Drugs pharmacokinetic, variability

Y. C. Tsang, R. Pop, G. P. Hems, and M. Spino, High variability in drug pharmacokinetics complicates determination of bioequivalence, Pharm. Res, 13, 846... 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

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. 

Pharmacokinetics Variable absorption following PO administration. Not metabolized. Approximately 50% of drug is excreted in urine. Unabsorbed drug is excreted intact in feces. Half-life 1-6 hr (oral) 6 hr (IV). 

Pharmacokinetics Variably absorbed from the GI tract. Protein binding low. Metabolized in liver. Primarily excreted in urine as morphineglucuronide con j ugates and unchanged drug—morphine, codeine, papaverine, etc. Unknown if removed by hemodialysis. Half-life 2-3 hr. 

Wrighton SA, Ring BJ. Predicting drug interactions and pharmacokinetic variability with in vitro methods the olanzapine experience. Drug Metab Rev 1999 31 15-28. 

Erratic DPD activity is a major cause of the marked pharmacokinetic variability of 5-FU. Drug-drug interactions (47,48), circadian patterns (12,49,50), and inter-gender (7,8) inter-ethnic differences (51,52,53,54,55) have been identified as putative causes for profound variations in DPD activities. Consequently, population studies of DPD activities displayed extremely wide ranges of values (17,56,57). 

The basic principles outlined above can be applied to the interpretation of clinical drug concentration measurements on the basis of three major pharmacokinetic variables absorption, clearance, and volume of distribution (and the derived variable, half-life) and two pharmacodynamic variables maximum effect attainable in the target tissue and the sensitivity of the tissue to the drug. Diseases may modify all of these parameters, and the ability to predict the effect of disease states on pharmacokinetic parameters is important in properly adjusting dosage in such cases. (See The Target Concentration Strategy.)... 

Welling PG, Tse FL. Factors contributing to variability in drug pharmacokinetics. I. Absorption Hosp Pharm, 1984 9 163-179. 

The preceding discussion has been intent upon breaking down equations and making sense of different variables and how each may be calculated from experimental Cp-time data. At the outset of this chapter, two parameters—clearance and volume of distribution—were set apart as the key pharmacokinetic variables for a drug. This brief section tries to establish the importance and utility of these two variables. The highlight of this subsection is Equation 7.12, which is shown again here. A rearranged form of Equation 7.12 is Equation 7.33. 

In oncology, drug dosage individualization for conventional cytotoxic anticancer therapy is performed according to mg/m2 or mg/kg. However, even after dose adjustment, the pharmacokinetic variability observed for many cytotoxic... 

Information on the clinical pharmacokinetics is also available of the recently approved TKIs. Vandatenib pharmacokinetics, studied in healthy volunteers and patients [80, 81] was found to be both influenced by patient s renal function and vulnerable to drug-drug interactions [82, 83], An important pharmacokinetic variability is noticeable in the mean steady state PK profiles published for verumafenib (formerly PLX4032) [27],... 

Tsang, Y., Pop, R., Gordon, P., Hems, J., and Spino, M., High variability in drug pharmacokinetics complicates determination of bioequivalence Experience with verapamil, Pharmaceutical Research, Vol. 13, No. 6, 1996, pp. 846-850. 

Steimer J, Mallet A, Mentre F (1985) Estimating interindividual pharmacokinetic variability. In Rowland M et aL (eds) Variability in Drug Therapy Description, Estimation and Control. Raven Press New York Tanigawara Y, Nomura H, Kagimoto N, Okumura K, Hori R (1995) Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases. Biol Pharm Bull 18(2) 315-320... 

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