Monitoring Recommendations for Anticonvulsants and Other Drugs Clinical Pharmacology Laboratory Auburn University Bromide is characterized by a half-life of approximately 21 days in dogs and 14 days in cats; variability among animals
is likely to be marked. Bromide is influenced by chloride intake (more chloride intake results in more rapid elimination). As such, during a 12 or 24 hr dosing interval, little drug is eliminated between doses and drug concentrations will accumulate. “Steady-state” should occur in 3 to 5 drug half-lives, or 2.5 to 3 months. Baseline steady-state concentrations can be determined only at that time. To pro-actively assess the appropriateness of your dose, we recommend that you check concentrations half-way to steady-state, that is, at one half-life (2 to 3 weeks). This concentration can be doubled to predict steady-state concentrations. A steady-state sample should be collected at 3 months to confirm baseline concentrations. If the patient is loaded, we suggest that a sample be collected the day after the loading dose is administered to determine “what was accomplished” with loading. Note that the patient is NOT at steady-state, and will not be at steady-state until it has been dosed with the same dose for 2.5 to 3 months. Thus, if the maintenance dose does not maintain what you accomplished with the loading dose, bromide concentrations will slowly decline (or increase, which is often not problematic) until steady-state is reached. The patient may start seizuring again at 3 to 4 weeks post load. Thus, a critical sample will be collected at 2 to 3 weeks to assure that the maintenance dose is “maintaining” what you achieved with loading. If you collect a 2-3 week sample without also collecting the post-load sample, we will not be able to tell you if concentrations are decreasing, as might occur if the maintenance dose is too low. A steady-state baseline should also be collected at 2.5 to 3 months. For routine monitoring, either a peak (2 hr) or trough (just before the next dose) is reasonable, although we suggest a trough sample to allow comparison across time. Remember that any time the dose is changed, you should monitor again at 2.5 to 3 months to establish a new baseline. You may also want to monitor at 2-3 weeks to make sure that the trend (increase or decrease) in response to your dose change is not too dramatic.
Levetiracetam (Keppra®) is characterized by a half-life of 2 to 4 hrs in dogs and 4 to 7 hrs in cats; variability among
animals is likely to be marked. As such, if the dosing interval is 8 hr most, if not all of each dose will be eliminated during a dosing interval in dogs and 50% to 75% of the dose will be eliminated in cats. “Steady-state” never truly occurs for levetiracetam in dogs (and may not in cats) because the drug does not accumulate with each dose. The therapeutic range recommended in dogs or cats currently is that recommended in a human that is 5 to 21 mcg/ml. As such, assuming a peak concentration of 21 mcg/ml is achieved, this means that two elimination half-lives can lapse before subtherapeutic concentrations are achieved: 21 to 10 mcg/ml for the first half-life, 10 to 5 mcg/ml for the second half-life. Assuming that this therapeutic range is appropriate for dogs or cats, we suggest that dosing regimens be designed to achieve the maximum therapeutic range of 21 mcg/ml and the interval be designed such that concentrations do not decline below 5 mcg/ml. We suggest both a peak and trough be collected as drug therapy is initiated thus allow us to calculate a half-life for your patient. For this first set of samples, the peak should be collected at about 2 hrs and the trough should be collected at about 6 to 8 hrs (to assure concentrations are still detectable). It is critical that the timing of sample collection be provided on the submission form. Once a half-life has been calculated for your patient, an appropriate dosing interval can be designed. Future monitoring can then consist of either a peak (2 hr) or trough (just before the next dose), as long as the same time is used for all subsequent monitoring (such that comparisons can be made across time). If only a single sample can be collected, we strongly encourage that the sample be a trough sample (if efficacy is a concern) such that the lowest concentration that occurs during a dosing interval can be measured. We do not suggest that the sample be collected at the same time during a dosing interval that the seizure occurred. A slow release levetiracetam (Keppra®) product is available for use in humans; our preliminary data suggests the half-life will be longer in dogs, allowing (potentially) a 12 to 24 hour dosing interval. However, monitoring both a peak and trough will be important to establishing the correct dosing interval in dogs or cats when using the slow release product.
Gabapentin is similar to Keppra® in terms of half-life and impact on dosing and steady-state. Accordingly, we suggest
using Keppra recommendations for sample collection. The therapeutic range in humans of 12 to 21 mcg/ml may or may not be relevant in animals. We are concerned the oral bioavailability of gabapentin is variable in dogs and accordingly recommend monitoring in animals receiving gabapentin for seizure control.
Phenobarbital is characterized by a half-life of approximately 54-72 hrs in dogs and similar in cats; variability among
animals is likely to be marked. We have measured a half-life as short as 12 hrs; for such patients, steady-state does not really occur. As such, during a 12 hr dosing interval, because little drug is eliminated between doses, drug concentrations will accumulated. “Steady-state” should occur in 3 to 5 drug half-lives, or 150 to 360 hrs (approximately 2 weeks). The therapeutic range recommended in animals is 15 to 40 mcg/ml, although we recommend that concentrations remain below 35 mcg/ml, and ideally, less than 25 mcg/ml to reduce the risk of hepatotoxicity. Baseline steady-state concentrations can be determined at 14 days. Because Phenobarbital can induce drug metabolism, we recommend another sample at 3 months, particularly for patients whose history includes severe seizures. For routine monitoring, either a peak (2 hr) or trough (just before the next dose) is reasonable, although we suggest a trough sample such that the lowest concentrations can be determined for the patient and so that concentrations can be compared across time. Also, in some patients, the half-life is short enough that trough concentrations are significantly lower than peak. Peak and trough samples are necessary only for animals in which a half-life less than 20 hrs is suspected such that a shorter dosing interval might be recommended. This might occur in a patient whose liver has been induced to more rapidly metabolize the drug. Remember that any time the dose is changed, you should monitor again at 2 to 4 weeks.
