Pharmacokinetics variation

Reanalysis of the data of Hattis et al. (1987) showed that the variation between individuals for the elimination half-life was quite small (Schaddelee 1997, as cited in Vermeire et al. 1999, 2001). Defining the interindividual factor as the ratio of the P50 (50th percentile) and P05 (5th percentile) resulted in a factor of 1.4. It was emphasized that although it appeared from this analysis that a 10-fold factor would be sufficient for pharmacokinetic variation, the real median to sensitive human variability is underestimated because variation also exists in pharmacodynamics and only data of healthy volunteers were available. 

Pharmacokinetics Variation in absorption among individuals and sites scrotum 36%, forehead 7%, scalp 4%, forearm 1%,... 

Because the British group applied extensively their statistical method to determine causation of large interindividual pharmacokinetic variations without describing its strengths and weaknesses, others have attempted to assess critically the application of multiple regression analysis for this particular purpose (31,32) While this statistical method has great potential, it requires considerable modification beyond its initial applications in this area (27-29), if that potential is to be realized (H,32). Thus far, its applications in pharmacokinetics (27-29) have been disappointing because those who have employed it neither formulated nor addressed, much less demonstrated fulfillment of, several fundamental assumptions inherent in its use ( 1, 32). 

It must be emphasized that the potential of multiple regression analysis to resolve sources of pharmacokinetic variations is much greater than has been realized by the particular canned1 model used previously. The technique itself is both sensitive and powerful. However, for multiple regression analysis to be used appropriately, a model must be developed that encompasses non-linear as well as linear relationships (JJ4). Error terms especially need to be appropriately modelled, rather than treated in a simply additive manner as in previous applications of this method. 

To minimize the risks of an incorrect biowaiver decision in terms of public health and risks to individual patients, the therapeutic indications of the API, known pharmacokinetic variations, food effects, etc. should be evaluated based on local clinical experience, taking into account the indications... 

In 2008, Katz and colleagues [42] extended the search for associations of greater pharmacogenetic interest, although they limited their study to associations with pharmacokinetic variation. They identified consistently replicated associations for at least one drug between gene variants and human... 

Interindividual pharmacokinetic variation usually makes it unrealistic to dose patients on the basis of body weight. 

A placebo-controlled study in 12 healthy subjects found that quinidine 50 mg had virtually no effect on the analgesic effects of tramadol 100 mg but it inhibited its effect on pupil size. The manufacturers say that quinidine increases the tramadol AUC and maximum level by 25%, but this is within the normal pharmacokinetic variation seen with tramadol. Tramadol is partially metabolised to the active metabolite O-desmethyltramadol (which affects opioid receptors), by the cytochrome P450 isoenzyme CYP2D6, and it is this enzyme that is inhibited by quinidine. Blockade of the production of this metabolite appears to have little effect on the analgesic effect of tramadol. No special precautions seem to be needed. 

The authors of the citalopram study say that while cimetidine certainly causes an increase in the serum levels of citalopram, the extent is only moderate and because the drug is well tolerated and there are very considerable pharmacokinetic variations between individual subjects, they consider that there is no need to reduce the citalopram dosage. This advice is most likely applicahle to escitalopram, the S-isomer of citalopram. However, the manufacturer of escitalopram suggests caution, and advises that a reduction in the dose of escitalopram may he necessary (based on monitoring of adverse effects) during concurrent treatment. ... 

In order to minimize these pharmacokinetic variations, indinavir was later developed as a sulfate salt, instead of the free base monohydrate. The sulfate salt had higher aqueous solubility (more than 500 mg mL ) and the pH of the resultant aqueous solution was also as low as 3, which facilitated its dissolution in the GI tract. As a result, the sulfate form of indinavir was favored more pharmacokinetically than the free base monohydrate form. 

Toxicity with TCAs can be life threatening, and can occnr when plasma concentrations exceed 500 ng/mL. Indeed, adverse effects associated with excessive TCA concentrations inclnde cardiac toxicity (7) and anticholinergic effects like dry month, constipation, urinary retention, decreased sweating, and hyperthermia. While an immunoassay for TCA quantification may assist with detection of toxic total concentrations, investigation of TCA-associated toxicity, pharmacokinetic variability, or other results inconsistent with clinical suspicions may require a technology that provides better specificity than an immunoassay. Only a chromatographic assay can independently detect and quantify TCAs and active metabolites such that pharmacokinetic variation or polypharmacy can be identified. Here a chromatographic technique, with mass spectrometric detection, is described. 

---