The pharmacokinetic properties of stavudine appear to be comparable in HIV-infected pediatric and adult patients. However, the bioavailability of stavudine in children (61 to 78%) (16
) is slightly lower than that in adults (82 to 99%) (5
). When CL was independently subjected to linear regression analysis with demographic parameters of age, BWT, and BSA, significant relationships were observed, which were expected or anticipated. When the measure of predicted CL was adjusted for BWT, a nonlinear relationship emerged. A previous investigation (12
) reported that for patients with BWTs of between 40 and 100 kg, a small component of stavudine clearance was related to BWT.
Selection of a correct dose for children is a process fraught with variability, both interindividual variability within a given age and intraindividual variability across ages, with significant sources of variability arising from growth and development, concomitant pathophysiology, and other therapeutic regimens (15
). Of the several independent variables that have been used to determine an appropriate drug dosage in children (age, BSA, BWT), drugs have generally been prescribed on the basis of BWT (drugs with wide therapeutic windows) or, to a lesser extent, BSA (drugs with narrow therapeutic windows) (19
). In most cases, BWT is appropriate to height and so should very closely match measures of BSA; therefore, in most cases it is appropriate to use BWT as the independent variable of choice to estimate an appropriate drug dosage when one is administering drugs that do not possess a narrow therapeutic window. BWT scaling principles have also been recommended for calculation of dosages for children (30
For stavudine, the determination of dosing guidelines for pediatric patients was based on the goal of achieving an exposure (i.e., AUC) in children equivalent to that achieved in adults receiving a dose with proven efficacy. Since CL relates dose to exposure, our strategy involved correlation of CL to age, BWT, and BSA, followed by prediction of the dose for a child by using the estimated 50th percentile of BWT and BSA at a given age for healthy children. Use of the predicted CL for a child based on age, BWT, and BSA resulted in three values for a dose, the median value of which was selected as the appropriate dose for a given BWT. This approach gave equal weights to the contributions of the three demographic parameters to dose calculation and an unbiased selection of stavudine dose at a given BWT. CL after intravenous administration was used in these estimations in order to avoid confounding due to variability in the extent of absorption. For convenience in clinical practice, the dose estimated for children was in milligrams per kilogram per day; the dose in milligrams per square meter per day was used to ascertain further whether a child would be under- or overdosed.
In this study, the method of estimating an appropriate dose to achieve an equivalent drug exposure (i.e., AUC) compared with that from a 1.0-mg/kg/day regimen in a 60-kg adult demonstrated that children require a higher dosage, typically twice the adult dosage, to achieve equal exposure to stavudine. This is similar to the case for lamivudine, a compound that is primarily renally eliminated with an age-dependent CL (20
). Accordingly, on the basis of these predictions and on the basis of a comparison of the actual results for identical dose regimens, the appropriate dose regimen for children of ≤30 kg of body weight is proposed to be 2.0 mg/kg/day; for children whose body weights are >30 kg, the daily adult dose (60 mg/day for those with body weights of <60 kg and 80 mg/day for those with body weights of ≥60 kg) is recommended.
When one is dosing pediatric patients with stavudine, the following should be kept in mind. (i) The pediatric powder for oral solution formulation is bioequivalent to the capsule formulation (unpublished data, Bristol-Myers Squibb Company). Therefore, the recommended doses for children are easily achievable by using either of the formulations. (ii) Stavudine distributes in total body water (24
). Since total body water correlates very well with lean body mass (or weight) (21
), the dosages of stavudine in obese children should be based on lean body weight. In cachectic patients, the dosage of stavudine should be based on the actual BWT of the pediatric patient. (iii) The dosing guidelines for female children are similar to those for male children since there are no sex differences in the pharmacokinetics of stavudine. (iv) Stavudine pharmacokinetics were investigated in only three children who were <1 year of age. Therefore, the data are not sufficient to make definitive recommendations for pediatric patients in this age range. Stavudine CL is dependent on renal and nonrenal mechanisms, but only renal impairment is associated with significant alterations in stavudine CL (18
). Since kidney function displays age-dependent increases in functional capacity and approaches the values for adults by 3 to 12 months of life (8
), dosing in newborns and infants ages <1 year should account for reduced renal CL in early life.
The nucleoside reverse transcriptase inhibitors are prodrugs, for their active moieties, the triphosphates, are believed to be active against HIV (10
). Therefore, doses and/or systemic exposure to the parent compound do not necessarily take into consideration the importance of the cellular metabolism that more directly reflects the pharmacological effects of this class of drugs. The in vitro formation of intracellular stavudine triphosphate shows a good dose-response with respect to extracellular concentrations of the drug (10
). The latter suggests that the intracellular concentrations of stavudine triphosphate may be easily and predictably modulated by extracellular exposure to stavudine.
In conclusion, the study of the pharmacokinetics of stavudine described here and the prospective identification of appropriate dosing guidelines for children infected with HIV demonstrated that children eliminate stavudine more quickly than adults and, consequently, require a higher dose to achieve drug exposures equivalent to those achieved in adults. Accordingly, it is recommended that in order to achieve exposure levels in children of ≤30 kg of body weight that are consistent with the clinically effective dose level of 1.0 mg/kg/day administered to adults (with a maximum of 80 mg/day), it is necessary to administer a stavudine dose of 2.0 mg/kg/day; the dose for children of >30 kg of body weight is 60 mg/day (with a maximum of 80 mg/day), the clinically recommended adult dose.