Pharmacokinetic evaluation of the combination of zidovudine and didanosine in children with human immunodeficiency virus infection.
As part of a phase I/II trial in children infected with human immunodeficiency virus, we studied the pharmacokinetics of zidovudine and didanosine administered as single agents and in combination. Zidovudine (60 to 180 mg/m2 per dose) was given orally every 6 hours, and didanosine (60 to 180 mg/m2 per dose) every 12 hours. Pharmacokinetic samples were obtained from 54 patients and the area under the plasma concentration-time curve (AUC) was estimated by means of a previously defined limited sampling strategy. Follow-up blood samples were obtained after 4 and 12 weeks of treatment. The mean AUC for zidovudine ranged from 4.8 mumol.hr per liter at 60 mg/m2 to 11.0 mumol.hr per liter at the 180 mg/m2 level, and increased in proportion to the dose. The mean AUC for didanosine ranged from 2.8 mumol.hr per liter (60 mg/m2) to 8.0 mumol.hr per liter (180 mg/m2), with a wide interpatient variability. The AUCs of zidovudine and didanosine remained unchanged when the agents were administered in combination. There was no significant change in the AUCs of either drug after 4 and 12 weeks in comparison with those on day 3 of therapy. However, there was greater interpatient and intrapatient variability with didanosine than with zidovudine. These observations have implications for the future utility of therapeutic drug monitoring with these agents.
Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
B U
BU
Mueller
P A
PA
Pizzo
M
M
Farley
R N
RN
Husson
J
J
Goldsmith
A
A
Kovacs
L
L
Woods
J
J
Ono
J A
JA
Church
P
P
Brouwers
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D008297:Male; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D015215:Zidovudine; D016049:Didanosine