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Prediction of Human Renal Clearance from Preclinical Species for a Diverse Set of Drugs That Exhibit Both Active Secretion and Net Re- Absorption

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Prediction of human renal clearance from preclinical species for a diverse set of drugs that exhibit both active secretion and net re- absorption Stuart W. Paine, Karelle Ménochet, Rebecca Denton, Dermot F. McGinnity, Robert J. Riley Table 1 Compound CLR Unbound CLR References Human Dog Rat Human Dog Rat Ampicillin 1.39 3.25 11.80 1.70 3.61 13.11 Shrewsbury, 1986; Goodman and Gilman, 1996; Griffin, 2002 Carbamazepine 0.13 0.53 0.45 0.42b 1.96b 2.24b Morselli and Frigerio, 1975; Remmel et al., 1990; Griffin, 2002; Goodman and Gilman, 2006 Cefazolin 0.76 3.14 4.92 9.27b 4.23b 41.02b Komiya et al., 1981; Sawada et al., 1984; Goodman and Gilman, 2006 Cefclidin 1.47 2.52 8.20 1.61 2.75 9.15 Nakashima et al., 1989; Kita et al., 1992 Cefmetazole 1.54 3.92 7.98 7.96b 4.36b 14.25 Sawada et al., 1984 Cefodizime 0.50 1.13 0.40 1.84 2.51 2.86 Klesel et al., 1984; Barre, 1990; Matsushita et al., 1992 Cefoperazone 1.20 3.24 3.11 6.82 4.11b 4.17 Sawada et al., 1984 Cefotetan 0.15 2.11 6.65 1.03 2.35b 9.45 Komiya et al., 1981; Goodman and Gilman, 2006 Cefozopran 2.55 2.69 6.99 3.68 3.00 7.47 Kita et al., 1992; Paulfeuerborn et al., 1993 Cefpiramide 0.07 3.62 3.35 1.78 5.17 6.21 Sawada et al., 1985 Cefpirome 1.17 2.63 8.32 1.30 2.83 9.88 Kavi et al., 1988; Kita et al., 1992; Sakamoto et al., 1993 Ceftazidime 0.88 2.29 8.41 1.12 2.56 8.83 Kita et al., 1992; Sakamoto et al., 1993; Araki et al., 2002; Goodman and Gilman, 2006 Cimetidine 5.15 6.53 37.65 6.35 7.73 45.06 Griffin, 2002; Goodman and Gilman, 2006 Dolasetron 5.02 4.83 34.0 10.25 10.98 77.27 Sanwald-Ducray and Dow, 1997 Donepezil 0.31 0.26 1.19 2.36b 0.43b 2.84b Matsui et al., 1999; Goodman and Gilman, 2006 Fluconazole 0.20 0.60 0.72 0.24b 0.67 0.81 Humphrey et al., 1985; Jezequel, 1994; Goodman and Gilman, 2006 Furosemide 1.18 11.9 2.83 84.19b 383.94b 141.50b Lee et al., 1986; Jang et al., 1994; Goodman and Gilman, 2006 Gabapentin 1.06 1.54 9.08 1.09 1.59 9.37 Radulovic et al., 1995; Goodman and Gilman, 2006 Garenoxacin 0.80 0.37 1.65 3.20 1.61 12.60 Gajjar et al., 2003; Hayakawa et al., 2003 Ibuprofen 0.008 0.06a 0.0002a 1.50b 5.83b 0.01b Goodman and Gilman, 2006 Indomethacin 0.21 0.07a 0.001a 22.11b 8.05b 0.50b Goodman and Gilman, 2006 Inogatran 3.05 3.40 15.7 4.01 4.47 20.66 Teger-Nilsson et al., 1995; Eriksson et al., 1998 Levetiracetam 0.63 0.69 2.18 0.70 0.77 2.42 Isoherranen et al., 2001; Benedetti et al., 2004; Goodman and Gilman, 2006 Losartan 0.97 3.03a 0.003a 48.60b 58.72b 0.33b Goodman and Gilman, 2006 Melagatran 1.71 2.98 8.60 2.00 3.33 9.56 Eriksson et al., 1998; Eriksson et al., 2003 Moxalactam 1.25 1.99 7.69 3.13 3.61 15.08 Sawada et al., 1984 Moxifloxacin 0.50 0.37 3.60 0.90 0.52 5.71 Siefert et al., 1999; Goodman and Gilman, 2006 Naproxen 0.004 0.02 0.06 4.00b 7.87b 22.64b Runkel et al., 1972; Sugawara et al., 1978; Griffin, 2002; Goodman and Gilman, 2006 Ramatroban 1.36 1.65a 0.64 56.67b 30.44b 12.57b Insight., ; Boberg et al., 1997 Ranitidine 7.18 10.1 7.78 8.44 14.43 8.64 Boom et al., 1998; Griffin, 2002; Goodman and Gilman, 2006 Sematilide 3.33 6.10 17.41 3.92b 6.78b 19.34b Hinderling et al., 1993 Sulfinpyrazone 0.08 0.37 0.05 12.02b 6.27b 20.35b Dieterle and Faigle, 1981; Pedersen et al., 1982 Sulfisoxazole 0.13 0.33 0.06 1.15b 0.55 6.00b Yacobi and Levy, 1979; Suber et al., 1981; Oie et al., 1982 Theophylline 0.12 0.82 0.57 0.27 1.46 1.43 Kuze et al., 1988; Poulin and Theil, 2002; Goodman and Gilman, 2006 UK-224,671 0.41 0.90 6.58 0.99 3.21 19.35 Beaumont et al., 2000 UK-240,455 3.66 5.33 6.84 28.15 35.53 228.00 Webster et al., 2003 a: Renal clearances measured