CYP2B6 Clinical Interpretation Error - Missing Drug Recommendations

[davidyuyuan]

There are three documents of guidelines for CYP2B6.

1. Only CPIC guidelines on CYP2B6 and Efavirenz are used for the recommendations. https://files.cpicpgx.org/data/guideline/publication/efavirenz/2019/31006110.pdf
2. Dosing for Methadone included in Drugs output, but not included in the recommendations. https://files.cpicpgx.org/data/guideline/publication/methadone/2024/38863207.pdf
3. Additionally, recommendations for Serotonin Reuptake Inhibitor Antidepressants are not included on report. https://files.cpicpgx.org/data/guideline/publication/serotonin_reuptake_inhibitor_antidepressants/2023/37032427.pdf

The call to the CPIC database: https://api.cpicpgx.org/v1/rpc/recommendation_lookup?diplotypelookup={"CYP2B6": {"*1": 2}}&drugname=in.(bupropion,efavirenz,methadone,nevirapine,sertraline)&order=drugname only returns recommendations for one drug efavirenz.

recommendationid	6348668
lookupkey	
CYP2B6	"Normal Metabolizer"
drugname	"efavirenz"
guidelinename	"CYP2B6 and efavirenz"
guidelineurl	"https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/"
implications	
CYP2B6	"Normal efavirenz metabolism"
drugrecommendation	"Initiate efavirenz with standard dosing (600 mg/day)"
classification	"Strong"
phenotypes	
CYP2B6	"Normal Metabolizer"
activityscore	
CYP2B6	"n/a"
population	"child >40kg_adult"
comments	"The ENCORE study showed that in treatment-naïve patients randomized to initiate efavirenz-based regimens (combined with tenofovir and emtricitabine), 400 mg/day was non-inferior to 600 mg/day regardless of CYP2B6 genotype (PMID 24522178)."

The output of the REST call is confirmed with the 2 select statements below. There is recommendation for efavirenz but no data for methadone, or recomendations for other genes but not for CYP2B6 (e.g. citalopram for CYP2C19 only and vortioxetine for CYP2D6 only).

cpic_db=# select * from recommendation_view where drugname='methadone';
 recommendationid | lookupkey | drugname | guidelinename | guidelineurl | implications | drugrecommendation | classification | phenotypes | activityscore | population | comments 
------------------+-----------+----------+---------------+--------------+--------------+--------------------+----------------+------------+---------------+------------+----------
(0 rows)

