The pharmacokinetic characteristics of indinavir determined in these 18 children are generally consistent with the limited data reported in the literature (11
). The pharmacokinetic characteristics determined for didanosine and stavudine are similarly comparable with data from pediatric investigations (2
). All concentration data from this study arise from subjects with a range of weights, oral clearances, and dosing regimens. In the case of indinavir, these dosing regimens vary not only across subjects but also for each subject. The composite plots of concentration versus time-postdose data (Fig. ) illustrate that the curves generated from typical pharmacokinetic parameters are reasonably characteristic of the observed data.
In three children that participated in a phase I study of indinavir, the 8-h AUC at a dose of 500 mg/m2
ranged between 14.4 and 18.3 mg · h/liter, and the estimated apparent oral clearance was between 27.3 and 34.7 liters/h/m2
; indinavir maximum concentrations ranged from 2.8 mg/liter to 8.8 mg/liter. In this same study, the estimated apparent oral clearance in eight children receiving a dose of 350 mg/m2
was 32 liters/h/m2
. The terminal half-life of indinavir averaged 0.9 h (11
). The mean AUC for indinavir in this study was 17.7 mg · h/liter, the apparent oral clearance was 39 liters/h/m2
, the mean maximum concentration in plasma was 7.3 mg/liter, and the half-life was 1.1 h. In this study, we attempted to administer an indinavir dose to children by using commercially available dosage forms, which would maintain trough concentrations of ≥0.1 mg/liter. We found that 50% of the children in this study required a more frequent dosing interval. After indinavir dose adjustments, the mean indinavir trough concentration was 0.29 mg/liter, and concentrations ranged from 0.01 to 1.28 mg/liter. Even with a change in dosing interval, five children still had trough concentrations of <0.1 mg/liter.
Sixteen children received concomitant therapy with didanosine, and 14 took some indinavir and didanosine doses simultaneously. This was allowed based upon our earlier finding with five children that coadministration of didanosine with indinavir did not reduce the concentrations of indinavir, in contrast with the substantial reduction reported in adults (9
; Crixivan package insert [Merck and Co., Inc.]). The consistency of the indinavir pharmacokinetic characteristics in these 18 children with those described in the literature (not receiving coadministration with didanosine) is further support that indinavir pharmacokinetic behavior was not substantially altered. The reasons for this discrepant finding are unknown. We would recommend that clinicians not coadminister indinavir with didanosine unless they can document with measured indinavir concentrations that pharmacokinetic disposition is unaltered by simultaneous administration.
In the present study, the average AUC and apparent oral clearance for didanosine were 0.73 mg · h/liter and 132 liters/h/m2
. In a study of children receiving a didanosine dose of 90 mg/m2
, the AUC was reported to average between 0.41 and 0.78 mg · h/liter (2
). From these data, the apparent oral clearance of didanosine is estimated to be 116 to 220 liters/h/m2
. In a phase I study of stavudine monotherapy in children, the average apparent oral clearance at a dose of 1 mg/kg was estimated at 16 to 19 liters/h/m2
). The elimination half-life averaged 1.13 h, and the mean stavudine AUC was 1.63 mg · h/liter. In the 18 children in our study, the average apparent oral clearance was 15.9 liter/h/m2
, and the average AUC was 1.83 mg · h/liter.
Appreciable concentrations of indinavir were found in the CSF of 4 children, with CSF-to-plasma ratios of 0.03 to 0.94. Indinavir has also been measured in the CSF of adults (S. L. Letendre, E. Capparelli, R. J. Ellis, D. Dur, and J. A. McCutchan, Abstr. 6th Conf. Retrovir. Opportunistic Infect. abstr. 407, 1999). In 22 individuals at steady state on an indinavir-containing regimen and free of opportunistic infections, the median indinavir concentration in CSF was 0.055 mg/liter (range, 0.016 to 0.18), and the median CSF-to-serum concentration ratio was 0.14 (range, 0 to 2.28). Both didanosine and stavudine have been previously shown to reach detectable concentrations in the CSF of children. CSF samples were obtained 2 h after an oral dose of didanosine in 20 children; concentrations in CSF were measurable in only three children (2
). Two children receiving a didanosine dose of 180 mg/m2
had concentrations in CSF of 0.095 and 0.083 mg/liter; one child receiving a dose of 90 mg/m2
had a concentration in CSF of 0.035 mg/liter (2
). Concentrations in CSF were obtained 2 to 3 h postdose in seven children receiving either 0.25, 1, or 2 mg of oral stavudine per kg per day (7
). Stavudine concentrations in the CSF ranged from 0.008 to 0.12 mg/liter; CSF penetration ranged from 16 to 97% of concomitant concentrations in plasma. At the dose of 1 mg/kg twice daily, the concentrations of stavudine in the CSF of two children were 0.063 and 0.12 mg/liter.
