Pharmacokinetics chnical

When considering the Hkely pharmacokinetic profile of a novel compound in man, it is important to recognize the variability that may be encountered in the cHnical setting. Animal pharmacokinetic studies are generally conducted in inbred animal colonies that tend to show minimal inter-subject variabiHty. The human population contains a diverse genetic mix, without the additional variability introduced by age, disease states, environmental factors and co-medications. Hence any estimate of pharmacokinetic behaviour in man must be tempered by the expected inherent variability. For compounds with high metabolic clearance (e. g. midazolam), inter-individual variability in metabolic clearance can lead to greater than 10-fold variation in oral clearance and hence systemic exposure [1]. 

By contrast, in the population approach, the raw data set that is analysed consists of concentration-time points (and other necessary data such as demographic information) taken from a large number (up to hundreds to thousands) of patients in Phase 11 and/or Phase 111 trials. The number of plasma samples per subject may be sparse but it is possible to estimate the individual pharmacokinetic characteristics of each subject and hence a measure of the mean parameters and their variability can be assessed. Relationships can be sought between patient characteristics (demographics, chnical status) and pharmacokinetic values is found, its consequence may be examined by looking for altered efficacy or safety which may not be possible in a traditional volunteer study. This might lead to demonstration of a therapeutic concentration range. 

Module 2 Common technical document summaries Overall common technical document table of contents Introduction Quahty overall summary Non-chnical overview Clinical overview Non-chnical summary Pharmacology Written summary Tabulated summary Pharmacokinetics Written summary Tabulated summary Toxicology... 

Much remains to be done to improve the physicochemical properties and the pharmacokinetic characteristics of the estabhshed compound classes. A critical observer cannot help but wonder about the PK/PD profiles of many of the compoimds currently undergoing chnical development with hmited oral bioavailability, often necessitating intravenous administration, and rather short half fives in combination with often transient acetylation effects, the need for HDAC inhibitors with a more beneficial pharmacokinetic profile seems key. 

Fig. 5. Selection of candidate genes for selection in a either a study examining the role of pharmacogenomics in drug disposition and/or action or alternatively, use as a chnical tool to individualize drug therapy. Those genes prioritized for inclusion should he those shown to contribute markedly to drug pharmacokinetics and/or dynamics.

Baumann P Chnical pharmacokinetics of citalopram and other selective serotonergic reuptake inhibitors (SSRIs). Int Chn Psychopharmacol 6 (suppl 5) 13-20, 1992... 

E. J. Ariens (1984). Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and chnical pharmacology. Eur. J. Clin. Pharmacol. 26 663-668. 

F. E. Simons, K. J. Simons (1999). Chnical pharmacology of new histamine HI receptor antagonists. Clin. Pharmacokinet. 36 329. 

The protein binding of compounds with such low partition coefficients is virtually non-existent as demonstrated by MRI and pharmacokinetic studies. The low protein binding of the extracellular gadoHnium complexes currently used in chnical practice correlates very well with their excellent safety profile. 

Gibaldi, M. Levy, G. Pharmacokinetics in chnical practice I. Concepts. JAMA 1976, 235, 1864-1867. 

Holford, N.H.G. Sheiner, L.B. Understanding the dose-effect relationship chnical application of pharmacokinetic-pharmacodynamic models. Chn. Pharmacokinet. 1981, 6, 429-453. 

Vasey, P. Kaye, S.B. Morrison, R. Twelves, C. Wilson, P. Duncan, R. Thomson, A.H. Murray, L.S. Hilditch, T.E. Murray, T. Burtles, S. Fraier, D. Frigerio, E. Cassidy, J. Phase I clinical and pharmacokinetics study of PKl (iV-(2-hydroxy propy l)methacrylamide copolymer doxorubicin) first member of a new class of chemotherapeutic agents - drug-polymer conjugates. Chnical Cancer Research 1999, 5, 83-94. 

