Pharmacokinetics therapeutic window

Tricyclic antidepressants Despite the numerous publications over the past 30 years on the determination of the TCAs (Tricyclic Antidepressants) by HPLC to establish possible therapeutic windows, both therapeutic drug monitoring and pharmacokinetic calculations have revealed there is considerable variation (10- to 50-fold) in plasma concentrations between individuals with these drugs. The plasma concentrations are usually in the range of 50-300 ng/ml. 

Rnally, pharmacokinetic and pharmacokinetic/pharmacodynamic modelling can be used for the purpose of prediction of the concentration-time profile of the drug and drug-carrier conjugate after repeated administration from single dose data, as well as for the prediction of the dose needed to maintain the concentration at the target site within a therapeutic window. 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

Despite the problems posed by the pharmacokinetic and physicochemical characteristics of ibuprofen (small therapeutic window, erratic absorption owing to its poor solubility, etc.), this pulsed release system results in good separation of the two plasma peaks (indicating that there is in fact delayed release of the second drug dose) at the desired concentrations. 

Pharmacokinetic principles, in addition to clinical factors such as the state of the patient, are utilized in determining dosage regimens. Factors that relate to the safety and efficacy of the drug, such as activity-toxicity relationships (therapeutic window and side effects), and pharmaceutical factors, such as dosage form and route of administration, must be considered.16... 

FIGURE 17-1 Pharmacokinetic model for PCA using opioid drugs. Conventional intramuscular injection is indicated by the long solid lines, PCA is indicated by the short dashed lines, and the therapeutic window for analgesia is indicated by the shaded area. CFrom Ferrante, et at Anesth Analg. 1988 67 457-461 with permission.)... 

Azithromycin (7.c) is an antibiotic. The bottom of its therapeutic window for most bacteria has been estimated at 2.0 jig/ml,. Azithromycin is typically dosed orally with 500 mg on day 1 and 250 mg on each of days 2 through 5. The relevant pharmacokinetic parameters of azithromycin are as follows kA = 0.0100 h-1, kab = 1.88 h-1, F = 38%, Vd = 31.1 L/kg. Estimate the Cpmax for azithromycin over the dosing interval. (To do this problem, you will need to determine the Cp separately for all five doses [at different start times] and add them together.)... 

A pharmacokinetic (PK) study in individuals with impaired renal function is recommended when renal impairment is likely significantly to alter the disposition of a drug/or its active metabolite(s) such that a dose adjustment may be needed. In the main, this is the case primarily for drags that are mainly eliminated (excretion and/or metabolism) by the kidneys and/or if a drug has a narrow therapeutic window. However, severe re-... 

In summary, a pharmacokinetic study in individuals with impaired hepatic function is recommended if the extent of hepatic metabolism is unknown, the hepatic metabolism/excretion accounts for > 20 % of the elimination of parent drag or metabolite(s), and for drugs with a narrow therapeutic window. The primary goal of such a study is to determine if the pharmacokinetic is altered to an extent that the dose and/or dosing regimen of a drug should be adjusted from that established in the confirmatory safety and efficacy trials. 

Although the kidney has been identified as a major target organ for all bisphosphonates at the high doses used in preclinical toxicity studies, a clear therapeutic window still exists, enabhng bisphosphonates to be safely administered in general clinical use for the inhibition of bone resorption. However, there are differences in the therapeutic indices between individual agents and in their pharmacokinetic and pharmacodynamic profiles in patients with both normal and impaired renal function. 

An ideal anticoagulant should have reproducible pharmacodynamic and pharmacokinetic properties such that no coagulation monitoring is necessary. It also should have a wide therapeutic window, a rapid onset and offset of action, and minimal adverse effects, particularly with minimal interactions with food and other drugs. 

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