Zonisamide (Zonegran®) is characterized by a half-life of approximately 20-40 hrs in dogs (unknown in the cat)
variability among animals is likely to be marked. As such, during a 24 hr dosing interval, drug concentrations will decline by approximately 50%. We recommend, therefore, that a 12 hr dosing interval be implemented to avoid inappropriate fluctuation during the dosing interval. “Steady-state” should occur in 3 to 5 drug half-lives, or 60 to 100 hrs (3 to 5 days). However, we have commonly measured half-lives longer than 150 hrs, suggesting that drug metabolism in dogs might “saturate” (the drug is acetylated, which is an enzyme in which the dog is deficient). Baseline steady-state concentrations can be determined at 7 to 14 days. Steady-state will thus take longer than 10 to 14 days in those patients. The half-life is likely to be shorter in dogs simultaneously receiving Phenobarbital; up to a 30% decrease in half-life or drug concentrations may occur. However, this is not consistent. The therapeutic range recommended in animals is currently that recommended in humans, that is, 10 to 40 mcg/ml. Assuming that this therapeutic range is appropriate for dogs or cats, we suggest that doses be designed to achieve a “low” concentration of 15 to 20 mcg/ml as therapy is begun. We have measured (often) concentrations well above 60 mcg/ml or higher; dogs appear to tolerate this concentration well, although safety has not been confirmed. Thyroid gland suppression may be more likely at this concentration. Baseline thyroid function testing is recommended as you begin zonisamide and repeated as concentrations reach the maximum. For routine monitoring, either a peak (2 hr) or trough (just before the next dose) is reasonable, although we suggest a trough sample such that the lowest concentrations can be determined for the patient and so that concentrations can be compared across time. Peak and trough samples are necessary only for animals in which a half-life less than 20 hrs is suspected such that a shorter dosing interval might be recommended. However, for some patients, a peak and trough might be prudent to detect longer half-lives that might lead to marked drug accumulation. We are concerned that the oral bioavailability of zonisamide varies among the generic human products, meaning that one product may be absorbed differently than another product in the same dog. Accordingly, clients may want to ask the pharmacist to let them know when the pharmacy has changed the manufacturer of the generic product; monitoring might be implemented after the change has been made in the patient. CYLCLOSPORINE Monitoring for cyclosporine is complicated; further it is limited by the lack of studies which correlate concentration and immune suppression in animals. As such, avoiding toxicity and assuring concentrations should be the initial goal, with establishing the patient’s therapeutic range and assuring it is maintained as the second goal. Our laboratory offers the following recommendations for monitoring of patients receiving cyclosporine for induction of immune-mediated disease therapy (and as such, the patient is being treated every 12 hours). Assuming a “normal” half-life (for example, the patient is not receiving drugs that inhibit drug metabolizing enzymes), a 2 hr peak and 11 to 12 hr, (just before the next dose) trough sample is recommended within 3 to 5 days of initiating therapy; the more life threating the target disease, the more important a peak and trough sample may be. For less serious situations, or as treatment shifts from induction to maintenance, a singe 2 hr peak sample may be sufficient for establishing and maintaining a target. If therapy is initiated such that CsA disposition might change (whether intentional, such as the addition of ketoconazole, or inadvertent, such as co-treatment with diltiazem or azithromycin or others), a peak and trough sample prior to and 1 week after therapy is initiated is suggested such that a half-life can be calculated and the time to steady-state concentrations can be determined. 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. For chronic allergic – inflammatory diseases, recommendations vary from those for immune mediated diseases. Recommendations (again from human medicine, with the exception of perianal fistuale) are largely based on trough concentrations. For atopy in particular, no recommendations are available, and the role of monitoring, if any, might be to establish a therapeutic range in the patient and to assure that concentrations are sufficiently high that response can be expected. Concentrations are not likely to be detectable at trough when dosing at 48 hr intervals. Thus, a single peak concentration may be reasonable. 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. Target concentrations vary with the condition. For immune mediated disease or host versus graft rejection, dosing should occur at12 hr intervals. For our laboratory (using a monoclonal antibody based assay) , a peak concentration of 800 to 1400 ng/ml and a trough concentration of 400 to 600 ng/ml (monoclonal based assay) is recommended. The target peak concentration is easier to reach in a patient: Because of the short half-life of cyclosporine in most patients (e.g., 5 hr average), a trough target of 400 to 600 ng/ml will require peak concentrations of 1600 to 2400 ng/ml. In animals, there is not data supporting better response if target trough or peak concentrations are met but the more aggressive approach would be to target the trough concentrations. For renal transplantation, trough concentrations of 750 ng/ml are suggested for the first month (peak concentration of 2600 to 3000 ng/ml or more may be necessary, depending on half-life of cyclosporine in the patient) and 350 to 400 ng/ml, thereafter. For chronic allergic inflammatory disorders, lower trough concentrations are recommended: 250 ng/ml trough concentrations for chronic inflammatory bowel disorders, and for perianal fistulae, 12 hour trough concentrations at 100 to 600 ng/ml (the higher for induction, the lower for maintenance).
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Ark Pharm, Inc. MATERIAL SAFETY DATA SHEET 1. CHEMICAL PRODUCT AND COMPANY IDENTIFICATION MSDS Name: Tretinoin CAS Number: 302-79-4 Catalog Numbers: AK-73126 Company Identification: 2. COMPOSITION, INFORMATION ON INGREDIENTS Molecular Formula: Molecular Weight: Component Concentration CAS Number 3. HAZARDS IDENTIFICATIONEMERGENCY OVERVIEW 3.1 Cla