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Antimicrobial Agents and Chemotherapy, January 2009, p. 95-103, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00752-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir {triangledown}

Fenglei Huang,1* Kristin Drda,1 Thomas R. MacGregor,1 Joseph Scherer,1 Lois Rowland,1 Thuy Nguyen,1 Charles Ballow,2 Mark Castles,1 and Patrick Robinson1

Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368,1 Buffalo Clinical Research Center, Buffalo, New York2

Received 9 June 2008/ Returned for modification 27 July 2008/ Accepted 20 October 2008

The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated.

* Corresponding author. Mailing address: Clinical Pharmacokinetics & Pharmacodynamics, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368. Phone: (203) 798-4537. Fax: (203) 791-6003. E-mail: fhuang{at}rdg.boehringer-ingelheim.com

{triangledown} Published ahead of print on 27 October 2008.

Antimicrobial Agents and Chemotherapy, January 2009, p. 95-103, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00752-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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