A population pharmacokinetic analysis of zanamivir in subjects with experimental and naturally occurring influenza: Effects of formulation and route of administration

被引:11
作者
Peng, AW [1 ]
Hussey, EK [1 ]
Moore, KHP [1 ]
机构
[1] Glaxo Wellcome Inc, Clin Pharmacol, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.1177/00912700022008900
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The pharmacokinetics of zanamivir were evaluated in subjects from three phase I single-center and two phase II multicenter, randomized, double-blind, multidose, placebo-controlled trials. A total of 96 phase I subjects received zanamivir (3.6 to 16 mg) intranasally two or six times daily for 4 to 5 days beginning 4 hours before or 1 to 2 days after inoculation with influenza virus. A total of 75 phase II subjects with influenza or a history of exposure to naturally occurring influenza virus were administered zanamivir as an intranasal spray (3.4 mg/nostril), inhaled powder (10 mg), or combination of intranasal and inhaled formulations twice daily for 5 days. population parameters (including demographic factors, zanamivir formulation, infection-related variables, and concurrent medication use) were estimated by a nonlinear mixed-effect modeling software program (NONMEM) using a one-compartment model with first-order absorption and conditional estimation algorithm. Formulation and route of administration were the most significant factors affecting the pharmacokinetics of zanamivir. Relative bioavailability of the inhaled powder to the intranasal drops and spray was 2.3 and 1.6 respectively. No significant differences in pharmacokinetic parameters were observed when demographic variables, indices of infection, or concurrent medication use were considered in either phase I or phase II population analyses.
引用
收藏
页码:242 / 249
页数:8
相关论文
共 15 条
[1]  
BETTS RF, 1995, PRINCIPLES PRACTICE, P1546
[2]   New approaches to influenza chemotherapy - Neuraminidase inhibitors [J].
Calfee, DP ;
Hayden, FG .
DRUGS, 1998, 56 (04) :537-553
[3]   Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers [J].
Cass, LMR ;
Efthymiopoulos, C ;
Bye, A .
CLINICAL PHARMACOKINETICS, 1999, 36 (Suppl 1) :1-11
[4]  
GROSSE C, 1995, 6 INT S PHARM BIOM A, VM, pA25
[5]   Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza [J].
Hayden, FG ;
Treanor, JJ ;
Betts, RF ;
Lobo, M ;
Esinhart, JD ;
Hussey, EK .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1996, 275 (04) :295-299
[6]   Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections [J].
Hayden, FG ;
Osterhaus, ADME ;
Treanor, JJ ;
Fleming, DM ;
Aoki, FY ;
Nicholson, KG ;
Bohnen, AM ;
Hirst, HM ;
Keene, O ;
Wightman, K .
NEW ENGLAND JOURNAL OF MEDICINE, 1997, 337 (13) :874-880
[7]   AMANTADINE AND RIMANTADINE RESISTANCE IN INFLUENZA-A VIRUSES [J].
HAYDEN, FG .
CURRENT OPINION IN INFECTIOUS DISEASES, 1994, 7 (06) :674-677
[8]  
HAYDEN FG, 1996, OPTIONS CONTROL INFL, V3, P718
[9]  
Nicholson K G, 1992, Semin Respir Infect, V7, P26
[10]   INHIBITION OF INFLUENZA-VIRUS REPLICATION IN MICE BY GG167 (4-GUANIDINO-2,4-DIDEOXY-2,3-DEHYDRO-N-ACETYLNEURAMINIC ACID) IS CONSISTENT WITH EXTRACELLULAR ACTIVITY OF VIRAL NEURAMINIDASE (SIALIDASE) [J].
RYAN, DM ;
TICEHURST, J ;
DEMPSEY, MH ;
PENN, CR .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1994, 38 (10) :2270-2275