Pharmacokinetics of didanosine and drug resistance mutations in infants exposed to zidovudine during gestation or postnatally and treated with didanosine or zidovudine in the first three months of life
ABSTRACT There are limited numbers of drugs that are available in formulations that are appropriate for neonates and few studies assessing resistance among infants born to human immunodeficiency virus (HIV)-infected women.
Pharmacokinetics and tolerance of didanosine (ddI) were determined for infants < or =120 days of age. Infants received at least 24 hours of zidovudine (ZDV) treatment, followed by a single ddI dose and pharmacokinetic sampling. The target area under the concentration-time curve (AUC) was between 2.5 and 5.0 microM . hour. Toxicity and drug resistance mutations were assessed at baseline and follow-up times.
The initial ddI pharmacokinetic dosing of 50 mg/m for infants >28 days of age achieved a median AUC0-infinity of 2.8 microM . hour. For infants < or =28 days of age, the target AUC was achieved after dose escalation from 25 mg/m (median AUC0-infinity, 1.4 microM . hour) to 50 mg/m (median AUC0-infinity, 5.40 microM . hour). At baseline, 25% of infected infants had drug resistance mutations (9 of 44 to ZDV and 2 of 44 to ddI). Resistance mutations were present for 29% of infants (5 of 17 infants) with in utero ZDV exposure and 25% (8 of 32 infants) with prior ZDV treatment. The most common ZDV mutation noted at baseline was the T215Y/F (n = 7) mutation; 2 of these infants also had the M41L mutation, which is associated with high level ZDV resistance. No prior exposure was noted for the 2 infants with ddI resistance, which indicates possible perinatal transmission of ddI-resistant virus to these infants.
A dose of 50 mg/m is the appropriate ddI dose for infants <120 days of age and is a safe treatment for newborns when used in combination with ZDV. Genotypic resistance occurs frequently among infected infants exposed to ZDV during gestation or postnatally, which suggests that resistance testing should be considered for infants with newly diagnosed HIV infection.
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ABSTRACT: Antiretroviral (ARV) therapy has been shown to achieve high therapeutic efficacy in treating pediatric HIV disease. The delivery of affordable, child friendly, and easy to store and administer ARV drugs is key to the successful management of HIV in children. In recent years, significant progress has been made in scaling up the access to pediatric ARV therapy among children worldwide. Despite the improved ARV drug access, multiple challenges remain concerning palatability and efficient delivery of ARV drugs to children from infancy into adolescence. Data are limited regarding developmental changes in pharmacokinetics of individual ARV drugs, and pediatric and adult fixed-dose combinations. This review provides a practical discussion regarding the pharmacokinetics of ARV agents in pediatric HIV-infected patients, as well as the practical challenges of currently available formulations, such as palatability of liquid formulations, challenges of crushing tablets, and using adult and pediatric fixed-dose combinations.Paediatric Drugs 06/2011; 13(3):175-92. DOI:10.2165/11587300-000000000-00000 · 1.72 Impact Factor
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ABSTRACT: IMPORTANCE Federal legislation has led to a notable increase in pediatric studies submitted to the Food and Drug Administration (FDA), resulting in new pediatric information in product labeling. However, approximately 50% of drug labels still have insufficient information on safety, efficacy, or dosing in children. Neonatal information in labeling is even scarcer because neonates comprise a vulnerable subpopulation for which end-point development is lagging and studies are more challenging. OBJECTIVE To quantify progress made in neonatal studies and neonatal information in product labeling as a result of recent legislation. DESIGN, SETTING, AND PARTICIPANTS We identified a cohort of drug studies between 1997 and 2010 that included neonates as a result of pediatric legislation using information available on the FDA website. We determined what studies were published in the medical literature, the legislation responsible for the studies, and the resulting neonatal labeling changes. We then examined the use of these drugs in a cohort of neonates admitted to 290 neonatal intensive care units (NICUs) (the Pediatrix Data Warehouse) in the United States from 2005 to 2010. EXPOSURE Infants exposed to a drug studied in neonates as identified by the FDA website. MAIN OUTCOMES AND MEASURES Number of drug studies with neonates and rate of exposure per 1000 admissions among infants admitted to an NICU. RESULTS In a review of the FDA databases, we identified 28 drugs studied in neonates and 24 related labeling changes. Forty-one studies encompassed the 28 drugs, and 31 (76%) of these were published. Eleven (46%) of the 24 neonatal labeling changes established safety and effectiveness. In a review of a cohort of 446 335 hospitalized infants, we identified 399 drugs used and 1 525 739 drug exposures in the first 28 postnatal days. Thirteen (46%) of the 28 drugs studied in neonates were not used in NICUs; 8 (29%) were used in fewer than 60 neonates. Of the drugs studied, ranitidine was used most often (15 627 neonates, 35 exposures per 1000 admissions). CONCLUSIONS AND RELEVANCE Few drug labeling changes made under pediatric legislation include neonates. Most drugs studied are either not used or rarely used in US NICUs. Strategies to increase the study of safe and effective drugs for neonates are needed.12/2013; 168(2). DOI:10.1001/jamapediatrics.2013.4208