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Plasma Concentrations of Efavirenz and Lopinavir in Children with and without Rifampicin-based Anti-TB Treatment
Yuan Ren*1, J Nuttall1, C Egbers2, B Eley1, T Meyers2, G Maartens1, P Smith1, and H McIlleron1
1Univ of Cape Town, South Africa and 2Univ of the Witswatersrand, Johannesburg, South Africa
Background: Adult studies have shown that plasma concentrations of efavirenz (EFV) are modestly reduced by rifampicin,
and that the profound reduction in lopinavir (LPV) concentrations
when rifampicin and Kaletra
(LPV: ritonavir [RTV] ratio, 1:1) are given together,
is ameliorated if additional RTV is given. There are no data on these 2
important interactions in pediatric populations.
Methods: We evaluated the plasma concentrations of EFV or LPV in
children taking EFV or Kaletra + 2 nucleoside reverse
transcriptase inhibitors (NRTI) with and without rifampicin-based
tuberculosis (TB) treatment. Standard recommended doses were used; extra RTV was
given during TB treatment to children receiving Kaletra.
EFV and LPV concentrations were determined by validated liquid chromatography-mass
spectrometry/mass spectrometry (LC-MS/MS) methods.
Results: The median estimated Cmin
of EFV was not significantly different (p
= 0.756) between the 2 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 13 children who returned for repeat sampling after completing TB treatment. Large
variability was observed between the children aged 8 months and those aged 3.9
years.
Conclusions: Rifampicin did not
significantly reduce EFV concentrations. That 50% of children had EFV Cmin below the minimum recommended concentration
raises concern that a substantial proportion may be at risk of the rapid
emergence of EFV-resistant mutations and treatment failure. This suggests that EFV
doses should be re-evaluated, especially because therapeutic drug monitoring is
seldom available in developing countries. LPV Cmin
was similar between the 2 groups. In all 28 children, LPV Cmin
was above the minimum therapeutic level (1 mg/L). This study confirmed that
additional RTV can be used to retard LPV elimination, thus overcoming the
reduction of LPV levels caused by rifampicin.
|
Pharmacokinetic
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 to
4.0)
|
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 (2.89 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
|
|
