Pharmacokinetics and Safety

HCV-796 is a non-nucleosidic NS5B polymerase inhibitor with potent antiviral activity in vitro. A phase lb study was performed to determine the antiviral activity, pharmacokinetics, and safety of HCV-796 in patients with chronic HCV infection. Maximum antiviral effects were achieved after 4 days of treatment with a mean reduction of HCV-RNA of 1.4 loglOIU/ml. Combination of HCV-796 with pegylated interferon-a led to a greater reduction of viral RNA load (3.3-3.5 loglO lU/ml) after a 14 days treatment interval. 

Since 1999, when the Food and Drug Administration allowed the first health claim for soy-fortified foods in the USA, there has been a large increase in the sales of food products claiming to contain soy isoflavones. At the same time, over-the-counter supplements have become widely available. However, concerns have been raised about the real health benefits of such supplements in the absence of adequate information about bioavailability, pharmacokinetics and safety. To fill this gap, an extensive study on pure isoflavones and commercial soy isoflavone supplements has recently been carried out (Setchell et al, 2001). A selection of 31 commercially available supplements showed a wide variation in isoflavone composition and in the amount provided by one tablet. Furthermore, a lower isoflavone content, with respect to the claimed levels, has been observed in almost 50% of the analysed products. In one case, no isoflavones at all could be detected (Setchell et al, 2001). 

J. Bradley, L. Compogiannis, W. Murray, M. Acasta, and G. Tsu, Pharmacokinetics and safety of intramuscular injection of concentrated ceftriaxone in children, Clin. Pharmacol., 11, 961 (1992). 

Sanchez-Ramos J., Mash D. Ibogaine Human Phase I Pharmacokinetic and Safety Trial. FDA IND. 3968, 1993 (revised 1995). 

Available parenteral iron preparations have similar efficacy but different pharmacologic, pharmacokinetic, and safety profiles (Table 33-5). The newer products, sodium ferric gluconate and iron sucrose, appear to be better tolerated than iron dextran. 

Chow, H.H. et al., Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals, Clin Cancer Res, 9, 3312, 2003. 

Purkins, L. et al. 2002. Pharmacokinetics and safety of of voriconazole following intravenous to oral dose escalation regimens. Antimicrob Agents Chemother. 46 2546. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

The types of trials to be undertaken demand a flexible approach, and depend on the seriousness of the disease, other therapeutic options and the pharmacokinetics at different ages. For example, if the disease process and efficacy endpoints are similar in adults and children, then an extrapolation from adult efficacy data, together with pharmacokinetic studies in the appropriate paediatric age range, together with safety studies, could form the basis of a successful application. Likewise, it may be possible to extrapolate efficacy from older to younger paediatric groups, with pharmacokinetic and safety studies in the relevant younger study subjects. Where there is no known correspondence between efficacy and... 

Children Use of stavudine in pediatric patients is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients. 

Lactation It is not known whether sirolimus is excreted in human breast milk. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Because of the potential for adverse reactions in nursing infants from sirolimus, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 

The focus of the present volume by Bernard Faller and Laszlo Urban is on methods and processes designed to predict drug-like properties, exposure and safety during hit and lead discovery. Distinguished authors from industry and academia discuss the current methods to generate pharmacokinetic and safety profiles of drug candidates, as well as how they must be balanced against one other for the best selection of candidates for further development. 

Casaer, R, Walleghem, D., Vandenbussche, L, Huang, M.-L., and DeSmedt, G. (1994) Pharmacokinetics and safety of risperidone in autistic children [abstract]. Pediatr Neurol 11 89. 

Animal data serve as the springboard to estimating a safe and effective range of doses for human therapeutic purposes. Initial doses in phase 1 studies are based on preclinical pharmacokinetic and safety data. First estimates of safe and effective drug concentrations in plasma in human studies are also based on animal data. The Clinical Studies section in the product label includes information derived from tolerance studies of the drug (phase I), pivotal human data demonstrating efficacy at a defined dose or dose range, and a description of untoward effects observed in... 

