Pharmacokinetics of paediatric tenofovir based regimens
Polly Clayden HIV i-Base
In an article in the September 2011 edition of Antimicrobial Agents and Chemotherapy, Jennifer R King and colleagues from the P1058 protocol team reported pharmacokinetic (PK) data from children and adolescents treated with tenofovir (TDF) in combination with antiretrovirals with potential interactions.
PK results were shown for 47 participants aged 8 to 18 years, receiving a 300mg once daily TDF-based regimen. Participants received regimens that also contained an NTRI plus efavirenz (EFV) or darunavir/ritonavir (DRV/r) or atazanavir/ritonavir (ATV/r). The antiretrovirals and doses combined with TDF in are shown in Table 1.
Plasma samples were obtained pre-dose and over 24 hours. Statistical comparisons determined whether the 90% confidence intervals of the geometric mean (GM) AUC and Cmin for each antiretroviral were within 25% of those observed in previous studies demonstrating safety and efficacy. The AUC and Cmin target ranges and GMs (90% CI) are shown in Table 2.
|Group (n)||ARV||Doses (n)|
|1 (17)||efavirenz||200mg (1), 400mg (4), 600mg (12) QD|
|2 (13)||darunavir/r||300mg (2), 600mg (11) /100mg BD|
|3 (17)||atazanavir/r||150mg (3), 300mg (14)/100mg QD|
BD: twice-daily; QD: once-daily.
|Parameter||Group 1||Group 2||Group 3|
|AUC target range||2.3-3.6||32-124||2.3-3.6||51-80||2.3-3.6||15-75|
|GM (90% CI)||2.9 (2.5-3.4)||88.4 (65-120)||3.0 (2.5-3.6)||60.3 (48.7-74.7)||3.6 (3.1-4.2)||36.9 (33-42)|
|Cmin target range||0.05-0.08||0.9-3.6||0.05-0.08||3.1-4.2||0.05-0.08||0.3-1.0|
|GM (90% CI)||0.07 (0.05-0.09)||2.7 (1.8-4.0)||0.06 (0.05-0.08)||2.7 (2.0-3.6)||0.07 (0.06-0.09)||0.5 (0.4-0.7)|
Values mg*h/liter (AUC) and mg/liter (Cmin)
In the presence of EFV only the GM for TDF Cmin was very slightly above the target upper limit of the 90% CI. In contrast the GM (90% CI) for EFV Cmin was above the target upper limit. The investigators noted that EFV exposure was high overall in this analysis although the participants were dosed according to FDA recommendations; six participants with high exposure were receiving the EFV-based triple fixed dose combination (Atripla) which they suggest may alter drug absorption in this population. They recommend a crossover study comparing Atripla to the individual formulations in children and adolescents to answer this question.
The GMs (90% CI) for TDF AUC and Cmin were within the target ranges when it was given with DRV/r, however they were below the target ranges for DRV. The investigators wrote that these data suggest that higher than recommended doses of DRV may be necessary in paediatric patients in the presence of TDF, but the small sample size warrants a larger study to confirm these findings.
The GMs (90%CI) for TDF AUC and Cmin were only slightly higher in the presence of ATV/r, in contrast with that observed in healthy adults where these elevations are significant.
The investigators also observed that TDF PK did not differ between groups 1,2 and 3. This finding was unexpected as several PIs modestly alter TDF concentrations.
They concluded that none of the 90% CI AUC and Cmin values for the drugs tested were entirely outside the target range. So the recommended doses should provide exposure levels similar to that seen in adults. However they recommended that if individual patients experience adverse events or reduced clinical outcomes, while taking these agents in combination, monitoring exposure could be considered.
Gilead has now filed with the FDA and EMA for an indication for tenofovir for the 2-12 year age group. In Europe tenofovir is not approved for adolescents aged 12-18 (although there is considerable off label use), so we may be faced with the curious situation of approval for the younger but not older age group of children and adolescents.
The WHO expert paediatric group, consider a fixed dose combination dispersible tablet of EFV/TDF/3TC, scored once on one side and twice on the other to make dividing easy, to be an essential missing formulation for treating children. Modelling suggests that dosing delivered with divided tablets could work with weight band tables.
WHO is producing a white paper on tenofovir use in children.
King JR et al. Steady state pharmacokinetics of tenofovir-based regimens in HIV-infected paediatric patients. Antimicrob Agents Chemother 55: 4290-4.