TDM: basic pharmacokinetics for dosage adjustments (Proceedings)

Therapeutic drug monitoring (TDM) provides insight on the internal exposure of drug available to reach the site of action. Since therapeutic success for most drugs depends on achieving plasma concentrations (Cp) known to be safe and efficacious, TDM helps minimize the time that elapses before corrective measures can be implemented. Knowledge of basic pharmacokinetic (PK) principles can be applied to the interpretation of clinical drug concentration measurements of the individual patient. Drug disposition may be altered by physiological, pathological and/or pharmacological factors. Being able to assess the effect of disease states on PK parameters through TDM is particularly important in properly adjusting dosages for the unhealthy patient.

Not all drugs require TDM. Drugs with serious toxicity coupled with poorly defined or difficult to detect clinical end points, steep dose-response curves for which a small increase in dose may result in a marked increase in desired or undesired response, and drugs recognized has having a narrow therapeutic ratio are good candidates for TDM. Drugs that exhibit complex PK such as marked interindividual PK variability, nonlinear PK that may lead to rapid accumulation of drug to toxic concentrations and drugs that are prone to toxicity/decrease efficacy due to potential drug interactions are also examples of the types of drug for which therapeutic management benefit from the use of TDM. Finally, TDM is also helpful in cases when drug interactions are suspected or when the cost justifies confirmation of effective Cp in order to minimize dose and duration of therapy with an expensive drug.

For drugs for which TDM is available, a therapeutic range of Cp is clinically established in human patients in order to achieve the desired effect while avoiding toxicity. These therapeutic ranges are generally "borrowed" for the interpretation of Cp measurements in veterinary patients. It is important to keep in mind however that most of these therapeutic ranges have not yet been confirmed in cats and dogs, and that dosage regimens should be tailored to the individual patient.

Objectives

1. Provide the practitioner with a list of situations and drugs for which TDM is recommended and available.

2. Provide the practitioner with an understanding of how some physiological, pathological and pharmacological factors may affect drug disposition and how TDM can be helpful.

3. Provide the practitioner with simple pharmacokinetic tools to make individualized dosage adjustments for their patients, according to TDM results.

4. Provide the practitioner with simple tools to make pro-active changes in the dosage regimen for drugs with long half-lives, according to TDM results.

Important factors required for TDM

1. Patient response must correlate with Cp of drug.

2. An effective therapeutic range must be identified for the drug, in the species and the disease for which it is intended to treat, keeping in mind that in general therapeutic ranges established for cats and dogs are extrapolated from human studies and have not been confirmed in these species.

3. Analytical methods must be available to rapidly and accurately detect the Cp in the blood of the particular species being tested.

4. Finally, TDM must be available at a reasonable cost.

Situations for which TDM is useful

1. To identify owner non compliance as a cause of therapeutic failure or toxicity.

2. When an expected therapeutic effect has not been observed.

3. When a high Cp is suspected to be the cause of drug toxicity.

4. To establish therapeutic Cp when dose response is difficult to detect.

5. When a trial and error adjustment in dose is considered unacceptable in cases of life-threatening diseases.

6. When chronic administration is anticipated to establish baseline Cp and monitor PK changes overtime.

Drugs for which TDM is available

1. Anticonvulsants (PB, primidone, KBr, selected benzodiazepines, zonisamide)

2. Aminoglycosides (gentamicin, amikacin)

3. Cardiac drugs (digoxin, procainamide, lidocaine, quinidine)

4. Respiratory drug (theophylline)

5. Immunomodulating drug (cyclosporine)

6. Endocrine drug (levothyroxine)

Important information needed for a successful TDM

1. Important information needed for the interpretation of TDM results include: dose and frequency of administration, start of treatment or change in dose, time of sampling (trough, peak), patient's physiological characteristics (species, age, breed, weight), patient's clinical status (current and past disease, dehydration, results of diagnostic tests), reason for TDM (unresponsive to treatment, suspicion of toxicity or routine check).

2. Steady-state (SS) is required for most drugs in order to interpret Cp results at maximal response. Steady-state is reached in 5-6 half lives for all drugs.

3. In most cases of routine monitoring, a single sample of blood collected just before the next dose (trough) is sufficient.

4. A peak sample can also be collected in situations when toxicity is suspected, however, the peak is harder to predict as it depends on the rate and extent of absorption of the drug in the individual patient.

5. Two-sample collection (trough and peak) collected during a single dosing interval is recommended in situations where drugs have a short half life (peak and trough very different within a dosing interval) and the patient is unresponsive to treatment, drugs have a narrow therapeutic ratio or when there is a change in the PK of the drug during treatment (potential hepatic induction, drug interaction or in response to treatment).

Table 1. Therapeutic Drug Monitoring Data for Dogs

6. Basic useful TDM information for various drugs as shown in Tables 1 and 2 below is available from many reference books (Tables adapted from Boothe, 2001).

Table 2. Therapeutic Drug Monitoring Data for Cats

Basic PK tools for the adjustment of a maintenance dose

1. Most maintenance dosage adjustments do not need PK calculations. Simple dosage adjustments can be made according to the following formulas:

     • For dose: New dose = Current dose x target Cp/measured Cp

     • For interval: New interval = Current interval x measured Cp/target Cp

2. According to a simple PK principle, the Cp measured for all drugs is at 50% of the anticipated SS Cp after one half-life, at 75% of the anticipated SS Cp after two half-lives and 87.5% after three half-lives. Knowing this, it is then possible to make pro-active dosage adjustments before SS Cp is reached, especially for drugs that have long half-lives (e.g. KBr).

