This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sadler, B. M.
Right arrow Articles by Roskell, N. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sadler, B. M.
Right arrow Articles by Roskell, N. S.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 1999, p. 1686-1692, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor, following Oral Administration of Single Doses to HIV-Infected Adults

Brian M. Sadler,* Cynthia D. Hanson, Gregory E. Chittick, William T. Symonds, and Neil S. Roskell

Glaxo Wellcome Inc., Research Triangle Park, North Carolina

Received 19 June 1998/Returned for modification 25 October 1998/Accepted 4 April 1999

We conducted a double-blind, placebo-controlled, parallel, dose-escalation trial to evaluate the pharmacokinetics and safety of single, oral doses of amprenavir (141W94; formerly VX-478), a potent inhibitor of human immunodeficiency virus (HIV) type 1 protease, administered as hard gelatin capsules in 12 HIV-infected subjects. The doses of amprenavir evaluated were 150, 300, 600, 900, and 1,200 mg. Amprenavir was rapidly absorbed, with the time to maximum concentration occurring within 1 to 2 h after dosing. On the basis of power model analysis, the increase in the maximum concentration of amprenavir in plasma (Cmax) was less than dose proportional, and the increase in the area under the concentration-time curve from time zero to infinity (AUC0-infinity ) was greater than dose proportional; mean slopes (with 90% confidence intervals) were 1.25 (1.16 to 1.35) and 0.78 (0.78 to 0.86) for AUC0-infinity and Cmax, respectively. Amprenavir was eliminated slowly, with a terminal-phase half-life of 8 h. A second study was conducted to determine the bioavailability of the hard gelatin capsule relative to that of a subsequently developed soft gelatin capsule. The capsules were bioequivalent in terms of AUC0-infinity but not in terms of Cmax; geometric-least-squares means ratios (with 90% confidence intervals) were 1.03 (0.92 to 1.14) and 1.25 (1.03 to 1.53) for AUC0-infinity and Cmax, respectively. Administration of soft gelatin capsules of amprenavir with a high-fat breakfast resulted in a 14% decrease in the mean AUC0-infinity (from 9.58 to 8.26 µg · h/ml), which is not likely to be clinically significant. The most common adverse events related to amprenavir were headache, nausea, and hypesthesia. Amprenavir appears to be safe and well tolerated over the dose range of 150 to 1200 mg. On the basis of the present single-dose studies, amprenavir is an HIV protease inhibitor with favorable absorption and clearance pharmacokinetics that are only minimally affected by administration with food.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, Glaxo Wellcome Inc., Research Triangle Park, NC 27709. Phone: (919) 483-1449. Fax: (919) 483-6380. E-mail: bms44974{at}glaxowellcome.com.

