Pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques

Abstract

To determine whether age affects the pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques (Macaca nemestrina), dideoxyinosine (10 mg/kg of body weight) was administered as a single intravenous bolus to macaques at ages <1 week, 1 month, and 4 months. Clearance from plasma at <1 week of age was significantly lower (P < 0.05) and the terminal half-life was significantly higher than the corresponding values obtained at 1 month and 4 months of age. Our data indicate that the pharmacokinetics of dideoxyinosine change significantly with age in M. nemestrina.The incidence of infection with the human immunodeficiency virus (HIV) is on the rise among women of childbearing age. As a result of the maternal-fetal transmission of HIV, the incidence of HIV infection among neonates and children is also on the rise. By 1990, AIDS was one of the 10 leading causes of death among children (16).The dideoxynucleoside analog dideoxyinosine (2',3'-dideoxyinosine; didanosine) is being used in the treatment of HIV infection. However, the question of possible age-dependent changes in the pharmacokinetics of dideoxyinosine in neonates has not been adequately addressed. Balis et al. (2) found no difference between the pharmacokinetics of dideoxyinosine in children (age range, 8 months to 18 years; median, 7.4 years) and adults. After intravenous administration of dideoxyinosine, the fraction of the dose excreted unchanged in the urine approximates the fraction that is metabolized (9). Although not all of the metabolic pathways of dideoxyinosine have been elucidated, dideoxyinosine is metabolized to hypoxanthine and uric acid (18). Given the potential use of dideoxyinosine in HIV-infected infants and children, with treatment starting at an early stage after birth, it is important to determine whether the pharmacokinetics of dideoxyinosine change significantly with age. This information would help to ensure the use of adequate treatment regimens in infants and children and minimize the risk of drug toxicity. Therefore, as part of an ongoing series of investigations on the pharmacokinetics of antiretroviral dideoxynucleosides, we studied the effect of age on the pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques (Macaca nemestrina).Previous studies in our laboratory have indicated that M. nemestrina is an excellent model to use in studying the dispositions of dideoxynucleosides. For example, the pharmacokinetics, including the metabolic and renal clearances of dideoxyinosine (17) and zidovudine (12), in adult macaques, have been shown to be similar to those in humans. In addition, the age-dependent changes in the pharmacokinetics of zidovudine in human infants (3) are similar to those previously reported by us in M. nemestrina (13). MATERIALS AND METHODSDideoxyinosine was supplied by the National Institute of Allergy and Infectious Diseases (Developmental Therapeutics * Corresponding author.Branch, Division of AIDS). All other chemicals used were of reagent grade.Animals. Infant M. nemestrina were serially studied ...

Pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in the neonatal macaque (Macaca nemestrina)

“…These ratios are similar to those reported for adult rhesus monkeys (0.15) at 1 h after drug administration (22). We also have observed an age-dependent change in CSF/plasma drug concentration ratios for zidovudine and ddI in neonatal macaques (13,21). The small but significant changes in the CSF/plasma drug concentration ratios for d4T, zidovudine, and ddI in the neonatal macaque may be attributed to age-related permeability changes in the blood-brain barrier.…”

“…We have chosen M. nemestrina for our studies because this species has proven to be an excellent animal model for the study of dideoxynucleoside disposition. Previous studies in our laboratory with zidovudine (14,15) and dideoxyinosine (ddI) (20,21) in the adult and infant M. nemestrina have shown that the pharmacokinetics of these drugs, including metabolic clearance and renal clearance, are comparable to those in human adults (10,11) and infants (4).…”

Pharmacokinetics of Didanosine in Antepartum and Postpartum Human Immunodeficiency Virus–Infected Pregnant Women and Their Neonates:An AIDS Clinical Trials Group Study

“…On the other hand, our studies in a nonhuman primate, the macaque, led to a different conclusion. The iv clearance of ddI in neonate macaques was significantly lower than in adults, which suggests that in this species the capability to excrete ddI is compromised in the early days of life [28]. This is the first time that the pharmacokinetics of ddI have been evaluated in pregnant women.…”

Maternal-Fetal Pharmacokinetics of Zidovudine in Rats

“…35 Similar results have been reported for 2′3′-dideoxyinosine clearance in neonatal macaques. 36 Although renal excretion of AZT is evident in neonatal macaques, renal clearance values are significantly lower than those in adult macaques. 37 Furthermore, the total clearance of AZT in infants is significantly lower than in adults.…”