Matsumura, Y. Hamguchi, T. Ura, T. Muro, K. Yamada, Y. Shimada, Y. Shirao, Y. Okusaka, T. Ueno, H. Ikeda, M. Watanable, N. Phase I chnical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. British Journal of Cancer 2004,91,1775-1781. 

R. S. Pharmacokinetics of transdermal testosterone gel in hypogonadal men apphcation of gel at one site versus four sites a general chnical research center study. J. Clin. Endocrinol. Metab. 2000, 85, 964—969. 

Gugler R, AUgayer H. Effects of antacids on the chnical pharmacokinetics of drugs. An update. Chn Pharmacokinet 1990 18(3) 210-19. 

Manson AJ, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, Lees AJ. Intravenous apomorphine therapy in Parkinson s disease chnical and pharmacokinetic observations. Brain 2001 124(Pt 2) 331 0. 

Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM. Glucuronidation of 3 -azido-3 -deoxythymidine (zidovudine) by human liver microsomes relevance to chnical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother 1998 42(7) 1592-6. 

Ciclosporin pharmacokinetics vary considerably between patients, and even in an individual patient from time to time, with changes in the chnical condition and treatment, particularly with administration of other drugs (301). Inadequate exposure to ciclosporin is a key factor in acute rejection and contributes to the development of chronic rejection and graft failure. Monitoring of ciclosporin concentrations is widely adopted as an accurate and practical measure of drug exposure (302). 

When a drug has a relatively narrow therapeutic index, such as acenocoumarol, pharmacokinetic interactions can have serious chnical consequences. 

Yukawa E, Nonaka T, Yukawa M, Ohdo S, Higuchi S, Kuroda T, Goto Y. Pharmacoepidemiologic investigation of a clonazepam-carbamazepine interaction by mixed effect modeling using routine chnical pharmacokinetic data in Japanese patients. J Clin Psychopharmacol 2001 21(6) 588-93. 

Pharmacokinetic and pharmacodynamic interactions between dofetihde 0.5 mg bd and verapamil 80 mg tds have been studied in 12 healthy men (62). At steady state verapamil increased the peak plasma concentration of dofetilide from 2.40 to 3.43 ng/ml, without other pharmacokinetic effects. This was accompanied by a small increase in the prolongation of the QTc interval produced by dofetilide alone, from 20 to 26 ms. Although this small effect is unlikely to be of chnical significance, it would be wise to avoid verapamil in patients taking dofetihde. 

Thyss A, Milano G, Renee N, Vallicioni J, Schneider M, Demard F. Chnical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer. Cancer Chemother Pharmacol 1986 16(l) 64-6. 

Shenfield GM, Griffin JM. Chnical pharmacokinetics of contraceptive steroids. An update. Chn Pharmacokinet 1991 20(l) 15-37. 

Davies NM, McLachlan AJ, Day RO, WUhams KM. Chnical pharmacokinetics and pharmacodynamics of cele-coxib a selective cyclo-oxygenase-2 inhibitor. Chn Pharmacokinet 2000 38(3) 225-42. 

Peters DH, Friedel HA, McTavish D. Azithromycin. A review of its antimicrobial activity, pharmacokinetic properties and chnical efficacy. Drugs 1992 44(5) 750-99. 

No serious adverse effects were noted in a phase 1 chnical study of GAB-88 aimed at determining its safety and pharmacokinetics in eight healthy men who were given three different doses (0.15 g/kg/hour, 0.3 g/kg/ hour, and 0.5 g/kg/hour) at 1-week intervals. Serum elec-troljdes did not change significantly, except for zinc (4). 

Zhao XJ, Ishizaki T. A further interaction study of quinine with chnically important drugs by human liver microsomes determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet 1999 24(3) 272-8. 

Kaye CM, Nicholls B. Chnical pharmacokinetics of ropinirole. Clin Pharmacokinet 2000 39(4) 243-54. 

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