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Therapeutic drug monitoring (TDM)
Therapeutic drug monitoring of voriconazole
From Mr A. B. Sutherland, MRPharmS
I write in order to impart a cautionary tale to my hospital colleagues
surrounding the use of voriconazole. I see this product used increasingly
in day-to-day practice as fungal infections become more common and resistance
to existing azole antifungals becomes an increasing problem.
My cautionary tale starts with a young patient called “A”.
She presented with a deep invasive aspergillus mediastinitis after complex
heart surgery. She was immediately started on intravenous voriconazole
7mg/kg twice a day (in keeping with the summary of product characteristics)
which she tolerated well. Over the first weekend the microbiologist requested
that a plasma level be taken. This was diligently done and the level
returned a week later at 0.12mg/L. This was reported by our laboratory
as “subtherapeutic” with a caveat that these levels had not
been ratified by Pfizer. Action was swift, with medics increasing the
dose to 12mg/kg twice a day and another “trough level” was
sent a few days later. This time, the level was returned as “undetectable”.
Again, action was swift. The dose was increased further to 18mg/kg twice
a day.
Over the weekend of the second dose increase, while on call, I received
a request for information. “A” had become covered in a bright
red, erythematous, exfoliative rash that was getting worse. On physical
examination of the child, the rash appeared to be well demarcated to
those areas of the body that were exposed to light — head, chest,
upper arms, feet and face. On discussion with “A’s” parents,
they commented that they had noticed some change in skin pigmentation
over the course of the last few days, but that it had only started getting
exceptionally bad in the last 48 hours. On review of drug administration
using our electronic patient record and prescribing system, it was quite
clear that the changes in skin condition were temporally related to the
dose increases with voriconazole. A discussion with senior medical staff
resulted in the reduction of voriconazole dose to standard 7mg/kg, the
initiation of sunblock therapy, and a consensus that voriconazole levels
would no longer be reviewed.
The evidence for therapeutic drug monitoring of voriconazole is weak.
In our hospital, the rationale is based on Smith et al.1 They noted that
those with low plasma levels (<2mg/L) tended to have poorer outcomes
in terms of disease progression and fungal breakthrough. However, on
closer inspection of this paper, there are several flaws — only
28 of the worst performing patients from a total cohort of 188 were reviewed
and patients on voriconazole who were not deteriorating did not have
their plasma levels monitored.
There have been no large-scale controlled studies to examine the thresholds
for treatment failure or toxicity with voriconazole and there is massive
interpatient variability in plasma levels due to the non-linear nature
of clearance of voriconazole.2 There is also likely to be a pharmacogenetic
component to voriconazole clearance, although this is yet to be proven.3 Therapeutic drug monitoring of voriconazole is expensive and slow and
therefore it is a measure of efficacy that is essentially useless at
the present time.
I would urge all pharmacists in all clinical areas to bear this in mind,
and remind our medical colleagues that we are supposed to be treating
patients and not “numbers”.
Adam Sutherland
Clinical Pharmacist, Paediatric Intensive Care
Yorkhill Hospital, Glasgow
References
1. Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose
PG. Voriconazole therapeutic drug monitoring. Antimicrobial Agents and
Chemotherapy. 2006;50:1570–2.
2. Brown J and Freeman BB. Rethinking the use of voriconazole therapeutic
drug monitoring in allogeneic haematopoietic stem cell transplant recipients.
Bone Marrow Transplantation 2005;36:177.
3. Leveque D, Nivoix Y, Jehl F, Herbrecht R. Clinical pharmacokinetics
of voriconazole. International Journal of Antimicrobial Agents 2006;27:274–84. |
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