Dosage pharmacokinetic studies

Palladone capsules are formulated using a con-trolled-release melt extrusion technology combining hydromorphone HCl with polymers to form pellets, which are then loaded into gelatin capsules. The capsules are designed to provide uniform, controlled release of hydromorphone over a 24 hour period and are produced in 12,16,24, and 32 mg dosages. Pharmacokinetic studies of Palladone demonstrated that a steady-state level is reached in 2 to 3 days and the formulation has an elimination half-life of approximately 18.6 hours. 

The present revised textbook on Pharmaceutical Drug Analysis caters for the much needed handbook and reference book, which is absolutely current with regard to the esteemed philosophy of analytical chemistry, an obvious solid support towards drug discovery, development, stability studies, bioavailability and pharmacokinetic studies, and above all the quality assurance of pure drugs together with their respective dosage forms. 

As a result, if dissolution from formulations is studied exclusively under low pH conditions, the formulators are likely to be in for a rude shock when the results come back from the pharmacokinetic studies—poor and highly variable absorption is the order of the day for drugs that have been formulated without an eye to robustness of the release from the dosage form as a function of pH. Instead, it is recommended that a formulation be sought that can release the drug even when there is not enough acid in the stomach to provide a sufficient boost to the solubility or when the gastric residence time is short. 

The design of pharmacokinetic studies that need to be conducted for product approval is a function of how much is known about the active drug moiety, its clinical pharmacokinetics, and the biopharmaceutical properties of the dosage form, and regulatory requirements. As a minimum,... 

Pharmacokinetic studies (59) in cattle treated with the recommended dosage showed that the drug was well dispersed from the injection site, with less than 1% of the dose remaining at 21 day withdrawal. By 14 days, 87% of the dose was excreted via the bile and feces whereas less than 1% was eliminated via urine. Mean plasma half-life was found to be 6.2 days for the parent compound and 5.9 days for total drug-related residues. 

Pharmacokinetic studies with sheep treated with the recommended dosage showed that praziquantel was rapidly absorbed, peak plasma concentration being reached within 2 h of dosing (72). A half-life of 4.2 h was determined and excretion from plasma was rapid, 98% being excreted within 72 h. At 8 h posttreatment, the maximum levels present in liver, kidneys, muscle, and fat were 2.87, 2.55, 0.19, and 0.1,3 ppb, respectively, of praziquantel equivalents. At 24 h post-... 

In Vivo Release In vivo dissolution of drug from a dosage form as determined by deconvolution of data obtained from pharmacokinetic studies in humans (patients or healthy volunteers). 

Numerous studies on the metabolism of 2,1t-dichlorophenoxy-acetic acid (2,1+-D) and related herbicides in animals have shown that these chemicals are absorbed and distributed rapidly in the body, and are excreted, undegraded, relatively quantitatively in the urine within a week after administration (M Pharmacokinetic studies with 2,1+,5-T in rats and dogs (5.) and in humans (6J supported these findings, and demonstrated that rates of clearance from plasma and elimination in urine depend on dosage level, animal species, and chemical structure of the phenoxy acid being studied ( + ). Corresponding chlorinated phenol metabolites were detected only in ruminants (M or in trace amounts in urine of rats fed very high doses of phenoxy herbicides (7.) ... 

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.

Dighe, S., Development of dissolution tests for immediate release oral dosage forms, Bio-International 2, Bioavailabilily, Bioequivalence and Pharmacokinetic Studies, edited by H. Blume and K. K. Midha, Med-pharm, Stuttgart, 1995, pp. 247-255. 

Provide the quantitative composition and lot number of each finished dosage form used in each clinical trial, bioavailability and pharmacokinetic study, clinical pharmacology study, and dose tolerance study conducted during the investigational phases of the drug product. Cross-reference each formulation to the study report in the application and explain any differences in formulation. 

A brief description of the pharmacokinetic characteristics of the active ingredient(s) and the performance of the dosage form, integrating conclusions from the bioavailability and pharmacokinetic studies and from clinical studies performed. Information on volume of distribution, half-life, routes and rates of excretion, and metabolism of each dosage form studies, and the proportionality of absorption over the therapeutic dose range should be included. If pertinent, a comparison with the bioavailability of other dosage forms should be provided. 

In this section, the pharmacokinetics for systemic dosage forms should be described, including absorption, routes of excretion, protein binding, metabolic changes to compounds of lesser or greater activity, and distribution into various pharmacokinetic compartments. References to the locations in the NDA of the full reports of the pharmacokinetics studies should be provided. 

There are several important exceptions to the first assumption that will be considered when we discuss the effects of impaired renal function on drug metabolism. Nonetheless, this approach is widely used for individualizing drug dosage for patients with impaired renal function. In addition. Equations 5.3 and 5.4 provide a useful tool for hypothesis generation during drug development when pharmacokinetic studies are planned for subjects with impaired renal function. 

Prescott LF, Wright N. The effects of hepatic and renal damage on paracetamol metabolism and excretion following over dosage. A pharmacokinetic study. Br J Pharmacol 1973 49 602-13. 

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. 

There was at least one episode of hepatotoxicity in 228 of 466 patients (49%) with renal transplants who took ciclosporin 110 (48%) had hyperalbuminemia, 108 (47%) a raised aspartate transaminase, and 167 (59%) a raised alkaline phosphatase (84). Ciclosporin dosage reduction resulted in resolution of hepatotoxicity in 185 patients (81%), while 32 (14%) had recurrent or persistent liver function abnormalities. Eleven (2.4%) developed biliary calculous disease. The serum ciclosporin concentration was high among the patients with hepatotoxicity. Pharmacokinetic studies showed an increased AUC in the patients with hepatotoxicity, probably due to reduced drug clearance. 

Meerum Terwogt JM, Groenewegen G, Pluim D, Maliepaard M, Tibben MM, Huisman A, ten Bokkel Huinink WW, Schot M, Welbank H, Voest EE, Beijnen JH, Schellens JM. Phase I and pharmacokinetic study of SPI-77, a hposomal encapsulated dosage form of cisplatin. Cancer Chemother Pharmacol 2002 49(3) 201-10. 

In one pharmacokinetic study in eight HIV-infected subjects, the renal clearance of zidovudine was significantly reduced by trimethoprim (201). The authors concluded that zidovudine dosages may need to be reduced if trimethoprim is given to patients with impairment of liver function or glucuronidation. Zidovudine, on the other hand, did not alter the pharmacokinetics of trimethoprim. 

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