This study was designed to evaluate the pharmacokinetics and safety of tenofovir DF in HIV-infected children. Age-related differences in drug disposition have been seen with many antiretrovirals (1
). Often these differences consist of higher clearance of the drug or lower bioavailability in children, necessitating higher doses per body weight or BSA. The present study was limited to a narrow age range of HIV-infected children, given the requirement that the children be able to swallow pills. The target dose, 175 mg/m2
, was chosen to match most closely in children the exposure associated with the approved 300-mg fixed dose in adults. The median dose administered, 208 mg/m2
, was higher than the target because of the constraints of the 75-mg tablet.
Pharmacokinetic analyses in HIV-infected adults who received 300 mg of tenofovir DF alone revealed a mean single-dose AUC of 3,265 ng · h/ml (range, 2,033 to 4,323), a mean steady-state AUC of 3,371 ng · h/ml (range, 2,097 to 6,050), a mean single-dose Cmax
of 362 ng/ml (range, 169 to 463), a mean steady-state Cmax
of 326 ng/ml (range, 155 to 532), and a median Tmax
of 2 h after single dose and 3 h at steady state (3
). Even though the first dose administered to the children in the present study was higher than the targeted adult-equivalent dose, the mean AUC and Cmax
were 34 and 27% lower, respectively, compared to the values reported in adults. The possible explanations for these findings include lower oral bioavailability and/or higher renal clearance in children relative to adults. With the first dose the median urinary recovery of tenofovir was 20% of the administered dose. These data are similar to results observed in adults, where 17 and 24% of the tenofovir dose was recovered in the urine over 48 h in the fasted and fed states, respectively (Kearney et al., submitted), and suggest that the oral bioavailability of tenofovir is comparable in children and adults. However, the renal clearance of tenofovir was approximately 1.5-fold higher in children relative to published data for HIV-infected adults and likely explains the lower exposures observed with the first dose of tenofovir DF in the present study. Urine collections were carried out carefully. However, if the collections were incomplete, both renal clearance and bioavailability would be underestimated.
Other antiretrovirals were added to the tenofovir DF monotherapy on day 7 to optimize the regimen in these children, and tenofovir pharmacokinetics were evaluated again at week 4. By this time, at steady state, the pharmacokinetic profile of tenofovir more closely resembled that seen in adults. Despite similar median renal clearance values at the two pharmacokinetic sampling periods, median apparent clearance in these children was approximately 25% lower at week 4 in comparison to the first dose. The reduced apparent clearance may be attributable to an effect of the additional antiretroviral agents and increased oral bioavailability of tenofovir at steady state. The addition of other antiretrovirals precluded a comparison of results from first dose and steady state to characterize the possibility of accumulation or nonlinear elimination. However, data in adults treated with tenofovir DF monotherapy for 4 weeks did not demonstrate unexpected drug accumulation or an effect of time on the pharmacokinetic parameters (3
It is important that the first-dose and steady-state pharmacokinetic profiles that have been reported for adults were measured in patients who received 28 days of tenofovir DF monotherapy (3
). In that study, a similar increase in the oral bioavailability of tenofovir DF was seen when the drug was taken with food compared to when it was taken in the fasted state. However, a food effect cannot be the explanation in the present study, since the drug was taken after breakfast at both pharmacokinetic time points.
Notably, due to their advanced disease, prior antiretroviral histories, and viral resistance profiles, all of the children evaluated at week 4 were receiving a protease inhibitor plus low-dose ritonavir as a pharmacokinetic boosting agent, most as the combination lopinavir-ritonavir. Pharmacokinetic drug interaction data in adults have shown that concomitant administration of tenofovir DF with lopinavir-ritonavir is associated with increased tenofovir exposures of approximately 34%, presumably via enhanced oral bioavailability, as tenofovir DF is eliminated as unchanged drug in the urine (J. F. Flaherty, B. P. Kearney, J. J. Wolf, J. R. Sayre, D. F. Coakley, Abstr. 1st IAS Conf. HIV Pathogenesis Treat., abstr. 336, 2001). A difference in bioavailability with and without low-dose ritonavir may explain the observed differences seen between first-dose and steady-state pharmacokinetics at week 4 in the present study.
Another study of tenofovir DF in HIV-infected children also revealed higher tenofovir exposures at steady state (day 7) compared to values observed in a separate group of subjects who received a single dose of tenofovir DF as monotherapy on day 1 (S. Blanche and J. Bresson, unpublished data). All of the subjects at steady state in that study were receiving tenofovir DF as part of a combination regimen that included lopinavir-ritonavir, and the results observed served to confirm the consistency of tenofovir DF pharmacokinetics in children.
Further elucidation of a possible mechanism for an interaction between low-dose ritonavir and tenofovir DF is necessary. In particular, studies in children receiving unboosted or protease inhibitor-sparing regimens are necessary to determine if higher tenofovir DF doses are warranted to achieve the desired drug exposure.
Tenofovir DF was well tolerated by HIV-infected children. Only 2 of 18 children in the present study experienced an event that required protocol-mandated permanent discontinuation of the study drug during the first 4 weeks. In both instances, the children developed asymptomatic grade 3 transaminase elevation during the monotherapy phase of the study, which resolved without sequelae. Longer-term toxicity and the efficacy of the combination regimens are being assessed as the study progresses.
Based upon its tolerability, safety, resistance profile, and pharmacokinetic properties in children, tenofovir DF could prove to be a beneficial agent for inclusion in pediatric HIV combination therapy regimens, particularly for those children who have failed prior antiretroviral therapy regimens. Because this study was limited to older children able to swallow pills, the pharmacokinetics, safety, and tolerability of the drug, including a liquid formulation, will need to be studied in younger children and infants. Steady-state absorption, elimination, and variability of tenofovir pharmacokinetics in children treated with tenofovir DF-containing combination regimens approached those seen in HIV-infected adults treated with 300 mg once daily.