3. Modification of the dosage regimen according to PK calculations can also be done by measuring the peak and trough Cp of the drug once SS has been reached. Dosage adjustment according to the drug half-life of the patient is then individualized (e.g. in cases of hepatic induction with the administration of PB).

4. Important PK formulas for the measurement of half-life are:

   •  • Elimination rate constant: kel = ln(peak Cp/trough Cp)/(ttrough-tpeak)

   •  • Drug elimination half-life: t½ = 0.693/kel

Basic PK tools for the calculation of a loading dose

1. A loading dose can be administered to rapidly achieve the therapeutic range of a safe drug that has a long half-life and requires that SS Cp be achieved rapidly.

2. As a loading dose may increase the risk of adverse effects, it is not recommended for drugs with a narrow therapeutic range or one that tends to be associated with serious side effects (e.g. digoxin).

3. See Table 3 for establishing both a loading and maintenance dose for KBr in dogs.

Table 3. Establishing a loading dose for KBr

Not so basic (but still easy to use) PK tools for TDM

1. Maximum time between doses (Max Time): the constant of elimination (kel) and the knowledge of the Cmax (peak) and Cmin (trough) can be used to determine the Max Time that can elapse between doses after which the Cp may fall below the recommended effective concentration i.e. Max Time = ln(Cmax/Cmin)/kel.

2. For intravenously administered drugs, the volume of distribution (Vd) (obtained from literature) can be used to calculate the amount of drug that must be administered to achieve Cmax (target maximum effective Cp at SS) for the calculation of a loading dose (DL) i.e. DL = Vd x target Cmax at SS.

3. The Vd can also be used to calculate the amount of drug necessary to replace the drug eliminated during the dosing interval (DM,max) i.e.

   •  • DM,max = Vd x (peak Cp – trough Cp)

   •  • Dose each interval: DM,max x Interval/ Max Time

4. For drugs with a long half-life, it is also possible to predict the peak and trough Cp at SS by multiplying the measured peak and trough of the first dose by the accumulation ratio (AR) based on half-life of the drug (from literature or calculated for the individual patient) and dosage interval i.e. AR = 1/(1-eT/ t½) where T = dosing interval. Hence, a drug whose half-life is equal to its dosing interval will have an AR of 2 i.e. at SS, anticipated Cp will be double the Cp measured after the first dose.

Additional details

• Several factors may alter drug disposition such as physiological (e.g. age, weight, species), pathological (e.g. liver, kidney or cardiac disease, dehydration, hypoalbuminemia) and pharmacological factors (e.g. drug interactions). Individualized adjustments can be made in accordance to TDM results.

• For drugs whose elimination depends on renal function and whose clearance is known to be decreased in renal disease (e.g. aminoglycosides, digoxin), dosing regimen can be appropriately changed (decrease dose or increase interval) to minimize adverse effects using the following formulas: New dose = current dose x normal Cr/ patient Cr and New interval = current interval x patient Cr/ normal Cr.

• Obesity may decrease the SS Cp of phenobarbital since it is a lipid soluble drug and tends to accumulate in adipose tissue as a reservoir.

• If a patient is obese, drugs that do not readily penetrate fat (e.g. digoxin) should have their dose calculated according to lean body mass.

• For aminoglycosides, use plastic containers to ship blood as glass binds the drug.

• For digoxin, red stoppers will bind the drug (do not store in monoject tubes), use glass containers only to ship blood.

• For cyclosporine, use whole blood in EDTA tube, keep cool and ship with icepack. Because of metabolites, in general, the assay often overestimates the true cyclosporine Cp, hence, a correction must be made for dogs (measured Cp x 0.7) and cats (measured Cp x 0.5).

Summary

Therapeutic drug monitoring is an important therapeutic tool that ensures establishment of prompt optimal individualized Cp. By measuring drug Cp at appropriate times, it is possible to explain the efficacy or failure of treatment and to prevent Cp from reaching toxic/inefficient levels. By analyzing paired samples (peak and trough), key PK parameters may be calculated in order to avoid prolonged period of ineffective drug therapy and help detect PK variability. As several factors can unpredictably influence drug disposition, TDM can easily be used to make rational adjustments of dosage regimens. Therapeutic drug monitoring is especially important in monitoring owner compliance.

References

Boothe, DM. 2001. Therapeutic Drug Monitoring. Chapter 4 in Small Animal Clinical Pharmacology. W.B. Saunders Company. pp 60-72.

Daigle, J.C. 2002. More economical use of cyclosporine through combination drug therapy. JAAHA 38: 205-208.

Gaskill, C.L. et al, 2005. Liver histopathology and liver and serum alanine aminotransferase and alkaline phospohatase activities in epileptic dogs receiving phenobarbital. Vet Pathol 42: 147-160.

Levitski, RE and Trepanier, LA. 2000. Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy. JAAHA 217(2): 200-204.

McAnulty, J.F. and Lensmeyer, G.L. 1999. The effects of ketoconazole on the pharmacokinetics of cyclosporine A in cats. Vet Surg 28(6): 448-455.

Mehl, M.L. 2003. Disposition of cyclosporine after intravenous and multi-dose oral administration in cats. JVPT 26: 349-354.

Robson, D. 2003. Review of the pharmacokinetics, interactions and adverse reactions of cyclosporine in people, dogs and cats. Vet Rec 152: 739-748.

Trepanier, L.A. et al, 1998. Therapeutic serum drug concentrations in epileptic dogs treated with bromide alone or in combination with other anticonvulsants: 122 cases. JAAHA 213(10): 1449-1453.

Vaughan S.T and Taylor, J.H. 1999. Drug choice and therapeutic drug monitoring in the management of canine primary epilepsy. J S Afr Vet Assoc 70(4): 172-176.