Page 5 - Levetiracetam (Keppra®)

The frequency of monitoring should vary with the disease being treated and patient response. We recommend
monitoring is recommended weekly to biweekly in critical patients, then monthly for the first several months of therapy
or until concentrations are stable. For long term maintenance, the frequency of sampling might range from 3 to 6 months.

In situations in which generic preparations are being used, because oral bioavailability of different generic
products may differ in the same dog initiated, proactive monitoring is recommended if one product is shifted to
another. In such cases, a single 2 hr peak concentration before and 3 to 5 days after the switch is recommended.

Leflunomide: Leflunomide is a prodrug. Its efficacy is based on conversion to an active metabolite, teriflunomide (A77
1726). The half-life of this metabolite in humans is greater than two weeks but in dogs, it approximates 24 hrs.

Therapeutic Range: In cats, Mehl et al (JVPT 2011) demonstrated ex vivo that a mean terifluonamide
concentration of 16 mcg/ml inhibited 50% lymphocyte activity. Further, van Roon et al (Ann Rheu Dis 2005)
demonstrated that human patients responded poorly to concentrations of the active metabolite if less than 16 mcg/ml. No
studies have been done in dogs. Accordingly, a concentration greater than 16 mcg/ml is a reasonble starting for
therapeutic response. Based on our assessment of responders versus no responders, all animals that responded did so at
concentrations between 5 and 45 mcg/ml.

When: Drug will accumulate 50% with a 24 hr dosing interval. Monitoring can occur within 5 to 7 days of a
new dosing regimen.

Sampling times: We currently recommend a single trough sample. The half-life is short enough in some
animals that a peak and trough may be indicated simply to detect the short half-life in problem patients. The 24 hr half-
life does suggest that the timing of sample collection be consistent if concentrations are going to be compared across time
in a patient.

Other considerations: Leflunomide appears to be a substrate for both p glycoprotein and cytochrome P450. As
such, drug interactions should be considered. We have measured concentrations higher than 140 mcg/ml in patients on
drugs which inhibit drug metabolizing enzymes or on drugs which also are substrates for p glycoprotein.

Mycophenolate: Mycophenolate is a prodrug; the active drug is mycophenolic acid (MPA). However, its aceyl
glucuromide metabolite also is active. After oral administration in people, MMF undergoes rapid absorption in the
gastrointestinal tract and conversion by liver, peripheral tissue, and plasma esterases into MPA. Plasma proteins bind 97%
of MPA. MPA is metabolized by the liver, with the major metabolite being to an inactive form 7-O-MPA glucuronide
(MPAG). However, , and the active the acyl glucuronide (AcMPAG) metabolite is active. In humans, the AcMAG
metabolite is equal to the parent in activity but only represented approximately 10% percent of the maximum drug
concentration or total area under the curve of bioactivity. The half-life of MPA is short in dogs and unknown in cats.

Testing: In human patients receiving mycophenolate, monitoring of MPA based on the emit immunoassay used
by this laboratory consistently measured up to 30% higher maximum drug concentrations but similar area under the curve
when compared to high performance liquid chromatography (Weber 2002). However, concentrations measured by Emit
have been demonstrated to correlate to response as well as an HPLC assay (Weber 2002). The assay available in this
laboratory is an FDA approved assay for detection of MPA in humans.

Sampling: This assay is not a standard test in our laboratory because of the cost of reagents. It can be added if
sufficient interest exist. Please call for pricing and sampling.

ANTIMICROBIALS

Theraepeutic range: Because target antibacterial concentrations generally are based on organism minimium inhibitory
concentrations, the therapeutic range will vary. For concentration dependent antibacterials such as the fluoroquinolones and
aminoglycosdies, peak concentrations should exceed 10X the infecting microbe MIC. Trough concentrations are unimportant from
an efficacy standpoint. From a toxicity standpoint, trough concentrations of the aminoglycosides should be < 2 mcg/ml. For time
dependent drugs (eg, vancomycin), drug concentrations should be above the infecting microbe MIC for most if not all of the
dosing interval. Half-life and thus both peak and trough are important. For antifungals, drug concentrations should be above the
MIC for most of the dosing interval. Because their half-life is generally long, a sample at any time, but preferably trough, is
recommended. Please call for further directions.