Pharmacodynamic relationships were explored only with the children that participated in the open pilot study of combination therapy with indinavir, didanosine, and stavudine. Only these children met standardized entry criteria of prior antiretroviral therapy and CDC clinical and immunologic category. Nine of these twelve children completed 24 weeks of therapy with indinavir, didanosine, and stavudine. There was a strong relationship between the baseline-to-week-24 fall in plasma HIV RNA and trough indinavir concentrations and didanosine AUC. The finding in this study of a relationship between indinavir trough concentrations and suppression of HIV RNA supports the use of trough concentrations as a relevant determinant of effect for this drug. The optimal trough concentration of indinavir, however, cannot be determined from this study with children. Our decision to target trough concentrations of more than 0.1 mg/liter is supported by the relationship found in these children predicting that at a trough concentration of <0.1 mg/liter, the suppression of plasma HIV RNA at 24 weeks would be <1 log10. Five children completed 48 weeks of therapy with indinavir, didanosine, and stavudine. Four of the five maintained a >1-log10 suppression in plasma HIV RNA from baseline, while one had a 0.9-log10 increase from baseline at week 48. All four children that maintained viral suppression had indinavir trough concentrations of >0.1 mg/liter and didanosine AUCs of >0.6 mg · h/liter. The child that had a rebound in viral load had an indinavir trough concentration of <0.02 mg/liter (model estimated concentration was 0.01 mg/liter) and a didanosine AUC of 0.47 mg · h/liter.
The observation of a relationship between indinavir trough concentration and antiviral effect has been reported by other investigators (1
). For example, in 23 protease inhibitor-naïve adults that received an indinavir-containing antiretroviral regimen, those that had suppression of plasma HIV RNA to undetectable levels had higher trough indinavir concentrations than did those with plasma HIV RNA that remained detectable (1
). The average trough concentration in the group with undetectable levels of plasma HIV RNA was 0.15 mg/liter versus 0.03 mg/liter in the detectable group (P
= 0.007). The finding of a relationship between the trough concentrations of indinavir and change in plasma HIV RNA levels is consistent also with observations for children receiving the protease inhibitor ritonavir. In a study of 41 children, trough ritonavir concentrations were found to be an important predictor of anti-HIV response (12
). Although the active moiety of didanosine is an intracellular triphosphate, relationships between plasma didanosine concentrations and anti-HIV effect have been observed (2
). For example, an evaluation of didanosine monotherapy in children found a relationship between didanosine AUC and response. Those children who responded with a decrease in HIV antigen and an improvement in IQ score had a higher didanosine AUC than did the nonresponders (0.46 mg · h/liter versus 0.19 mg · h/liter) (2
). No pharmacodynamic relationship between stavudine and a drop in viral load was detected in this study. There was a trend of greater suppression of plasma HIV RNA with a higher stavudine AUC, but there was no statistically significant relationship (r2
= 0.3; P
= 0.12). This of course does not mean that stavudine is a dispensable component of the therapeutic regimen. Rather, it is most likely that in these children, stavudine was contributing its maximal pharmacodynamic effect at the doses used.
An indinavir regimen of 500 mg/m2
every 8 h is currently being used in clinical trials evaluating the safety and anti-HIV effect in children. If the pharmacokinetic and pharmacodynamic characteristics of the simulated population of 500 subjects approximate those of real-world children, this regimen may not be adequate to maintain a sustained anti-HIV response. The regimen of 500 mg/m2
every 8 h produced trough concentrations of >0.1 mg/liter in only 28% of the simulated population; an indinavir regimen of 500 mg/m2
every 6 h was predicted to yield trough concentrations of >0.1 mg/liter in 52% of subjects in this simulation. The usual didanosine dosing regimen is 90 mg/m2
every 12 h, although a range of 90 to 150 mg/m2
every 12 h has been recommended (5
). At a dose of 90 mg/m2
, 57% of the simulated subjects would have a didanosine AUC of >0.6 mg · h/liter. An increase in the standard dose to 120 mg/m2
every 12 h would be expected to increase the percentage of subjects with AUCs of >0.6 mg · h/liter to 88. These simulation studies suggest that alternative dosing strategies should be evaluated clinically to determine if therapeutic benefit could be safely optimized.
Contemporary pharmacotherapy of HIV infection is a challenging undertaking. This is particularly true with HIV-infected children, where therapeutic options are limited by available and palatable dosage forms and lack of pediatric-specific pharmacokinetic and pharmacodynamic information. This study illustrates the ability to obtain pharmacokinetic information for children from concentration data collected during routine clinic visits. Furthermore, we have described an approach for using this pharmacokinetic information to adjust dosing regimens in an attempt to achieve a pharmacologic objective and provide a safeguard against underdosing. Lastly, the relationships found between systemic drug concentrations and changes in plasma HIV RNA levels contribute to our understanding of the pharmacologic characteristics associated with therapeutic failure and success. We believe the incorporation of pharmacologic knowledge with virologic and immunologic data and behavioral considerations will result in improved clinical outcomes for children infected with HIV.