The optimal dose of indinavir for HIV-infected children has not yet been established. The first phase I/II study was performed using three different formulations: two kinds of suspensions of indinavir base and dry-filled capsules of indinavir. Because of the poor absorption of indinavir from the suspensions, further research was conducted only with the capsules containing indinavir sulfate, now marketed as Crixivan capsules (8
; R. P. Nelson, J. Sleasman, J. Cervia, G. Scott, R. Rutstein, R. McKinney, M. Nessly, L. Hawe, and B.-Y. Nguyen, Program Abstr. 6th Conf. Retroviruses Opportun. Infect., abstr. 425, 1999). Most children have been treated with an indinavir dose of 500 mg/m2
q8h, although this dose had to be reduced to 350 mg/m2
q8h in the phase I/II study because of a high incidence of nephrolithiasis in children receiving the higher dose (13
We have evaluated three dose levels of indinavir in this study. We started with a dose of 33 mg/kg of MW q8h, but this resulted in low AUC values in a substantial proportion of the children. A dose increment to 50 mg/kg of MW q8h resulted in AUC values that were comparable to values observed in adults. Five children received the highest indinavir dose of 67 mg/kg of MW qh8, but this led to large increases in plasma indinavir concentrations and serious toxicity (nausea and vomiting) in these children. Therefore, the optimal dose appeared to be 50 mg/kg of MW q8h. After 6 months of treatment, 16 of the 25 patients still on indinavir treatment were now receiving this dose. Seventy percent of these children had reached the goal of an undetectable viral load (<500 copies/ml).
We have chosen to use the MW of a child to calculate the indinavir dose. The use of MW instead of normal body weight is based on the assumption that metabolic clearance in children is higher than that in adults, even when corrected for body weight. Although we had anticipated this higher oral clearance of indinavir in children, we made the incorrect assumption that we should use an adult of 70 kg to calculate the indinavir dose of 33 mg/kg of MW (800 mg/700.75 kg). For most medications, children 10 to 12 years old already receive the adult dose. In retrospect, it would have been better to use an estimated body weight of 45 kg of an 12-year-old child to calculate the indinavir dose: the MW is then 17.3 kg, and 800 mg divided by 17.3 kg of MW results in an indinavir dose of 46 mg/kg of MW q8h. This is close to the 50 mg/kg of MW that we have found in this study to be the optimal dose of indinavir. This dose results in a median AUC value of 20.6 mg/liter · h, which is just above the median adult value of 19 mg/liter · h. An indinavir dose of 500 mg/m2 q8h is now under investigation in a phase III clinical trial (Nelson et al., Program Abstr. 6th Conf. Retroviruses Opportun. Infect.). The two methods used to calculate pediatric doses, i.e., MW and body surface area, are based on similar physiological mechanisms. Because pediatricians are more familiar with dosing based on body surface area, this may be preferred over dosing based on MW. The 50 mg/kg of MW q8h that we found to be the optimal dose approximates a dose of 600 mg/m2 q8h.
A higher metabolic clearance of indinavir in children is not the only factor that may have caused the differences in clearance values between children and adults. Because indinavir is administered orally, impaired absorption of the drug may result in higher apparent oral clearances of indinavir. The reasons for possible malabsorption may be variable, but one of the mechanisms may be reduced solubility of indinavir at relatively high gastric pH values (10
). It is known that children younger than 3 years have reduced gastric acid secretion (3
), and this may result in lower indinavir exposure. However, peak concentrations of indinavir were achieved rapidly and were often higher than what is seen in adults. Furthermore, dose increments would not lead to increased concentrations of indinavir in plasma if drug solubility is problematic. In contrast, more-than-proportional increases in Cmax
and AUC were seen (Table ). This makes impaired absorption due to increased gastric pH unlikely.
Yet another possible explanation of lower plasma indinavir levels may be an increased volume of distribution. Young children have more total body water (80 to 90% of body weight) than adults (55 to 60% of body weight) (3
), so water-soluble drugs, such as indinavir, will have a larger apparent volume of distribution in children than in adults (Table ).
In adults there are a number of observations showing that the concentration of indinavir in plasma is related to the antiviral response (2
). Therefore, instead of using a fixed dose regimen for each child, it seems logical to monitor the levels of indinavir in plasma shortly after the start of an indinavir-containing regimen and adjust the indinavir dose if necessary. For adults a trough level of 0.1 mg/liter has been proposed as the minimum effective concentration, which is equal to 75% of an average population value (2
). These values can be extrapolated to an AUC value of approximately 15 mg/liter · h (75% of 20), but our data show that for children this will not be enough. The AUC threshold in children appears to be 20 mg/liter · h, because none of the children with an AUC higher than 20 mg/liter · h had a detectable viral load after 6 months of treatment (Fig. ). Not all of the children with an AUC below this threshold of 20 mg/liter · h can be considered nonresponders, but it is clear that the risk of virological failure is much greater with these lower AUC values. The fact that a higher AUC of indinavir is needed in children than in adults to have a virological response may be explained by the faster clearance of the drug in children than in adults. Table illustrates that with similar AUCs in a child and an adult, a higher peak level and a lower trough level of indinavir are observed in the child. Therefore, if trough levels are important to obtain a durable antiviral response (2
), children will need higher AUC values than adults to obtain similar trough levels. It is remarkable that in this group of pediatric patients the success of combination antiretroviral therapy can be explained to a large extent by the plasma concentrations of only one of the three components of the drug regimen. A similar observation was made for adults (2
). Because the majority of children used zidovudine plus lamivudine as the nucleoside background and this may have influenced the observed relationship between indinavir AUC and virological outcome, it cannot be concluded from our data that the target AUC of indinavir is also valid for other nucleoside combinations.
There has been some concern that the risk of indinavir-induced nephrological toxicity (kidney stones, hematuria, and flank pain) in children may be higher than in adults. As noted above, for that reason the maximum indinavir dose was originally reduced to 350 mg/m2
in the first phase I/II trial of indinavir in the United States (13
). Because urological toxicity is the result of precipitation of indinavir crystals and this is correlated with the level of indinavir in plasma (4
), one would expect a high incidence of urological toxicity in our study because most children received an indinavir dose that is even higher than 500 mg/m2
. However, this was not the case. None of the children developed kidney stones, and only three children developed hematuria, which resolved after dose interruption. An explanation of this low incidence of urological toxicity in our children cannot be given, but differences in the amount of fluid intake and climatological influences (higher temperatures in the United States than in The Netherlands) are some of the possible reasons.
In conclusion, we found that the optimal dose of indinavir in children to obtain drug exposure similar to that observed in adult patients is 50 mg/kg of MW q8h, which approximates 600 mg/m2 q8h. Using this dose, 70% of the children reached the goal of an undetectable viral load (<500 copies/ml) after 6 months of treatment, without the occurrence of serious adverse events. We also found that it would be even better to adjust the indinavir dose based on an AUC0–8 greater than 20 mg/liter · h, because in that situation 100% of the children could be regarded as responders.