Pharmacokinetics therapeutic index

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

In terms of pharmacokinetics, many host factors, such as the route of administration, the metabolism, the catabolism and clearance will considerably determine the anti neoplastic success of a drug. One major difficulty with the clinical effectiveness of chemotherapy of neoplastic diseases is the requirement that it kill malignant tumor cells at doses that allow cells in the patient s vital organs to survive so that the recovery can occur. In other words, it is to obtain a reasonably safe therapeutic index favoring introduction into clinical practice. 

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. 

In turn, whether significant pharmacokinetic differences arising from the pol)nnorphisms translate into relevant alterations in pharmaco-d)mamics (and clinical efficacy) depends on the operating region of the concentration-response relationship, therapeutic index and utility, and whether kinetic variability is outweighed by variability in receptor sensitivity or number, or in the turnover of the natural receptor ligand. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

Pharmacokinetic parameters are also important in relation to toxicity. The toxicity of antimicrobial drugs varies considerably and is usually concentration dependent. The therapeutic index is the ratio between the concentration of drug that is toxic for the... 

Members of this class of antidepressants are likely to be involved in pharmacodynamic and CYP-mediated pharmacokinetic drug-drug interactions. The latter are of concern because of the narrow therapeutic index of TCAs. 

Kelly HW. Establishing a therapeutic index for the inhaled corticosteroids. Part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids. J Allergy Clin Immunol 1998 102(4 Pt 2) S36-51. 

Clonidine is one of the most widely used sedating medications in pediatric and child psychiatry practice, particularly in children with sleep onset delay and ADHD. It is a central alpha2 agonist. Pharmacokinetics show rapid absorption, with an onset action within 1 h, peak effects at 2-4 h and a half-life 6-24 h. Effects on sleep architecture are fairly minimal but may include decreased REM, so that discontinuation can lead to REM rebound. Clonidine has a narrow therapeutic index, and there has been a recent dramatic increase in reports of overdose with this medication. Potentially significant side effects including hypotension, bradycardia, anticholinergic effects, irritability, and dysphoria rebound hypertension may occur on abrupt discontinuation. Tolerance often develops, necessitating increases in dose. 

The anticoagulant activity of UFH varies among patients and therefore has a narrow therapeutic index, unpredictable pharmacokinetics, and requires frequent monitoring of the ACT The optimal ACT for minimizing both ischemic and hemorrhagic complications during PPI in patients not treated with a glycoprotein llb/llla inhibitor or thrombolytic is approximately 300 seconds. 

The clinical consequences of altering the pharmacokinetics of the victim dmg (which may or may not be a cause for concern depending on the drug s therapeutic index). 

As introduced in Chapter 1, there are many limitations associated with conventional drag therapy. An intravenously administered drag is subject to a number of pharmacokinetic processes in vivo which can decrease the drugs therapeutic index, including ... 

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