Antimicrobial Agents and Chemotherapy, July 1999, p. 1686-1692, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Landman, R., Capitant, C., Descamps, D., Chazallon, C., Peytavin, G., Katlama, C., Pialoux, G., Bentata, M., Brun-Vezinet, F., Aboulker, J.-P., Yeni, P., on behalf of the ANRS 127 study group, (2009). Efficacy and safety of ritonavir-boosted dual protease inhibitor therapy in antiretroviral-naive HIV-1-infected patients: the 2IP ANRS 127 study. J Antimicrob Chemother 64: 118-125 [Abstract] [Full Text]  
  • Okusanya, O., Forrest, A., DiFrancesco, R., Bilic, S., Rosenkranz, S., Para, M. F., Adams, E., Yarasheski, K. E., Reichman, R. C., Morse, G. D., and the ACTG 5043 Protocol Team, (2007). Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks. Antimicrob. Agents Chemother. 51: 1822-1826 [Abstract] [Full Text]  
  • Morse, G. D., Rosenkranz, S., Para, M. F., Segal, Y., DiFrancesco, R., Adams, E., Brizz, B., Yarasheski, K. E., Reichman, R. C., the ACTG 5043 Protocol Team, (2005). Amprenavir and Efavirenz Pharmacokinetics before and after the Addition of Nelfinavir, Indinavir, Ritonavir, or Saquinavir in Seronegative Individuals. Antimicrob. Agents Chemother. 49: 3373-3381 [Abstract] [Full Text]  
  • Yogev, R., Kovacs, A., Chadwick, E. G., Homans, J. D., Lou, Y., Symonds, W. T. (2005). Single-Dose Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus Type 1 (HIV-1) Protease Inhibitor, in HIV-Infected Children. Antimicrob. Agents Chemother. 49: 336-341 [Abstract] [Full Text]  
  • Treluyer, J. M., Bowers, G., Cazali, N., Sonnier, M., Rey, E., Pons, G., Cresteil, T. (2003). Oxidative Metabolism of Amprenavir in the Human Liver. Effect of the CYP3A Maturation. Drug Metab. Dispos. 31: 275-281 [Abstract] [Full Text]  
  • Marcelin, A.-G., Lamotte, C., Delaugerre, C., Ktorza, N., Ait Mohand, H., Cacace, R., Bonmarchand, M., Wirden, M., Simon, A., Bossi, P., Bricaire, F., Costagliola, D., Katlama, C., Peytavin, G., Calvez, V. (2003). Genotypic Inhibitory Quotient as Predictor of Virological Response to Ritonavir-Amprenavir in Human Immunodeficiency Virus Type 1 Protease Inhibitor-Experienced Patients. Antimicrob. Agents Chemother. 47: 594-600 [Abstract] [Full Text]  
  • Demarles, D., Gillotin, C., Bonaventure-Paci, S., Vincent, I., Fosse, S., Taburet, A. M. (2002). Single-Dose Pharmacokinetics of Amprenavir Coadministered with Grapefruit Juice. Antimicrob. Agents Chemother. 46: 1589-1590 [Abstract] [Full Text]  
  • Sadler, B. M., Gillotin, C., Lou, Y., Eron, J. J., Lang, W., Haubrich, R., Stein, D. S. (2001). Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir. Antimicrob. Agents Chemother. 45: 3663-3668 [Abstract] [Full Text]  
  • Huang, L., Wring, S. A., Woolley, J. L., Brouwer, K. R., Serabjit-Singh, C., Polli, J. W. (2001). Induction of P-Glycoprotein and Cytochrome P450 3A by HIV Protease Inhibitors. Drug Metab. Dispos. 29: 754-760 [Abstract] [Full Text]  
  • Sadler, B. M., Gillotin, C., Lou, Y., Stein, D. S. (2001). In Vivo Effect of {alpha}1-Acid Glycoprotein on Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Protease Inhibitor. Antimicrob. Agents Chemother. 45: 852-856 [Abstract] [Full Text]  
  • Sadler, B. M., Gillotin, C., Lou, Y., Stein, D. S. (2001). Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing. Antimicrob. Agents Chemother. 45: 30-37 [Abstract] [Full Text]  
  • Schmidt, B., Korn, K., Moschik, B., Paatz, C., Überla, K., Walter, H. (2000). Low Level of Cross-Resistance to Amprenavir (141W94) in Samples from Patients Pretreated with Other Protease Inhibitors. Antimicrob. Agents Chemother. 44: 3213-3216 [Abstract] [Full Text]  
  • Mammano, F., Trouplin, V., Zennou, V., Clavel, F. (2000). Retracing the Evolutionary Pathways of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors: Virus Fitness in the Absence and in the Presence of Drug. J. Virol. 74: 8524-8531 [Abstract] [Full Text]  
  • Duval, X., Le Moing, V., Longuet, P., Leport, C., Vildé, J.-L., Lamotte, C., Peytavin, G., Farinotti, R. (2000). Efavirenz-Induced Decrease in Plasma Amprenavir Levels in Human Immunodeficiency Virus-Infected Patients and Correction by Ritonavir. Antimicrob. Agents Chemother. 44: 2593-2593 [Full Text]  
  • Ziermann, R., Limoli, K., Das, K., Arnold, E., Petropoulos, C. J., Parkin, N. T. (2000). A Mutation in Human Immunodeficiency Virus Type 1 Protease, N88S, That Causes In Vitro Hypersensitivity to Amprenavir. J. Virol. 74: 4414-4419 [Abstract] [Full Text]  
  • Veronese, L., Rautaureau, J., Sadler, B. M., Gillotin, C., Petite, J.-P., Pillegand, B., Delvaux, M., Masliah, C., Fosse, S., Lou, Y., Stein, D. S. (2000). Single-Dose Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Type 1 Protease Inhibitor, in Subjects with Normal or Impaired Hepatic Function. Antimicrob. Agents Chemother. 44: 821-826 [Abstract] [Full Text]  
  • Brophy, D. F., Israel, D. S., Pastor, A., Gillotin, C., Chittick, G. E., Symonds, W. T., Lou, Y., Sadler, B. M., Polk, R. E. (2000). Pharmacokinetic Interaction between Amprenavir and Clarithromycin in Healthy Male Volunteers. Antimicrob. Agents Chemother. 44: 978-984 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»