in-house. b: Plasma protein binding measured in-house. Araki H, Ogake N, Tsuneda R, Minami S, Watanabe Y, Tamai I and Tsuji A (2002) Muscle distribution of antimicrobial agents after a single intravenous administration to rats. Drug Metab Pharmacokinet 17:237-244. Barre J (1990) Pharmacokinetics of cefodizime: a review of the data on file. J Antimicrob Chemother 26 Suppl C:95-101. Beaumont K, Harper A, Smith DA and Abel S (2000) Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dog and human. Xenobiotica 30:627-642. Benedetti MS, Coupez R, Whomsley R, Nicolas JM, Collart P and Baltes E (2004) Comparative pharmacokinetics and metabolism of levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog. Xenobiotica 34:281-300. Boberg M, Ahr HJ, Beckermann B, Buhner K, Siefert HM, Steinke W, Wunsche C and Hirayama M (1997) Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals. 1st communication: absorption, concentrations in plasma, metabolism, and excretion after single administration to rats and dogs. Arzneimittelforschung 47:928-938. Boom SP, Meyer I, Wouterse AC and Russel FG (1998) A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog. Biopharm Drug Dispos 19:199-208. Dieterle W and Faigle JW (1981) Species differences in the disposition and metabolism of sulfinpyrazone. Xenobiotica 11:559-568. Eriksson UG, Bredberg U, Hoffmann KJ, Thuresson A, Gabrielsson M, Ericsson H, Ahnoff M, Gislen K, Fager G and Gustafsson D (2003) Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. 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Hayakawa H, Fukushima Y, Kato H, Fukumoto H, Kadota T, Yamamoto H, Kuroiwa H, Nishigaki J and Tsuji A (2003) Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters. Drug Metab Dispos 31:1409-1418. Hinderling PH, Dilea C, Koziol T and Millington G (1993) Comparative kinetics of sematilide in four species. Drug Metab Dispos 21:662-669. Humphrey MJ, Jevons S and Tarbit MH (1985) Pharmacokinetic evaluation of UK- 49,858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrob Agents Chemother 28:648-653. Insight. ARD. http://www.adisinsight.com// Isoherranen N, Yagen B, Soback S, Roeder M, Schurig V and Bialer M (2001) Pharmacokinetics of levetiracetam and its enantiomer (R)-alpha-ethyl-2-oxo- pyrrolidine acetamide in dogs. Epilepsia 42:825-830. Jang SH, Lee MG and Kim ND (1994) Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats. Biopharm Drug Dispos 15:185-206. Jezequel SG (1994) Fluconazole: interspecies scaling and allometric relationships of pharmacokinetic properties. J Pharm Pharmacol 46:196-199. Kavi J, Andrews JM, Ashby JP, Hillman G and Wise R (1988) Pharmacokinetics and tissue penetration of cefpirome, a new cephalosporin. J Antimicrob Chemother 22:911-916. Kita Y, Yamazaki T and Imada A (1992) Comparative pharmacokinetics of SCE- 2787 and related antibiotics in experimental animals. Antimicrob Agents Chemother 36:2481-2486. Klesel N, Limbert M, Seeger K, Seibert G, Winkler I and Schrinner E (1984) Cefodizime, an aminothiazolylcephalosporin. II. Comparative studies on the pharmacokinetic behavior in laboratory animals. J Antibiot (Tokyo) 37:901-909. Komiya M, Kikuchi Y, Tachibana A and Yano K (1981) Pharmacokinetics of new broad-spectrum cephamycin, YM09330, parenterally administered to various experimental animals. Antimicrob Agents Chemother 20:176-183. Kuze T, Miyazaki H and Taneike T (1988) [Theophylline: pharmacokinetics, metabolism and urinary excretion in dogs]. Nippon Yakurigaku Zasshi 91:325-334. Lee MG, Li T and Chiou WL (1986) Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of furosemide. Biopharm Drug Dispos 7:537-547. Matsui K, Taniguchi S and Yoshimura T (1999) Correlation of the intrinsic clearance of donepezil (Aricept) between in vivo and in vitro studies in rat, dog and human. Xenobiotica 29:1059-1072. Matsushita H, Suzuki H, Sugiyama Y, Sawada Y, Iga T, Kawaguchi Y and Hanano M (1992) Effect of benzylpenicillin on the disposition of cefodizime in rats: no net effect on total clearance due to decreased hepatobiliary clearance and increased renal clearance.
