Population pharmacokinetic analysis of pegylated interferon alfa-2b and interferon alfa-2b in patients with chronic hepatitis C.
BACKGROUND
This study quantified pharmacokinetic changes in pegylated and nonpegylated interferon alfa-2b during 48 weeks of treatment and the influences of covariates on the basis of sparsely sampled serum concentrations and activity values. Possible relationships between pharmacokinetic and pharmacodynamic variables were investigated.


METHODS
Patients with chronic hepatitis C were enrolled in a clinical trial that compared the efficacy of pegylated interferon alfa-2b with interferon alfa-2b. Single blood samples were obtained from each patient at weeks 4, 12, 24, 36, and 48. Three pharmacostatistical models were developed for 2 immunoassays and 1 bioassay.


RESULTS
Apparent clearance values of pegylated interferon alfa-2b and interferon alfa-2b at the end of treatment declined 33.7% and 80.0%, respectively, from their week 4 values. Bioactivity increased 41% to 58% at week 48 for different treatment groups. Changes were greatest in the first weeks of administration and diminished during the subsequent months. Body weight had a modest positive effect on clearance values and activity. Within each dose level, no significant associations were observed between pharmacokinetic variables and any pharmacodynamic variables (hepatitis C virus--RNA responses or changes in neutrophils and platelets).


CONCLUSIONS
This analysis confirms earlier observations of progressive pharmacokinetic changes in the patients with hepatitis C during 48 weeks of treatment. The absence of a relationship between toxicity or efficacy variables and interferon concentration or activity (within a dose level) suggests that clinical management of patients (eg, for efficacy or to manage toxicity) should be based on clinically derived dosing guidelines rather than on serum concentration or activity criteria.
Jen
J F
JF
Department of Statistics, Schering-Plough Research Institute, Kenilworth, NJ 007033, USA. frank.j.jen@spcorp.com.
Glue
P
P
Ezzet
F
F
Chung
C
C
Gupta
S K
SK
Jacobs
S
S
Hajian
G
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001792:Blood Platelets / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism; D011092:Polyethylene Glycols; D011153:Population; D011994:Recombinant Proteins
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a