Atazanavir pharmacokinetics in infants, children and adolescents

An article in the July 31 2011 edition of AIDS describes atazanavir (ATV) pharmacokinetics (PKP in infants, children and adolescents given alone and boosted with ritonavir (ATV/r). Jennifer J Kiser and colleagues from the IMPAACT 1020A phase I/II study evaluated two formulations of ATV, capsules and a dispersible orange-vanilla flavoured powder across a range of age groups in treatment naive and experienced participants from the United States and South Africa.

Participants were aged 91 days to 21 years and received unboosted or boosted (using ritonavir capsule or liquid formulations) ATV as part of a combination antiretroviral regimen. All participants underwent intensive 24-hour PK sampling on day 7; 195 enrolled and 172 had evaluable data.

All groups were started at a target dose of 310mg/m2. To establish an acceptable ATV or ATV/r dose for an age group, 10 participants had to meet PK and safety criteria as defined by the protocol.

For PK these were: ATV AUC AUC0-24hr of at least 30,000ng x h/mL and C24 of at least 60ng/mL in at least 80% of participants; no AUC0-24hr less than 15,000ng x h/mL and median AUC0-24hr of 60,000ng x h/m/L or less. And for safety: no life threatening toxicities; one or fewer participants with grade 3 or 4 toxicities (excluding bilirubin) linked to study treatment, and two or fewer participants with total bilirubin values greater than 5.1 times the upper limit of normal.

If these criteria were not met, the ATV starting dose was modified for the age group, either increased to 415, 520 then 620mg/m2 or decreased to 205mg/m2.

Nearly half (45%) of the participants were antiretroviral naive at enrollment; 62% received ATV capsules and the remaining 38% ATV powder.

The investigators found unboosted ATV capsules met PK criteria at a dose of 520mg/m2 for participants >2 to 13 years of age and 620mg/m2 for those >13 to 21 years of age. Boosted ATV capsules met PK criteria at a dose of 205mg/m2 for those >2 to 21 years of age. Boosted ATV powder met PK criteria at a dose of 310mg/m2 for those >2 to 13 years of age.

Infants and young children aged 3 months to 2 years dosed with boosted ATV powder failed to meet PK criteria. There was a lot of intersubject variability in exposures this age group so that a dose escalation to 415mg/mL may have given ATV exposures in some young children greater than 90,000ng x h/mL.

The investigators wrote that additional studies are needed in this age group to determine if an appropriate ritonavir boosted dose can be identified.

Kiser JJ et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV infected infants, children and adolescents. AIDS 2011, 25:1489-96.