Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis.
OBJECTIVE
Rifampicin dramatically reduces plasma lopinavir concentrations (coformulated with ritonavir in a 4:1 ratio). A study in healthy adult volunteers showed that this reduction could be ameliorated if additional ritonavir is given. We evaluated the effect of additional ritonavir on plasma lopinavir concentrations in HIV-infected children receiving rifampicin-based treatment for tuberculosis.


METHODS
We measured plasma lopinavir concentrations in 2 parallel groups receiving combination antiretroviral therapy that included lopinavir-ritonavir, with and without rifampicin-based antitubercular treatment. Additional ritonavir was given (lopinavir/ritonavir ratio of 1:1) during antitubercular treatment. Lopinavir concentrations were determined using liquid chromatography-tandem mass spectrometry.


RESULTS
There were 15 children (aged 7 months to 3.9 years) in each group. Lopinavir pharmacokinetic measures (median [interquartile range]) for children with and without rifampicin, respectively, were maximum concentration (Cmax) of 10.5 [7.1 to 14.3] versus 14.2 [11.9 to 23.5] mg/L (P = 0.018), area under the curve from 0 to 12 hours (AUC0-12) of 80.9 [50.9 to 121.7] versus 117.8 [80.4 to 176.1] mg/h/L (P = 0.036), and trough concentration (Cmin) of 3.94 [2.26 to 7.66] versus 4.64 [2.32 to 10.40] mg/L (P = 0.468). Thirteen of 15 children receiving antitubercular treatment (87%) had a lopinavir Cmin greater than the recommended minimum therapeutic concentration (1 mg/L).


CONCLUSIONS
The effect of rifampicin-based antitubercular treatment on lopinavir concentrations was attenuated by adding ritonavir to rifampicin. Although the median Cmax and AUC0-12 were lowered by 26% and 31%. respectively, the Cmin was greater than the minimum recommended concentration in most children.
Ren
Yuan
Y
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Nuttall
James J C
JJ
Egbers
Claire
C
Eley
Brian S
BS
Meyers
Tammy M
TM
Smith
Peter J
PJ
Maartens
Gary
G
McIlleron
Helen M
HM
D000904:Antibiotics, Antitubercular / Q000627:therapeutic use*; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D006678:HIV; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D061466:Lopinavir; D008297:Male; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
D000904:Antibiotics, Antitubercular; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir; D012293:Rifampin