Pharmacokinetics in children and infants

Polly Clayden, HIV i-Base

Pharmacokinetic evaluations are becoming increasingly common and useful in the management of HIV-infected adults. Since drug plasma concentrations can be highly variable across different age groups of children receiving antiretrovirals, measuring these levels would seem to be particularly important for paediatric patients, especially amongst very young infants whose concentrations overall are lower than those seen in adult and older paediatric populations.

Two paediatric pharmacology studies were reported, one assessing PK interactions in children receiving NFV-containing regimens, another looked at NFV doses in infants less than 2 years of age.

In order to simplify combination regimens, strategies utilising PK interactions are being used more frequently. Both RTV and NVP alter CYP450 activity, and a report from Acosta and colleagues evaluated their effects when co-administrated with NFV [1]. Adult data indicates a small but favourable interaction between NFV and RTV when dosed BID, and the interaction between NFV and NVP had not been previously studied in children.

This was a phase II, randomised, open label, 48-week study. A group of 21 PI and NNRTI naive children (age range >4 months to 21 years) were randomised to either NFV/RTV/ddI (arm A) or NFV/NVP/d4T (arm B), n=13; n=8 respectively (see table). Two subjects in arm A, and 1 in arm B completed both week 4 and week 20 assessments (total n=24).


Drug Dose
Arm A ddI 240mg/m2 QD
NFV 30mg/kg BD
RTV 400mg/m2 BD
Arm B d4T 1.0mg/m2 QD
NFV 50-55mg/kg BD
NVP 120mg/m2 BD

Note. NVP was dosed at 120mg/m2 QD for 14 days after initiation of therapy.

PK assessments were performed at steady state for all drugs in both arms at 4 weeks and at 20 weeks. For these assessments 1 pre-dose blood sample was taken and then further samples were taken at 0.5, 1, 2, 4 and 8 hours post dose. Standard non-compartmental techniques were used to estimate PK parameters, and the pre-dose level was counted as the 12-hour time point.

NFV plasma concentrations varied greatly across children receiving RTV or NVP. CVs on Cmin were 127% and 100% respectively. When administered concomitantly with RTV, the NFV AUC in children was similar to NFV alone TID in adults and the active metabolite M8 AUC was approximately 4-fold higher. The addition of RTV had little effect on the NFV concentrations compared to NFV/NVP. M8 systematic exposure was significantly increased in arm A compared to arm B. In the presence of NVP the NFV AUC was similar to that achieved in adults using 750 mg NFV TID alone. NVP did not appear to appreciably lower M8 concentrations.

Another study [2] reported similar results to those (described in the last issue of PTN [3]) from the PENTA 7 trial ie. a need for increased doses of NFV in very young babies to achieve equivalent concentrations to older children and adults. The overall interpatient variability reported in both these studies further reinforces ever-growing evidence for recommending use of regular TDM in paediatric populations of all age groups.


  1. Acosta et al, Pharmacokinetic evaluation of nelfinavir in combination with nevirapine or ritonavir with HIV-infected children – PACTG 403. Abstract 1642. 40th ICAAC, Toronto, Canada, September 17-20, 2000.
  2. Capparelli et al, Pharmacokinetics of nelfinavir in HIV-infected infants. Abstract 1658. 40th ICAAC, Toronto, Canada, September 17-20, 2000.
  3. Litalien et al – Nelfinavir doses should be increased in infants less than 3 months. Programme and abstracts of the 13th International AIDS Conference;Durban, July 9-14. Abstract MoPeB2213

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