Pharmacokinetic studies control

Pharmacokinetic studies in patients yielded an estimated product half-life of approximately 20 days (11-50 days range) and the product clearance was found to be variable according to body weight, gender and tumour burden. Safety and efficacy were established by three randomized, controlled trials. The first study was a randomized double-blind trial involving 813 patients. The primary end-point measured was overall survival, which was extended from a median of 15.6 months to 20.3 months. 

In our laboratories, a cycle time of 90 sec can be achieved with a dilution factor of 1 25 for a given sample concentration, allowing the purity and identity control of two and a half 384-well microtiter plates per day. The online dilution eliminated an external step in the workflow and reduced the risks of decomposition of samples in the solvent mixture (weakly acidic aqueous solvent) required for analysis. Mao et al.23 described an example in which parallel sample preparation reduced steps in the workflow. They described a 2-min cycle time for the analysis of nefazodone and its metabolites for pharmacokinetic studies. The cycle time included complete solid phase extraction of neat samples, chromatographic separation, and LC/MS/MS analysis. The method was fully validated and proved rugged for high-throughput analysis of more than 5000 human plasma samples. Many papers published about this topic describe different methods of sample preparation. Hyotylainen24 has written a recent review. 

When the amount of drug given to a subject must be precisely controlled (e.g., in many pharmacokinetic studies), it is preferable to use a parenteral (usually IV) route of administration. 

In vitro and in vivo pharmacokinetic studies with tretinoin cream and gel indicated that less than 0.3% of the topically applied dose is bioavailable. Circulating plasma levels of tretinoin are only slightly elevated above those found in healthy normal controls. Estimates of in vivo bioavailability ot Retin-A M/cro following single and multiple daily applications, for a period of 28 days with the 0.1 % gel, were... 

As of the date of this chapter (circa March, 2002), labeling changes regarding pediatric use have resulted from only two programs—the study of buspirone in pediatric GAD and a pharmacokinetic study of fluvoxamine in pediatric OCD (fluvoxamine already had a controlled clinical trial in pediatric patients). Two placebo-controlled trials with buspirone in pediatric GAD did not reveal a treatment effect, and this negative outcome is reflected in Buspar labeling. A pharmacokinetic study of fluvoxamine dosed at 100 mg bid in pediatric... 

Detailed pharmacokinetic studies were performed on transscleral iontophoresis of various drugs [38-40,42,75-78]. Each drug resulted in different patterns of distribution in the vitreous. Carboplatin distribution in the vitreous after iontophoretic delivery demonstrated heightened levels in a controlled manner from 1 to 6 h after treatment [39], Foscarnet iontophoresis demonstrated a very low elimination rate, thus therapeutic levels in the vitreous were maintained for up to 60 h [78]. Methylprednisolone obtained a relatively low peak concentration 2 h after treatment [38], and gentamicin showed a peak concentration 16 h after the transscleral iontophoresis [42]. 

A selective, sensitive, and rapid hydrophilic interaction liquid chromatography with electrospray ionization tandem mass spectrometry was developed for the determination of donepezil in human plasma [32], Donepezil was twice extracted from human plasma using methyl-ferf-butyl ether at basic pH. The analytes were separated on an Atlantis HILIC Silica column with the mobile phase of acetonitrile ammonium formate (50 mM, pH 4.0) (85 15, v/v) and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r = 0.9994) over the concentration range of 0.10-50.0 ng/ ml and the lower limit of quantification was 0.1 ng/ml using 200 /d plasma sample. The CV and relative error for intra- and inter-assay at four quality control levels were 2.7% to 10.5% and —10.0% to 0.0%, respectively. There was no matrix effect for donepezil and cisapride. The present method was successfully applied to the pharmacokinetic study of donepezil after oral dose of donepezil hydrochloride (10 mg tablet) to male healthy volunteers. 

C. Alexander, D. Gorecki, and P. Caliceti. Physico-Chemical and Pharmacokinetic Studies of Avidin Bioconjugates with Thermosensitive Polymers, 5th International Symposium on Controlled Release of Bioactive Materials, June 21-24, 1998,... 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

Pharmacokinetic studies must be provided that document the fate of the drug, including absorption, distribution, metabolism, and excretion. In addition, the company must supply information on chemistry, manufacturing, and quality control... 

Clinical trials and clinical trial authorizations in the European Union are controlled under the Clinical Trial Directive, 2001/20/EC [9], and all member states are bound by its requirements. Under the provisions of the Directive, a clinical trial is an investigation in human subjects that is intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more medicinal products, identify any adverse reactions or study the absorption, distribution, metabolism, and excretion, with the object of ascertaining the safety and/or efficacy of those products. This definition includes pharmacokinetic studies. 

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... 

Numerous cases have been reported in which latanoprost therapy has been associated with the development of cystoid macular edema (CME). Considering the role that prostaglandins play in the pathogenesis of CME, it may be reasonable to assume that topically applied latanoprost can increase the risk of CME. However, latanoprost itself is not known to be vasoactive or to affect vascular permeability. Furthermore, pharmacokinetic studies have feiled to demonstrate significant levels of latanoprost in the posterior segment of the eye after topical application. Indeed, controlled clinical studies... 

Nedocromil was developed as a result of research for compounds to control asthma. Its activity has been studied in vitro in a variety of inflammatory cells, including mast cells, eosinophils, and polymorphonuclear leukocytes. Nedocromil appears to be more potent than cromolyn in its ability to inhibit immimologic release of mast cell mediators. It can also modify the actions of eosinophils, neutrophils, monocytes, macrophages, and platelets. Pharmacokinetic studies indicate that ocular penetration of nedocromil is slow, and clearance from the eye is relatively rapid. Nedocromil differs from the other mast cell stabilizers in that it is effective within 15 to 30 minutes. 

The use of GC was first included in the United States Pharmacopoeia (USP) in the sixteenth edition in 1960, and became an official method of the British Pharmacopoeia (BP) in 1968. GC has found widespread use in pharmaceutical analysis by virtue of its applications to purity and control analysis of raw materials, content and quality assessment of dosage forms (including product stability), and in the quantitative measurement of drugs in biological fluids. The latter application is important for therapeutic drug monitoring, pharmacokinetic studies, and bioavailability assessments. In fact, in a survey on GC use, ° a major application of this technique was in the field of pharmaceuticals. 

Nakane, S. Kakumoto, M. Yukimatsu, K. Chien, Y.W. Oramucosal delivery of LHRH pharmacokinetic studies of controlled and enhanced transmucosal permeation. Pharm. Dev. Technol. 1996,1, 251-259. 

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