Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children.
The purpose of this study was to assess the population pharmacokinetics (PK) and pharmacodynamics (PD) of zidovudine (ZDV) in infants and children. This evaluation includes 394 subjects who participated in Pediatric AIDS Clinical Trials Group (PACTG) Study 152 and received either ZDV alone or in combination with didanosine. The most significant PK covariate was age, with infants < 2 years of age having reduced size-adjusted clearance. ZDV exposure was weakly related to maximal reduction in immune complex-dissociated (ICD) p24 antigen but not to reduction at 6 months. Mild chronic anemia occurred in 7.6% of subjects with ZDV average concentration < 1.3 microM (350 ng/mL) versus in 23.4% subjects with higher ZDV concentrations (p < 0.001). There was a direct linear relationship between hemoglobin and ZDV levels. It was concluded that ZDV oral clearance is reduced in infants compared to older children. This lower clearance leads to higher ZDV exposure in infants and contributes to increased hematologic toxicity.
Capparelli
Edmund V
EV
University of California, San Diego, School of Medicine, La Jolla, California, USA.
Englund
Janet A
JA
Connor
James D
JD
Spector
Stephen A
SA
McKinney
Ross E
RE
Palumbo
Paul
P
Baker
Carol J
CJ
D000293:Adolescent; D000375:Aging / Q000378:metabolism; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D015215:Zidovudine