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    Antithrombotic Agents in the Management of Sepsis !"#$ Loyola University Medical Center, Maywood, Illinois-60153, USA ABSTRACT Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with mul- tiple organ dysfunction is termed, severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading bacteria may be considered as a balance between proinflammatory and antiinflammatory reaction. While an inadequate proinflammatory reaction and a strong antiinflammatory response could lead to overwhelming infection and death of the patient, a strong and uncontrolled pro- inflammatory response, manifested by the release of proinflammatory mediators may lead to microvas- cular thrombosis and multiple organ failure. Endotoxin triggers sepsis by releasing various mediators inc- luding tumor necrosis factor-alpha and interleukin-1(IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen speci- es and nitric oxide (NO). Other mediators involved in the sepsis syndrome include IL-1, IL-6 and IL-8; arachidonic acid metabolites; platelet activating factor (PAF); histamine; bradykinin; angiotensin; comp- lement components and vasoactive intestinal peptide. These proinflammatory responses are counterac- ted by IL-10. Most of the trials targeting the different mediators of proinflammatory response have failed due a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable better treatment options. Targeting the coagulation system with various anticoagulant agents inc- luding antithrombin, activated protein C (APC), tissue factor pathway inhibitor (TFPI) is a rational appro- ach. Many clinical trials have been conducted to evaluate these agents in severe sepsis.
  • Center for Drug Evaluation and Research Application

    Center for Drug Evaluation and Research Application

    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-512 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology Review By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology OND IO NDA: 22-307 Submission date: 4/19/2010 Drug: Pradaxa™ (Dabigatran etexilate mesylate) Sponsor: Boehringer Ingelheim Pharma GmbH & Co. KG Indication: Prevention of stroke and systemic embolism in patients with atrial fibrillation Reviewing Division: Division of Cardiovascular and Renal Products Comments: The pharm/tox reviewer and supervisor found the nonclinical information submitted for dabigatran to be sufficient to support the proposed use. The reviewer proposes pregnancy category C for the labeling. Dabigatran induced some reproductive toxicity in rats manifest as a decreased number of implantations, decreased number of viable fetuses, increase in the resorption rate, increase in post-implantation loss, and an increase in the number of dead offspring when given at doses of 70 mg/kg (about 2.6 to 3 times the MRHD of 300 mg/day on a mg/m2 basis). Dabigatran also induced some fetal structural variations but did not induce fetal malformations in rats or rabbits. Dabigatran was evaluated for carcinogenicity in 2-year rat and mouse studies. The Executive Carcinogenicity Assessment Committee concluded that these studies were adequate and there were no drug-related tumors in either study. Conclusions: I concur with the Division pharm/tox conclusion that the nonclinical data support approval of this NDA. No additional nonclinical studies are recommended at this time. The proposed Established Pharmacologic Class for dabigatran is "direct thrombin inhibitor". This is appropriate because it is consistent with other moieties of this class.