The genesis of linezolid (2) began in 1978 when a DuPont patent described a novel oxazolidinone antibacterial agent S-6123 (37). This compound and two subsequently optimized drug candidates DuP 721 and DuP 105 did not materialize as marketed drugs due to unacceptable toxicity. Inspired by this innovation, scientists at Upjohn further developed this class of compounds via intensive SAR studies, obtaining linezolid (2), a compound with favorable pharmacological, pharmacokinetic, and safety profiles. 

C.F. Nagy, D. Kumar, E.I. Cullen, W.K. Bolton, T.C. Marbury, M.J. Gutierrez, H.W. Hutman, R.D. Pratt, Steady-state pharmacokinetics and safety of donepezil HC1 in subjects with moderately impaired renal function, Br. J. Clin. Pharmacol. 58 (2004) 18-24. 

The pharmacokinetics and safety profile of lamivudine are described above (see Lamivudine). The more prolonged intracellular half-life in HBV cell lines (17-19 hours) than in HIV-infected cell lines (see above) allows for lower doses, administered less frequently, for hepatitis. Lamivudine can be safely administered to patients with decompensated liver disease. 

Roden DM, Reele SB, Higgins SB, Wilkinson GR, Smith RF, Oates JA, Woosley RL. Antiarrhythmic efficacy, pharmacokinetics and safety of A-acetylprocai-namide in human subjects comparison with procainamide. Am J Cardiol 1980 46 463 168. 

When the early work on the amino-containing compounds showed that they had significant spectrum improvements and intrinsic water solubility, additional analogues were screened for a variety of biological and chemical properties, and especially for once per day dosing. MK-0911 (L-743,872, the heminaminal aza analogue of L-733,560, (Fig. 2) was found to have pharmacokinetic and safety advantages over other derivatives and was therefore selected as the clinical candidate. 

Experience has shown that the exploratory profiling of the impact of gender, high age, and food intake (in the form of a food screen for worst case food effects) on drug disposition (pharmacokinetics) and safety can be conveniently done in one study with the design described in this article. If a notable effect of these parameters is/are seen, then confirmatory studies need to be performed. 

Danne T, Rave K, Bittner C, Heise T, Frick A, Becker R (2004) Pharmacokinetics and Safety of Insulin Glulisine in Children and Adolescents with Type 1 Diabetes. Abstract and poster presentation at the annual eutopean diabetes congress EASD (European Association for the Study of Diabetes)... 

The impact of selected phenotypes on candidate drug pharmacokinetics and safety can be conveniently investigated in an explorative study with the design described in this section. Typically, this study would run shortly after key data are available, indicating the influence of polymorph DME+T. The dose should be adjusted (i.e. reduced, compared to the clinical dose) based on the expected degree of interaction. 

Comparison of pharmacokinetics and safety of extended release formulations of 600 mg XYZ1234 with that of an immediate release formulation -a single-center, open-label, cross-over study in healthy men. 

Drug Metabolism, Pharmacokinetics and Safety A company of the Sanofi-Aventis Group Vitry-Alfortville France... 

However, the majority of natural products were not created to meet human needs and domestication in the form of chemical manipulation is required to increase potency, improve selectivity and reach a clinically acceptable pharmacokinetic and safety profile. Thus, while antibiotics are generated by microorganisms to fight other microorganisms and can be employed clinically to do so, natural cytotoxic agents are not produced to kill cancer cells and they... 

Tang-Liu, D. D., and Acheampong, A. (2005), Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye, Clin. Pharmacokinet.,44,247-261. 

Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The effect of fluoxetine on the pharmacokinetics and safety of risperidone in psychiatric patients. Pharmacopsychiatry 2002 35(2) 50-6. 

Demling J, Huang ML, De Smedt G. Pharmacokinetics and safety of combination therapy with lithium and risperidone in adult patients with psychosis. Int J Neuropsychopharmacol 1999 2 S63. 

Zhao Q, Xie C, Pesco-Koplowitz L, Jia X, Parier J-L. Pharmacokinetic and safety assessments of concurrent administration of risperidone and donepezil. J Clin Pharmacol 2003 43 180-6. 

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