Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children
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The population pharmacokinetics (PK) of lopinavir in tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected South African children taking super-boosted lopinavir (lopinavir/ritonavir ratio 1:1) as part of antiretroviral treatment in the presence of rifampicin were compared with the population PK of lopinavir in HIV-infected South African children taking standard doses of lopinavir/ritonavir (ratio 4:1).
Lopinavir concentrations were measured in 15 TB/HIV-co-infected paediatric patients who were sampled during and after rifampicin-based TB treatment and in 15 HIV-infected children without TB. During TB therapy, the dose of ritonavir was increased to lopinavir/ritonavir 1:1 in order to compensate for the induction of rifampicin. The children received median (interquartile range=IQR) doses of lopinavir 292 mg/m2 (274, 309) and ritonavir 301 mg/m2 (286, 309) twice daily. After TB treatment completion the children received standard doses of lopinavir/ritonavir 4:1 (median [IQR] lopinavir dose 289 mg/m2 [286, 303] twice daily) as did those without TB (median [IQR] lopinavir dose 265 mg/m2 [249, 289] twice daily).
Lopinavir oral clearance (CL/F) was about 30% lower in children without TB than in co-infected children treated with super-boosted lopinavir. However, the predicted lopinavir Cmin was above the recommended minimum therapeutic concentration during TB/HIV co-treatment in the 15 children. Lopinavir CL/F increased linearly during the dosing interval.
Increasing the ritonavir dose to achieve a lopinavir/ritonavir ratio of 1:1 when given in combination with rifampicin-based TB treatment did not completely compensate for the enhancement of lopinavir CL/F caused by rifampicin. The time-dependent lopinavir CL/F might be due to a time-dependent recovery from ritonavir inhibition of lopinavir metabolism during the dosing interval.
KeywordsLopinavir Ritonavir Pharmacokinetics HIV Tuberculosis
This study was supported by grants from the South African Department of Health (research programme for the comprehensive HIV and AIDS care, management and treatment plan for South Africa), the European and Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (SIDA) and the National Research Foundation South Africa (NRF).
- 3.Lopinavir/ritonavir (Kaletra) [package insert]. Abbott Laboratories, ChicagoGoogle Scholar
- 6.WHO (2006) Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Available from: http://www.who.int/child-adolescent-health/New_Publications/CHILD_HEALTH/WHO_FCH_CAH_2006.7.pdf. Accessed October 2009
- 10.WHO (2006) Antiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach. Available from: http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf. Accessed October 2009
- 11.CDC (2007) Table 2. Recommendations for coadministering protease inhibitors and non-nucleoside reverse transcriptase inhibitors with RIFAMPIN. Available from: http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/Table2.htm. Accessed October 2009
- 15.Jullien V, Urien S, Hirt D, Delaugerre C, Rey E, Teglas JP, Vaz P, Rouzioux C, Chaix ML, Macassa E, Firtion G, Pons G, Blanche S, Tréluyer JM (2006) Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years. Antimicrob Agents Chemother 50(11):3548–3555CrossRefPubMedGoogle Scholar
- 16.Rakhmanina N, van den Anker J, Baghdassarian A, Soldin S, Williams K, Neely MN (2009) Population pharmacokinetics of lopinavir predict suboptimal therapeutic concentrations in treatment-experienced human immunodeficiency virus-infected children. Antimicrob Agents Chemother 53(6):2532–2538CrossRefPubMedGoogle Scholar
- 20.Beal SL, Sheiner LS (1994) NONMEM user's guide, NONMEM Project Group. University of California at San Francisco, San FranciscoGoogle Scholar
- 23.Keulen (2006) Recommendations for performing TDM of antiretroviral agents. Available from: http://hivpharmacology.production.tdclighthouse.com/content.cfm?lang=1&id=573&id2=639&ch=4&cid=639. Accessed October 2009
- 27.+Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, Downey A, Mudra D, Graham R, Carroll K, Xie J, Madan A, Parkinson A, Christ D, Selling B, LeCluyse E, Gan LS (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 30:795–804CrossRefPubMedGoogle Scholar
- 30.Kappelhoff BS, Huitema AD, Crommentuyn KM, Mulder JW, Meenhorst PL, van Gorp EC, Mairuhu AT, Beijnen JH (2005) Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients. Br J Clin Pharmacol 59:174–182CrossRefPubMedGoogle Scholar
- 31.Ritonavir (Norvir) [product monograph]. Abbott LaboratoriesGoogle Scholar