J Clin Pharmacol xxxx;xx:x-x 93 J Clin Pharmacol 2011;51:93-101 93 T igecycline is a glycylcycline antibiotic, an ana- logue of minocycline, which was developed in response to the growing worldwide problem of antibi- otic resistance. It inhibits protein translation by bind- ing to the 30S bacterial ribosomal subunit and by blocking entry of amino-acyl transfer RNA molecules into the A site of the ribosome. 1,2 It has been shown to circumvent bacterial resistance mechanisms mediated by cell membrane efflux 3,4 and ribosomal protection proteins. 5 The bulky 2-butylglycylamido substitute at position 9 is required to overcome both bacterial resistance mechanisms. 2 The structure is shown in Figure 1. Tigecycline is available commercially for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community-acquired pneumonia. The recom- mended dose is 100 mg followed by 50 mg every 12 hours administered as 30- to 60-minute intravenous (IV) infusions. 6,7 The pharmacokinetics of tigecycline have been well characterized in healthy volunteers and in patients, and the pharmacokinetic parameters observed in patients with infections are similar to those observed in healthy subjects. 8,9 After IV infu- sion, serum concentrations fall rapidly at first as the drug distributes to the tissues and then more slowly during elimination. The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1-1.0 μg/mL). The steady-state volume of distribution of tigecycline averages 500 to 700 L (7-9 L/kg). Tigecycline is excreted mainly as unchanged drug by the biliary and fecal routes, with approximately 20% Tigecycline belongs to a new class of tetracyclines, the glycylcyclines, less than 20% of which is metabolized in the liver. Twenty-five patients with cirrhosis with varying degrees of functional hepatic reserve (Child-Pugh A, n = 10; B, n = 10; C, n = 5) and 23 healthy adults, matched by age, sex, weight, and smoking habits, received 100 mg of tigecycline infused intravenously over 60 minutes. Serum and urine samples were collected up to 120 hours after dosing. Pharmacokinetic data were derived using non- compartmental methods. The most common treatment- emergent adverse events in healthy volunteers were nausea (56.5%), vomiting (21.7%), and headache (21.7%) and in the patients with cirrhosis, albuminuria (12%). Mean (±1 SD) tigecycline clearance values were 29.8 ± 11.3 L/h in healthy subjects and 31.2 ± 13.9 L/h (Child-Pugh A), 22.1 ± 9.3 L/h (Child-Pugh B), and 13.5 ± 2.7 L/h (Child-Pugh C) in the patients. A single intravenous dose of tigecycline 100 mg was safe and well-tolerated in patients with cir- rhosis with varying degrees of hepatic functional reserve. No adjustment of tigecycline maintenance dosage is war- ranted in patients with compensated or moderately decompensated cirrhosis; doses should be reduced by 50%, to 25 mg, every 12 hours in patients with severely decompensated disease. Keywords: Glycylcycline; hepatic impairment; tigecycline Journal of Clinical Pharmacology, 2011;51:93-101 © 2011 The Author(s) From Pfizer, Clinical Pharmacology, Collegeville, Pennsylvania (Dr Korth- Bradley); Pfizer, Early Development and Clinical Pharmacology, Paris, France (Dr Baird-Bellaire); Biotrial, Rennes, France (Dr Patat); Shire Pharmaceuticals, Wayne, Pennsylvania (Mr Troy); Department of Clinical Pharmacology, University Hospital of Tuebingen, Germany (Dr Böhmer, Dr Gleiter, Dr Buecheler); and the Centre for Hepatology, Royal Free Campus, University College London Medical School, University College London, UK (Dr Morgan). Submitted for publication September 11, 2009; revised version accepted January 17, 2010. Address for corre- spondence: J. M. Korth-Bradley, Pfizer, 500 Arcola Road, Collegeville, PA 19426; e-mail: korthbj@wyeth.com. DOI:10.1177/0091270010363477 Pharmacokinetics and Safety of a Single Intravenous Dose of the Antibiotic Tigecycline in Patients With Cirrhosis Joan M. Korth-Bradley, PharmD, PhD, Susan J. Baird-Bellaire, PhD, Alain A. Patat, MD, Steven M. Troy, MS, Gabriele M. Böhmer, MD, Christoph H. Gleiter, MD, Reinhild Buecheler, MD and Marsha Y. Morgan, MB, ChB SPECIAL POPULATIONS