PVmap™ of the Week
ProSanos has initiated a program to publicly provide a limited set of PVmaps™
generated from the FDA's Adverse Event database. A different map will be posted
each week focusing on a drug and adverse event combination that is a current topic
of discussion within the industry or in the published literature. For more
information about PVmaps
or the PVmap of the Week program, .
Anti-EGFR antibodies and Hypomagnesemia (5/28/07)
A column in Medscape Hematology-Oncology discusses a prospective study
which determined the extent of magnesium wasting during the treatment of
colorectal cancer with antibodies targeted to the epidermal growth factor
receptor (EGFR).47 EGFR receptor antibodies are important therapeutic
agents for a number of types of cancer. They are associated with low levels of
serum magnesium through a mechanism involving compromise of renal magnesium
retention. Hypomagnesemia is a listed on the label as a potential adverse event
for these drugs.
For our Map of the Week, we examined the publicly-available data from the FDA
Adverse Event Reporting System (AERS) using data covering the period from 2001
through the first quarter of 2006 to see whether this database reflects evidence
of the association between EGFR antibodies and hypomagnesemia (MedDRA preferred
term hypomagnesaemia). This week's map is an Event-focused PVmap where
we use the flexibility of PVmaps to reverse the usual paradigm and ask, "What
drugs are most highly associated with a particular adverse event?" rather
than the other way around. In this case, the adverse event is the MedDRA term
hypomagnesaemia.
The Event-focused PVmap for hypomagnesaemia (above) shows a
strong statistical relationship between this condition and cetuximab (marketed
as ERBITUX®), a commonly-used anti-EGFR antibody used in the US
during the time period when this data was collected. The map also points out
known relationships between hypomagnesemia and ribavirin (marketed as
VIRAZOLE®), as well as the chemotherapy agent cisplatin. Some of
the lower-ranked drugs may represent bystanders co-prescribed with the
higher-ranked ones. In an actual safety investigation rather than the illustration
shown here, additional maps, particularly Potential Interactions PVmaps and
Co-prescribed Medication PVmaps, would be used to further investigate these
potential relationships.
In this example, we have taken advantage of the fact that hypomagnesemia is a
relatively uncommon adverse event—or, more precisely, that it is uncommon to find
it singled out for reporting, rather than as a component of a more generalized
disorder of mineral homeostasis. This simplifies the task of pinpointing a
particular drug or drugs which may be associated with this adverse event.
In a talk at the 2007 Drug Information Association EuroMeeting, Dr. Simon Day
raised an important point regarding drugs that are products of biotechnology and
genomic/proteomic knowledge: As these drugs come out of the pipeline over the
next several years, we will be modulating biological pathways that have not been
altered heretofore. Off-target effects and effects in non-targeted tissues and
organs may result in unexpected and unusual adverse events associated with these
drugs. The case study shown here may be viewed as an example of this phenomenon.
When these unusual adverse events occur, the Event-focused PVmap may be a useful
tool for obtaining a statistical picture of the pharmaceutical products that are
involved.
Event-focused PVmaps
The first PVmap shown in the case study above is an Event-focused PVmap that
allows you to visualize which drugs are most highly associated with a particular
adverse event (rather than the other way around). In this case, the adverse
event is the MedDRA term hypomagnesaemia and the red dots represent
drugs reported in the AERS database to be associated with this condition. On the
horizontal axis of this graph is the reporting ratio, which compares the number
of times that a drug is reported with the specified adverse event to the number
expected due to chance alone. The vertical axis expresses the statistical
significance of the finding. Dots above the horizontal blue line and to the
right of the vertical blue line represent "significant signals". The
drugs with the strongest association with hypomagnesemia appear at the top and
to the right on the PVmap.
Sponsor companies have used ProSanos PVMaps for multiple therapeutic areas.
To learn more about PVMaps projects in your therapeutic area or indication,
please .
Disclaimers
- Potential risks highlighted by drug safety analysis must be balanced against
the clinical benefit attained by the use of a pharmaceutical product in a given
clinical situation. Nothing in these analyses is intended to influence the
practice of medicine, nor to weigh the benefits of one product over another.
- Whether the reporting ratio of an adverse event is high enough to influence the
decision to use a given product or products can only be determined by a complete
analysis of the benefits, risks, and therapeutic alternatives.
- Use of the publicly available FDA AERS data does not imply endorsement or
agreement of the findings by the FDA Center for Drug Evaluation and Research.
- There are many factors that can influence how the adverse events are reported
in the AERS database and may impact the resulting safety signal. These include but
are not limited to: publicity and media attention, litigation, length of time drug
is on the market, whether the event in question has been previously attributed
to the drug, the source of the report, etc.
- AERS data must often be "cleaned" prior to analysis. This process may include
de-duplication, reconciliation of misspelled product names, mapping of adverse
events terms, and other manipulations which could introduce bias into the analysis.
- PVmaps has been evaluated as a safety signal investigation tool for over two years.
References
- Tejpar S, Piessevaux H, Claes K, et al.
Magnesium wasting associated with epidermal-growth-factor receptor-targeting
antibodies in colorectal cancer: a prospective study. Lancet Oncol
2007;8:387-394.
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