cpic_db=# select * from recommendation_view where drugname='efavirenz';
recommendationid |               lookupkey                | drugname  |    guidelinename     |                                     guidelineurl                                      |                                                                                       implications                                                                                        |                           drugrecommendation                           |  classification   |               phenotypes               |   activityscore   |    population     |                                                                                                                                                                                                                                                                 comments                                                                                                                                                                                                                                                                  
------------------+----------------------------------------+-----------+----------------------+---------------------------------------------------------------------------------------+-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------+------------------------------------------------------------------------+-------------------+----------------------------------------+-------------------+-------------------+-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
          6110974 | {"CYP2B6": "Ultrarapid Metabolizer"}   | efavirenz | CYP2B6 and efavirenz | https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/ | {"CYP2B6": "Slightly lower dose-adjusted trough concentrations of efavirenz compared with normal metabolizers"}                                                                           | Initiate efavirenz with standard dosing (600 mg/day)                   | Strong            | {"CYP2B6": "Ultrarapid Metabolizer"}   | {"CYP2B6": "n/a"} | child >40kg_adult | n/a
          6110975 | {"CYP2B6": "Rapid Metabolizer"}        | efavirenz | CYP2B6 and efavirenz | https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/ | {"CYP2B6": "Slightly lower dose-adjusted trough concentrations of efavirenz compared with normal metabolizers"}                                                                           | Initiate efavirenz with standard dosing (600 mg/day)                   | Strong            | {"CYP2B6": "Rapid Metabolizer"}        | {"CYP2B6": "n/a"} | child >40kg_adult | n/a
          6110976 | {"CYP2B6": "Normal Metabolizer"}       | efavirenz | CYP2B6 and efavirenz | https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/ | {"CYP2B6": "Normal efavirenz metabolism"}                                                                                                                                                 | Initiate efavirenz with standard dosing (600 mg/day)                   | Strong            | {"CYP2B6": "Normal Metabolizer"}       | {"CYP2B6": "n/a"} | child >40kg_adult | The ENCORE study showed that in treatment-naïve patients randomized to initiate efavirenz-based regimens (combined with tenofovir and emtricitabine), 400 mg/day was non-inferior to 600 mg/day regardless of CYP2B6 genotype (PMID 24522178).
          6110977 | {"CYP2B6": "Intermediate Metabolizer"} | efavirenz | CYP2B6 and efavirenz | https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/ | {"CYP2B6": "Higher dose-adjusted trough concentrations of efavirenz compared with normal metabolizers; increased risk of CNS adverse events"}                                             | Consider initiating efavirenz with decreased dose of 400 mg/day        | Moderate          | {"CYP2B6": "Intermediate Metabolizer"} | {"CYP2B6": "n/a"} | child >40kg_adult | If therapeutic drug monitoring is available and a decreased efavirenz dose is prescribed, consider obtaining steady-state plasma efavirenz concentrations to ensure concentrations are in the suggested therapeutic range (~1 to 4 μg/mL). To prescribe efavirenz at a decreased dose of 400 mg/day or 200 mg/day in a multidrug regimen may require prescribing more than one pill once daily. If so, the provider should weigh the potential benefit of reduced dose against the potential detrimental impact of increased pill number.
          6110978 | {"CYP2B6": "Poor Metabolizer"}         | efavirenz | CYP2B6 and efavirenz | https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/ | {"CYP2B6": "Higher dose-adjusted trough concentrations of efavirenz compared with normal metabolizers; significantly increased risk of CNS adverse events and treatment discontinuation"} | Consider initiating efavirenz with decreased dose of 400 or 200 mg/day | Moderate          | {"CYP2B6": "Poor Metabolizer"}         | {"CYP2B6": "n/a"} | child >40kg_adult | If therapeutic drug monitoring is available and a decreased efavirenz dose is prescribed, consider obtaining steady-state plasma efavirenz concentrations to ensure concentrations are in the suggested therapeutic range (~1 to 4 μg/mL). To prescribe efavirenz at a decreased dose of 400 mg/day or 200 mg/day in a multidrug regimen may require prescribing more than one pill once daily. If so, the provider should weigh the potential benefit of reduced dose against the potential detrimental impact of increased pill number.
          6110979 | {"CYP2B6": "Indeterminate"}            | efavirenz | CYP2B6 and efavirenz | https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/ | {"CYP2B6": "n/a"}                                                                                                                                                                         | No recommendation                                                      | No Recommendation | {"CYP2B6": "Indeterminate"}            | {"CYP2B6": "n/a"} | child >40kg_adult | n/a
(6 rows)

[davidyuyuan]

FYI. The version of the local database version is v1.47.0.

[whaleyr]

Hi David,

Since you're got the DB running let's just do everything via SQL queries (the REST API is really just an abstraction of SQL queries).

Before you look at the data there's an important thing to understand about CPIC guidelines in general. Just because a gene-drug pair has been evaluated as part of a guideline, that does NOT mean it has a recommendation. In fact, there are many gene-drug pairs that are intentionally marked as "No Recommendation" by the guideline authors meaning they intentionally looked at that pair and are making no recommendation.

On to the data:

To get a definitive list of the guidelines that apply to a particular gene I recommend using the pair table or pair_view view. In this case, I would use the following query:

cpic=# select drugname, cpiclevel, guidelinename, usedforrecommendation from pair_view where genesymbol='CYP2B6' and provisional != true order by drugname;
  drugname  | cpiclevel |                                      guidelinename                                      | usedforrecommendation 
------------+-----------+-----------------------------------------------------------------------------------------+-----------------------
 efavirenz  | A         | CYP2B6 and efavirenz                                                                    | Yes
 methadone  | C         | CYP2B6 and methadone                                                                    | Yes
 sertraline | B         | CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants | Yes
(3 rows)

Important things to note:

1. filter out the "provisional" pairs (provisional != true) since those don't have guidelines yet (and, thus, no recommendations)
2. check the usedforrecommendations column to see if there should be recommendations available

For efavirenz, that looks as expected. It's a level A and marked as Yes for usedforrecommendation.

For methadone, you found a bug. That usedforrecommendation field should be marked as No. We will get that fixed in the next release. However, check the ClinPGx annotation of CYP2B6 and methadone and you can clearly see the authors issued no recommendations for that drug. Therefore, you will get no results in the recommendation table.

