Pharmacokinetic profile half-life

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, t 2 — 0.4/z) and is poorly bioavailable F — 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUCo oo = 0.2pMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC5q< 10 nM) and with an adequate pharmacokinetic profile for oral absorption. 

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased half-life (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo. 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

Ward et al. [130] studied the pharmacokinetics of (+)- and (—)-primaquine in the isolated perfused rat liver preparation. The perfusate plasma concentrations of primaquine in the isolated, perfused rat liver, declined biexponentially following the addition of either (+)- or (—)-primaquine at doses 0.5-2.5 mg in the perfusate reservoir. There were no differences between pharmacokinetic profiles of the two isomers at the 0.5 mg dose. By contrast, the elimination of (—)-primaquine was greater than (+)-primaquine when either was added in a dose of 2.5 mg also, the clearance of the (—)-isomer was greater, the half-life was shorter, and the area under the plasma concentration curve was shorter. The volume of distribution was similar for the two isomers. These results are relevant to both the therapeutic efficacy and toxicity of primaquine. 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

A number of different approaches may be used in order to alter a protein s pharmacokinetic profile. This can be desirable in order to achieve a predefined therapeutic goal, such as generating a faster-or slower-acting product, lengthening a product s serum half-life or altering a product s tissue... 

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

An increase in the elimination half-life in rats was achieved by blocking the benzylic position of the propionic acid chain by introduction of a cyclopropane ring 22 (%F = 88, Vdss = 1 L/kg, f1/2 = 6.3 h) however, in the case of 22, this led to a reduction in the receptor subtype selectivity (EC50 on SI Pi/1,5 = 0.21,123 and 5.1 nM, respectively). Similarly, blocking the benzylic position by cyclizing onto the phenyl ring to form indanylacetic acid 23 resulted in an improved elimination of half-life (%F — 71, Vdss = 0.4L/kg, f1/2 = 6.7h). Acid 23 showed a similar pharmacokinetic profile in the dog and showed efficacy in the rat skin transplantation model when combined with sub-therapeutic doses of CsA. Compound 23 has been reported to be efficacious in the rat EAE model when dosed therapeutically or prophylactically [94—96]. 

In elderly volunteers, the pharmacokinetic profile is similar to that in younger subjects. However, clearance is reduced from 541 ml/min to 421 ml/min and the half-life is increased from 3.2 to 5.0 h. 

Phase I clinical evaluation of BMS 599626 is ongoing [79,80] however, no efficacy data have been reported to date. Dose escalation has proceeded to 660 mg/day and is ongoing since a MTD has not been reached. The pharmacokinetic profile in both healthy volunteers and cancer patients supports once-daily dosing with a half-life of ca. 20 h. An area under the curve of ca. 2.4 xgh/ml with a maximum concentration of ca. 0.18 xg/ml was achieved at steady state after 100-mg dosing in patients. In mice at a dose that resulted in modest antitumor activity (ca. 50% TGI), significantly higher plasma levels were achieved (AUC ca. 14.5 xgh/ml and Cmax ca. 5.0 xg/ml) [76]. 

Pharmacokinetics The pharmacokinetic profile is characterized by rapid absorption from the Gl tract and a short elimination half-life. Zolpidem is converted to inactive... 

The blood concentration-time profile for a theoretical drug given extravascularly (e.g., orally) is shown in Figure 5.2. Some pharmacokinetic parameters, such as Cmax, T x> area under the curve, and half-life, can be estimated by visual inspection or computation from a con-... 

While essentially all ACE inhibitors have a similar mechanism of action and therefore exhibit similar efficacy in the treatment of hypertension and congestive heart failure, these drugs differ slightly in their pharmacokinetic profiles. Enalapril, lisinopril, and quinapril are excreted primarily by the kidney, with minimal liver metabolism, while the other prodrug compounds are metabolized by the liver and renally excreted. Thus, in patients with renal insufficiency, the half-life of renally excreted ACE inhibitors is prolonged. In addition, patients with impaired liver func-... 

All the SSRIs have similar spectrums of efficacy and similar side-effect profiles. However, they are structurally and in some instances clinically distinct. For example, allergy to one SSRI does not predict allergy to another. Similarly, response or nonresponse to one SSRI does not necessarily predict a similar reaction to another medication in the class. SSRIs also have distinct pharmacokinetic properties, the most important of which are differences in half-life (Table 2-1) and the propensity to inhibit cytochrome P450 (CYP) enzymes (Table 1-1). 

Pharmacokinetics The absorption rate of Gonal-F following subcutaneous or intramuscular administration was found to be slower than the elimination rate. Hence the pharmacokinetics of Gonal-F are absorption rate-limited. After intravenous administration to pituitary down-regulated, healthy female volunteers, the serum profile of FSH appears to be described by a two-compartment open model with a distribution half-life of about 2 to 2.5 hours. Steady-state serum levels were reached after 4 to 5 days of daily administration. 

Pharmacokinetics Serum levels considered therapeutic (40pg/ml or greater) are achieved in most high-risk infants on intramuscular administration of the recommended dose. In studies in adult volunteers, palivizumab had a pharmacokinetic profile similar to a human IgGi antibody in regard to the volume of distribution and the half-life (mean 18 days). In pediatric patients less than 24 months of age, the mean half-life of palivizumab was 20 days. 

Atazanavir is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. It should be taken with a light meal to enhance bioavailability. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility therefore, separation of ingestion from acid-reducing agents by at least 12 hours is recommended. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6-7 hours, which increases to approximately 11 hours when -administered with ritonavir. The primary route of elimination is biliary atazanavir should not be given to patients with severe hepatic insufficiency. 

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