Pharmacokinetic and Pharmacodynamic Studies

PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES Scleral Plugs Containing GCV 

For in vivo release studies, scleral plugs prepared from blends of PLA-70,000 and PLA-5000 at weight ratios of 80/20 and 25% of GCV were used. The scleral plugs containing GCV were implanted in pigmented rabbits. Animals were killed at days 1 and 3 and at weeks 1,2, 3,4, 6, 8, 10, 12, 14, 16,18,20, and 24 after implantation, and the eyes were enucleated. Five rabbits were used at each time point. The intravitreal GCV concentration was determined by high-performance liquid chromatography (HPLC). 

The scleral plugs maintained a constant vitreous GCV concentration within the ED50 range (0.1 2.75 pg/mL) for six months without any sudden burst (Fig. 10) (4). However, further studies may be needed to evaluate effective GCV concentrations clinically, as the ED50s are values determined in various conditions in vitro. 

We used 20 eyes of 20 pigmented rabbits to study in vivo release of BP from the implant and to evaluate pharmacodynamics in the ocular tissues after implantation. A scleral pocket was made at a depth of about one-half the total scleral thickness with a crescent knife 2 mm from the limbus. The scleral implant was inserted in the scleral pocket. At one, two, four, and eight weeks after implantation, animals were killed and four eyes were immediately enucleated at each time point. The concentrations of BP in the implants and samples of ocular tissues (aqueous humor, vitreous, and retina/choroid) were determined by HPLC. 

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Osborn BL, Olsen HS, NardeUi B, Murray JH, Zhou JX, Garcia A, Moody G, Zaritskaya LS, Sung C (2002) Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 303 540-548 Ozes ON, Reiter Z, Klein S, Blatt LM, Taylor MW (1992) A comparison of interferon-Conl with natural recombinant interferons-alpha antiviral, antiproliferative, and natural kiUer-inducing activities. J Interferon Res 12 55-59... 

Pharmacokinetic and pharmacodynamic studies lead to a greater understanding of chemical interactions at the molecular level and may identify specific receptors for drug activity. With more specific knowledge of how a drug works, it may become easier to more accurately establish what effects are actually caused by a particular drug. Thus, studies in these two areas of pharmacology will always be necessary. 

Galluppi, G.R., M.C. Rogge, L.K. Roskos, L.J. Lesko, M.D. Green, D.W. Feigal, Jr., and C.C. Peck, Integration of pharmacokinetic and pharmacodynamic studies in the discovery, development, and review of protein therapeutic agents a conference report. Clin Pharmacol Ther, 2001. 69(6) 387-99. 

Ziprasidone s pharmacokinetics permit rapid and predictable dose adjustment, with metabolites that are considered to be clinically inactive ( 134). The results of PET pharmacokinetic and pharmacodynamic studies indicate that a twice daily dosage regimen is appropriate. 

Carl, P, Hogskilde, S., Nielsen, J.W., Sorensen, M.B., Lindholm, M., Karlen, B., and Backstrom, T. (1990) Pregnanolone emulsion. A preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic ageMhaesthesia, 45 189-197. 

Kenyon, E.M., Del Razo, L.M., Hughes, M.F. and Kitchin, K.T. (2005b) An integrated pharmacokinetic and pharmacodynamic study of arsenite action 2. Heme oxygenase induction in mice. Toxicology, 206(3), 389-401. 

E.C. Jones, S.L. Goldenberg, J. Powers, and M.E. Gleave. 2004. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2 -methoxyethyl antisense to clusterin, in patients with localized prostate cancer prior to radical prostatectomy. In 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA. 

Kentala E, Kaila T, Iisalo E, Kanto J (1990) Intramuscular atropine in healthy volunteers a pharmacokinetic and pharmacodynamic study. Int J Clin Pharmacol Ther Toxicol... 

Katashima, M., Yamamoto, K., Tokuma, Y., Hata, T., Sawada, Y., and Iga, T., Pharmacokinetic and pharmacodynamic study of a new nonsteroidal 5 alpha-reductase inhibitor, 4-[3-[3-[Bis (4-isobutylphenyl)methylamino]benzoyl]-lH-indol-l-yl]-butyric acid, in rats, Journal of Pharmacoloqy and Experimental Therapeutics, Vol. 284, No. 3, 1998, pp. 914-920. 

Drug-Demographic and Drug-Disease Interactions. The information from pharmacokinetic and pharmacodynamic studies as well as clinical trials should be analyzed in the same way as were done to determine drug-drug interactions. 

In a double-blind, crossover, pharmacokinetic and pharmacodynamic study of the interaction of ketoconazole with alprazolam and triazolam, two CYP3A4 substrate drugs with different kinetic profiles, impaired clearance by ketoconazole had more profound clinical consequences for triazolam than for alprazolam (39). 

In an open, randomized, crossover, pharmacokinetic and pharmacodynamic study in 12 healthy volunteers who took clarithromycin 250 mg bd for 5 days, azithromycin 500 mg/day for 3 days, or no pretreatment, followed by a single dose of midazolam (15 mg), clarithromycin increased the AUC of midazolam by over 3.5 times and the mean duration of sleep from 135 to 281 minutes (69). In contrast, there was no change with azithromycin, suggesting that it is much safer for co-administration with midazolam. 

The SA CSPs have been used in a variety of pharmacokinetic and pharmacodynamic studies. Because of the nature of these columns, they are most often used in coupled achiral-chiral systems. Two examples of this approach are the following ... 

Yacobi, A., Lai, Chii-Ming, and Levy, G, (1984). Pharmacokinetic and pharmacodynamic studies of acute interaction between Warfarin enantiomers and Metronidazol. /. Pharmacol Exp, Ther., 232 72-79,... 

Liquid chromatography/electrochemistry (LCEC) has become recognized as a powerful tool for the trace determination of easily oxidizable and reducible compounds. This is because detection of as little as 0.1 pmol of material is readily accomplished with relatively simple and inexpensive equipment. Initial interest in LCEC was generated by the determination of several aromatic metabolites of tyrosine in the central nervous system. However, the application of LCEC into other areas of analysis including pharmaceutical analysis and especially pharmacokinetic and pharmacodynamic studies has become common. ... 

Phase I Safety and tolerance evaluation in human volunteers or in a small number of patients and pharmacokinetic and pharmacodynamic studies (human pharmacology). 

Sadler BM, Gillotin C, Lou Y, Stein DS. Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing. Antimicrob Agents Chemother 2001 45(l) 30-7. 

Londong W, Londong V, Federle C, Tanswell P, Voderholzer U. Pharmacokinetic and pharmacodynamic studies in man simulating acute and chronic treatment with oral pirenzepine. Eur J Clin Pharmacol 1989 36(4) 369-74. 

Zamboni WC, Egorin MJ, Van Echo DA, Day RS, Meisenberg BR, Brooks SE, Doyle LA, Nemieboka NN, Dobson JM, Tait NS, Tkaczuk KH. Pharmacokinetic and pharmacodynamic study of the combiuatiou of docetaxel aud topotecan in patients with sohd tumors. J Chn Oncol 2000 18(18) 3288-94. 

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