6 | 0 | 0 | 100.0% | 100.0% |
| *3/*3 | 1 | 1 | 0 | 0 | 100.0% | 100.0% |
| Total | 399 | 398 | 1 | 0 | 99.7% | 99.7% |

Table 5: Detection of Samples by CYP2C19 Genotype

4 One sample, shown by sequencing to be CYP2C19 2/ 10*, was miscalled as a CYP2C19 *2/*2 genotype.

Performance Compared to Other CYP450 Genotyping Methods 6.3.1.

The sensitivity and specificity of the identification of the CYP2C19 alleles was determined as compared to PCR-RFLP and DNA sequencing. The results are summarized in Table 6.

Table 6: Reference Method for CYP2C19 Allele Identification

| Method(s) | Number of
Samples Tested | Number of
Correct Calls | Number of
Miscalls | Number of
No Calls |
|-----------------------------|-----------------------------|----------------------------|-----------------------|-----------------------|
| PCR-RFLP | 276 | 276 | 0 | 0 |
| DNA Sequencing and PCR-RFLP | 123 | 122 | 1 | 0 |

6.4. Whole System Failure

The robustness of the AmpliChip CYP450 Test was evaluated by testing 100 replicates of genomic DNA purified from a whole blood specimen using the QIAamp DNA Blood kit. The test solution contained approximately 50 ng DNA/PCR of *1/*1 CYP2C19 genotype. There was one System Failure event where no result was obtained due to inability to scan the stained AmpliChip CYP450 Microarray resulting in a Whole System

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Failure rate of 1% with a 95% confidence interval from 94.55 - 99.97% due to the instrument or the AmpliChip CYP450 Microarray. There was a 0% Whole System Failure rate due to the AmpliChip CYP450 Test amplification and detection reagents.

Of the 100 valid replicates, one chip failed to scan the initial and subsequent attempts resulting in failure.

Cross Contamination 6.5.

Potential carryover contamination was assessed with five runs of alternating two specimens of distinct genotype, along with the appropriate controls. The position of the specimens plus controls was varied between the runs. No carryover contamination was observed; the appropriate CYP2C19 genotype was obtained for all specimens.

Reproducibility 6.6.

To evaluate the reproducibility of the AmpliChip CYP450 Test a six-member panel was constructed from cell lines that represent all known 2C19 alleles. The Reproducibility Panel samples were tested at a concentration of 50 ng DNA/PCR. The genotype and ' predicted phenotype (extensive metabolizer) of the Reproducibility Panel samples are provided in Table 7.

CYP2C19 GenotypePredicted Phenotype
*1 / *1Extensive
*1 / *2Extensive
*1 / *3Extensive
*1 / *1Extensive
*1 / *2Extensive
*1 / *2Extensive

Table 7: AmpliChip CYP450 Test Panel

Testing was conducted at three sites; including two external sites and a laboratory at Roche Molecular Systems. The Reproducibility Panel was tested in triplicate for five runs by one operator at each of the three sites, using three lots of reagents.

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The 809 results from this study are summarized in Table 8. Genotype calls for CYP2C19 were made for 807/809 (99.8%) samples. Two results did not provide a genotype call. There was one incorrect call for CYP2C19 *1/*1 (99.9% [806/807] correct).

| CYP2C19 genotype | Predicted
Phenotype | No.
Tested | Genotype
Calls
N (%) | Correct
Genotype
Calls | Correct Call
Rate Estimate
(95% CI) |
|------------------|------------------------|---------------|----------------------------|------------------------------|-------------------------------------------|
| *1 / *1 | Extensive | 134 | 134 (100.0) | 133 | 0.99 (0.97) |
| *1 / *2 | Extensive | 135 | 135 (100.0) | 135 | 1.00 (0.98) |
| *1 / *3 | Extensive | 135 | 135 (100.0) | 135 | 1.00 (0.98) |
| *1 / *1 | Extensive | 135 | 135 (100.0) | 135 | 1.00 (0.98) |
| *1 / *2 | Extensive | 135 | 134 (99.3) | 134 | 1.00 (0.98) |
| *1 / *2 | Extensive | 135 | 134 (99.3)) | 134 | 1.00 (0.98) |
| Total | | 809 | 807 (99.8) | 806 | 1.00 (0.99) |

Table 8: Reproducibility Panel Results for CYPC19 Genotype

Interference Studies 6.7.

Ten random specimens of whole blood collected in EDTA, adjusted to a level approximating or exceeding 50 ng DNA/PCR were tested in the absence of, and with, elevated levels of one of three potential endogenous interfering substances (albumin, bilirubin or lipids). The endogenous interfering substances were spiked into the specimens from concentrated stock solutions to at high-test levels as defined by the Clinical and Laboratory Standards Institute. These test levels were intended to reproduce the states of hyperalbuminemia, icterus and lipemia in native specimens. Results from this study demonstrated that elevated levels of lipids, bilirubin and albumin in specimens do not to interfere with the performance of the AmpliChip CYP450 Test.

6.8. Conclusions

The AmpliChip CYP450 Test accurately identifies the CYP2C19 genotype of clinical specimens using DNA purified from human blood.

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CLINICAL VALIDITY 7.

Individual differences in metabolic rates alter the expected relationship between the dose of a drug and its concentration in the blood or the length of time it stays in the blood. Therefore, a polymorphism in the CYP2C19 enzymes can lead to excessive or prolonged therapeutic effect or drug-related toxicity after administration of a "typical" dose by failing to clear a drug from the blood or by changing the pattern of metabolism to produce toxic metabolites. This is particularly true of drugs with a narrow therapeutic index. Adjustment of drug dosage could be beneficial based upon knowledge of these differences in metabolism, particularly for individuals possessing the poor metabolizer phenotype. Table 9 lists some clinically relevant drugs that are known substrates of CYP2C19 enzymes.

Table 9: Clinically Relevant Drug Substrates for Metabolism by CYP2C19 Enzymes

Proton Pump InhibitorsAnti-epilepticsOthers
OmeprazoleDiazepamAmitriptyline
LansoprazolePhenytoinClomipramine
PantoprazolePhenobarbitoneCyclophosphamide
Progesterone

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Geographic Distribution of Allele Frequencies 7.1.

The vast majority of poor CYP2C19 metabolizers are accounted for by the two common CYP2C192 and CYP2C193 alleles. Each of these null alleles is caused by a single nucleotide polymorphism that either causes a splice site defect or a stop codon. These two alleles are quite common among Asian populations where approximately 13-23% exhibit the poor metabolizer phenotype. The CYP2C19 poor metabolizer phenotype is present in about 3-5% of Caucasian and African-American populations.

AllelePredicted Enzymatic ActivityChineseBlackCaucasian
*1Normal
*2None30%17%15%
*3None5%acting
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Device Evaluation and Safety

510(k)K043576
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