In this study of ATV pharmacokinetics administered without or with ritonavir, we identified doses for infants, children and adolescents that met protocol-defined pharmacokinetic criteria. An unboosted ATV dose (capsule formulation) of 520 mg/m2 met the study pharmacokinetic criteria for children > 2 to ≤ 13 years and a dose of 620 mg/m2 met the criteria for adolescents > 13 to ≤ 21 years. A ritonavir-boosted ATV dose (powder formulation) of 310 mg/m2 met the criteria for children > 2 to ≤ 13 years and a dose (capsule formulation) of 205 mg/m2 met the criteria for ages > 2 to ≤ 21 years. A ritonavir-boosted ATV dose of 310 mg/m2 (powder formulation) in children ages 3 months-2 years achieved average ATV exposures that approximated, but did not meet protocol targets; there was greater variability in exposures among children in this age range. This study was unable to find an unboosted ATV dose with acceptable exposures in children ages 3 months to 13 years using ATV powder. Additional studies on the use of ATV powder are proceeding, using only ATV/r.
On average, ATV pharmacokinetics in the ritonavir-boosted and unboosted dosing cohorts of IMPAACT P1020A that satisfied protocol-defined pharmacokinetic criteria, approximated values for ATV in adults. Geometric mean (%CV) adult historic values for ATV AUC0–24hr
, Cmax, and C24 following a ritonavir-boosted dose of 300mg (176 mg/m2
) are 44.2 mcg*hr/mL (34), 4427 ng/mL (28), and 709 ng/mL (60), respectively.[12
] As illustrated in , ATV CL/F is faster in infants and children less than 12 years of age relative to adults.[10
] This could be due to a number of physiologic factors including, but not limited to, decreased bioavailability, increased drug transporter expression or activity, and/or greater hepatic enzyme capacity or function in younger children. Unboosted ATV CL/F appears similar for children ages 6–13 years with historical data in adults; CL/F is faster, however, in adolescents 13–22 years (). As noted, we were not able to find a dose of unboosted ATV powder that satisfied our pharmacokinetic parameters for children between 3 months to 13 years. This likely arose because of a combination of factors including low bioavailability, fast clearance and wide intersubject variability in these pharmacokinetic characteristics.
a. Mean (SD) Ritonavir-Boosted ATV Apparent Oral Clearance (L/hr/m2) in Dosing Cohorts which Met Protocol-Defined ATV Pharmacokinetic Targets Relative to Historical Data in Adults
Once a BSA-based dose was identified that satisfied protocol-defined pharmacokinetic criteria for the various age and formulation cohorts, day seven (steady-state) ATV exposures were not predicted by or correlated with age, BSA, weight, formulation and ritonavir-boosting. There were also no racial or gender differences in exposures. However, there were significant differences in ATV exposures at day seven between American and South African children. This difference was driven primarily by the two groups on unboosted ATV (groups 3 and 4) and infants 3–6 months on ATV/r (5A). The South African children in these groups had faster BSA- adjusted ATV CL/F than the American children (). The reasons for faster CL/F in South African children are unclear. It may be a consequence of differences in type and amount of food consumed for the intensive pharmacokinetic visits (as meals were not standardized). Helicobacter pylori is more prevalent in South African children relative to the United States, which may give rise to poorer ATV absorption because of a higher gastric pH in South African children.[13
] Finally, genetic differences in drug metabolizing enzyme or transporter expression or function between American and South African children could provide an explanation.
The unboosted ATV capsule doses, which satisfied protocol-defined pharmacokinetic criteria in these children, are higher than the FDA-approved unboosted ATV dose for adults (520 and 620 mg/m2 vs. 235 mg/m2), and in general, Cmax and C24 were higher and lower, respectively compared with ATV/r cohorts. The data from this study provided the basis for the FDA-approved ritonavir-boosted ATV dosing regimen in children ages 6–18 years. However, the FDA-recommended doses are based on body weight rather than BSA. The approved dose is also capped at the adult ritonavir-boosted dose, 300mg once daily. There were 33 children ages 6–18 years in ritonavir-boosted dosing cohorts that passed our protocol-defined pharmacokinetic criteria (Groups 6, 7, and 8). We compared the starting doses of these 33 children in our study with the FDA-approved weight-based dose. Fourteen (42%) children would have received different starting doses of ATV when based on weight vs. BSA. Twelve of 14 (86%) would have received a lower dose based on body weight than they received in the study with the BSA-based dose. This may lead to differences in therapeutic outcomes in practice relative to those observed in this clinical trial.
There are limitations to this study that may impact generalizability. First, both abacavir and tenofovir disoproxil fumarate were excluded. ATV concentrations are reduced with concomitant tenofovir disoproxil fumarate administration; thus, if tenofovir disoproxil fumarate was coadministered with ATV (and ritonavir) in children, concentrations of ATV would be expected to be lower than those observed in this study.[14
] Additionally, gastric acid modifiers were not exclusionary medications to participation in the study. However, only three children (all from the United States) were receiving gastric acid modifiers during the day seven intensive pharmacokinetic visits. Two of these children were in group 5.
This study demonstrated once daily BSA-determined doses using the capsule formulation of ATV, when given with and without ritonavir, can provide ATV exposures in children that approximate concentrations in adults receiving ATV/r. Once daily unboosted ATV powder was unable to achieve protocol-defined pharmacokinetic targets. While the powder formulation of ATV when given with ritonavir met protocol-defined pharmacokinetic criteria for children ages 2–13 years, there was significant variability in exposures in those less than 2 years of age, driven primarily by lower exposures in South African infants. Additional studies are needed in this age group to determine if an appropriate ritonavir-boosted dose can be identified. Studies are also needed to elucidate the explanation for lower unboosted ATV exposures in South African children relative to American children. A manuscript describing the safety and efficacy of ATV and ATV/r in P1020A is forthcoming. An investigation of pharmacokinetic-dynamic relationships at the conclusion of the study may provide additional guidance for future studies of ATV dosing in children.