Dosage pharmacokinetic

DIFFUSION OF LIGAND TO RECEPTOR Drug clearance, dosage, PHARMACOKINETICS Drug distribution kinetics, PHARMACOKINETICS Drug excretion rates,... 

FIGURE 4.1 Schematic representation of the interrelationship between drug input (dosage), pharmacokinetics (concentration), pharmacodynamics, and clinical effects. 

Human (clinical) testing Phase 1 Determine effects, safe dosage, pharmacokinetics Small number (< 100) of healthy volunteers <1 yr... 

Numerous other ACE inhibitors have been synthesized and evaluated since captopril was announced in 1977. As of 1996, 16 were in use worldwide (157), all of which are variations of the designs exemplified in Table IX. Reviews are available that describe dosage, pharmacokinetics, metabolism, and routes of elimination of many of them (111,156-159). 

Drug Dosage Pharmacokinetics Adverse Effects Drug Interactions... 

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. 

In cases of all but intravenous adininistration, dosage forms must make the active moiety available for absorption, ie, for dmg release. This influences the bioavailabiUty and the dmg s pharmacokinetic profile. Ideally the dmg is made available to the blood for distribution and elimination at a rate equal to those processes. Through technological developments dmg product design can achieve release, absorption, and elimination rates resulting in durations of activity of 8—12 hours, ie, prolonged action/controlled release dmg products (21,22). Such products improve the compliance rate of dmg usage by patients. 

To avoid confusion, several researchers have incorporated therapeutic intention into the definition of controlled release (4—7). Thus, controUed-release pharmaceuticals release dmgs in vivo according to a predictable, therapeutically rational, programmed rate to achieve the optimal dmg concentration in the minimal time (4). Specification by release rate complements specification by quantity jointly considered, they fix the duration of dmg release. Therefore, the dmg s duration of action can become a design property of a controlled release dosage form rather than an inherent pharmacokinetic property of the dmg molecule. 

Design of a controUed release dosage form requires sufficient knowledge of both the desired therapy to specify a target plasma level and the pharmacokinetics. The desired dmg input rate from a zero order system may be calculated by ... 

Czock D, Giehl M, Keller F (2000) A concept for pharmacokinetic-pharmacodynamic dosage adjustment in renal impairment the case of aminoglycosides. Clin Pharmacokinet 38(4) 367—375. Erratum in Clin Pharma-cokinet 2000 39(3) 231... 

Dettli L (1976) Drag dosage in renal disease. Clin Pharmacokinet 1(2) 126—1115. 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

A monograph on the larch arabinogalactan has been published, containing pharmacokinetics, clinical indications, the lack of side-effects and dosage [60]. In a report from 2003, the effect over time of in-vivo administration of the larch arabinogalactan on the immune and hemopoietic cell... 

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Pharmacodynamic tolerance to barbiturates develops over weeks to months, whereas pharmacokinetic tolerance occurs in a period of days. At maximum tolerance, the dosage of a barbiturate may be six times the original dosage. 

Although most CF patients have shorter half-lives and larger volumes of distribution than non-CF patients, some patients exhibit decreased clearance. Possible causes include concomitant use of nephrotoxic medications, presence of diabetic nephropathy, history of transplantation (with immunosuppressant use and/or procedural hypoxic injury), and age-related decline in renal function in older adult patients. Additionally, CF patients are repeatedly exposed to multiple courses of IV aminoglycosides, which can result in decreased renal function. Evaluation of previous pharmacokinetic parameters and trends, along with incorporation of new health information, is key to providing appropriate dosage recommendations. 

Antiemetics can be administered either intravenously or orally in this situation, depending on patient characteristics such as ability to take oral medications, dosage form availability, and cost considerations.5,10 The intravenous and oral routes are equally effective. When used at equipotent doses, the 5-HT3 antagonists have similar efficacy in preventing acute CINV, despite pharmacokinetic and receptor binding affinity differences.5,10,36... 

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

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