Plasma concentrations of efavirenz and lopinavir in children with and without rifampicin-based TB treatment
Polly Clayden, HIV I-Base
In adults, there is an interaction between efavirenz and rifampicin giving a modest (25%) reduction in plasma concentrations of efavirenz (EFV). Although there is a large (>90%) reduction in lopinavir (LPV) concentrations when rifampicin and Kaletra are used together, this can be overcome with a higher dose of RTV (an additional 100mg per Kaletra capsule, 300mg twice a day).
Yuan Ren from South Africa showed data from a study comparing plasma concentrations of EFV or LPV in children (n=58) taking EFV or Kaletra + 2 NRTI with and without rifampicin based tuberculosis (TB) treatment.
The children received standard recommended doses from package insert; the children receiving Kaletra with TB treatment were given extra RTV. EFV and LPV concentrations were determined by validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methods.
In the efavirenz study – as the children took the EFV at night – three consecutive blood samples were taken between 12 and 24 hours post-dose and Cmin was estimated from the log linear regression line of the three concentration time points. The investigators found that the median estimated Cmin of EFV was not significantly different (p=0.756) between the two groups (n=15 in each group). The estimated Cmin was <1 mg/L (the recommended minimum therapeutic level) in 50% of children; 20% with high Cmin (>4 mg/L) had significantly lower elimination rate constants (p=0.0011).
The Cmin was not significantly increased in the 13 children who returned for repeat sampling after completing their TB treatment. The investigators noted, Large variability was observed between the children aged 8 months and those aged 3.9 years.
For the children receiving Kaletra plus additional RTV (to a ratio of LPV:RTV, 1:1), LPV Cmin was similar between the 2 groups (n=15 children without and n=13 with rifampicin). In all 28 children, LPV Cmin was above the minimum therapeutic level (1 mg/L). As with adults this study found that additional RTV can be used to mitigate accelerated LPV elimination, overcoming the reduction of LPV levels caused by rifampicin.
Table 1: Plasma concentrations of efavirenz and lopinavir in children with and without rifampicin-based TB treatment
|PK measures – Median (IQR)||With rifampicin (LPV:RTV = 1:1, n=13)||Without rifampicin (LPV:RTV = 4:1, Kaletra, n=15)||p-value|
|Tmax (h)||3.0 (2.0 to 4.07)||3.92 (2.78 to4.0||0.660|
|Cmax (mg/L)||11.9 (7.24 to 14.3)||14.2 (11.9 to 23.5)||0.038|
|Cmin (mg/L)||4.12 92.89 to 7.66)||4.64 (2.32 to 10.4)||0.872|
|AUC0-12||84.29 (53.51 to 113.37)||113.70 (78.81 to 168.61)||0.056|
|Half life (h)||10.98 (5.44 to 16.61)||4.86 (3.82 to 8.29)||0.062|
Although this study found that rifampicin did not significantly reduce EFV concentrations, the fact that 50% of children had EFV Cmin below the minimum recommended plasma concentration raises concern that many children may be at risk of the rapid emergence of EFV-resistant mutations and treatment failure. Dr Yen suggested, EFV doses should be re-evaluated, especially because therapeutic drug monitoring is seldom available in developing countries.
From this study, it appears that children have similar PK interactions to adults with ARVs and rifampicin and that similarly reductions in LPV levels can be overcome with additional RTV boosting.
As with most childrens PK studies the investigators noted considerable interpatient variability between the children particularly at younger ages.
The most troubling finding from this study is that 50% of the children in the EFV group appear to be under-dosed when dosed according to package insert, irrespective of whether they were receiving EFV with or without rifampicin.
Ren Y, Nuttall J, Egbers C et al. Plasma concentrations of efavirenz and lopinavir in children with and without rifampicin-based anti-TB treatment. 14th CROI, 25-28 February 2007, Los Angeles. Abstract 77.