For sertraline, that one is a bit more complicated. You can see the previous query it's part of the SSRI guideline. That guideline actually uses two genes for recommendation lookup, not just CYP2B6. You can see this by querying the recommendation table to see which genes are used for the lookupkey:

cpic=# select distinct jsonb_object_keys(lookupkey) from recommendation_view where drugname='sertraline' order by 1;
 jsonb_object_keys 
-------------------
 CYP2B6
 CYP2C19
(2 rows)

The recommendation_lookup function in the db is not a very sophisticated function since it's a stored procedure in the DB. It will work for two-gene lookups but only if you have alleles specified. Your call didn't specify a diplotype for CYP2C19 so it doesn't come back with a match.

If you run:

cpic=# select recommendation_lookup('{"CYP2B6": {"*1": 2}, "CYP2C19": {"*1": 2}}');

You'll get back a bunch of results for recommendations on both CYP2B6 and CYP2C19, including sertraline. (I'm not posting the query result here because it's big, but you can run it yourself).

If you don't use recommendation_lookup as a shortcut and do the query using phenotypes then you get a recommendation lookup. That query would look like this:

cpic=# select * from recommendation_view where lookupkey <@ '{"CYP2B6": "Normal Metabolizer", "CYP2C19": "No Result"}';
 recommendationid |                        lookupkey                         |  drugname  |                                      guidelinename                                      |                                     guidelineurl                                      |                                       implications                                        |                  drugrecommendation                  | classification |                        phenotypes                        |            activityscore            |    population     |                                                                                                                    comments                                                                                                                    
------------------+----------------------------------------------------------+------------+-----------------------------------------------------------------------------------------+---------------------------------------------------------------------------------------+-------------------------------------------------------------------------------------------+------------------------------------------------------+----------------+----------------------------------------------------------+-------------------------------------+-------------------+------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
          6348668 | {"CYP2B6": "Normal Metabolizer"}                         | efavirenz  | CYP2B6 and efavirenz                                                                    | https://cpicpgx.org/guidelines/cpic-guideline-for-efavirenz-based-on-cyp2b6-genotype/ | {"CYP2B6": "Normal efavirenz metabolism"}                                                 | Initiate efavirenz with standard dosing (600 mg/day) | Strong         | {"CYP2B6": "Normal Metabolizer"}                         | {"CYP2B6": "n/a"}                   | child >40kg_adult | The ENCORE study showed that in treatment-naïve patients randomized to initiate efavirenz-based regimens (combined with tenofovir and emtricitabine), 400 mg/day was non-inferior to 600 mg/day regardless of CYP2B6 genotype (PMID 24522178).
          6349400 | {"CYP2B6": "Normal Metabolizer", "CYP2C19": "No Result"} | sertraline | CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants | https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/      | {"CYP2B6": "Normal metabolism of sertraline to less active compounds.", "CYP2C19": "n/a"} | Initiate therapy with recommended starting dose.     | Strong         | {"CYP2B6": "Normal Metabolizer", "CYP2C19": "No Result"} | {"CYP2B6": "n/a", "CYP2C19": "n/a"} | general           | CYPC19 metabolizer status, drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be also considered.
(2 rows)

If you want to do an SQL query for a recommendation lookup you must specify a value for all phenotypes used in the recommendation, even if that value is No Result which means I don't have any phenotype to specify for that gene.

In conclusion, I will fix that methadone pair data and recommendation lookup is tricky when you get into fine details. Also, know that not every gene-drug pair that's part of a guideline is guaranteed to have recommendations.

[davidyuyuan]

Thank you for the very detailed explanation. I think that I need to go through your comments to turely understand the schema and the design behine it.

[davidyuyuan]

I think that I understand the results of the recommendation lookup for efavirenz and methadone now. I also have a bug to fix in my code when listing gene-drug pairs.

If I understand correctly, I must include CYP2C19 when call the recommendation_lookup function or query the recommendation_view in order to get a recommendation for CYP2B6 alone for sertraline. It seems a workaround although I understand that the data in the current form is a strict 1:1 translation from the guideline. I was wondering whether it is sensible to add a lookup key {"CYP2B6": "Normal Metabolizer"} for sertraline. Perhaps, there are other similar cases for other genes and drugs. It's just a suggestion for your consideration.

[davidyuyuan]

As I commented in #49, the current design for recommendation_view works well. Please close this issue once the flag for methadone is updated.

Perhaps, you may want to eventually retire the recommendation_lookup function and remove the examples of the RPC calls: https://documenter.getpostman.com/view/1446428/Szt78VUJ?version=latest#a8b1caed-296c-4e8d-93ea-1e7e119ac998. They are too tempting. After addressing the same requirements in Python, I can understand why it is difficult to implement it as a function.