Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB

Summary

The purpose of this study is to determine the lopinavir levels in blood of HIV and TB infected children (3-15kg) when given lopinavir/ritonavir in a 1:1 ratio with rifampicin containing TB regimen and its safety.

Timeline

Start

2013-01

Primary completion

2016-12

Completion

2016-12

Outcome

Met primary endpoint

paper The difference of -1·1% (95% CI -6·9 to 3·2), at a non-inferiority margin of 10%, confirmed the non-inferiority of lopinavir trough concentrations during rifampicin co-treatment. PMID 30529029 ↗

Publications

• Background Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F; Ghent International AIDS Society (IAS) Working Group on HIV Infection in Women and Children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004 Oct 2-8;364(9441):1236-43. doi: 10.1016/S0140-6736(04)17140-7.
• Background Johnson LF, Davies MA, Moultrie H, Sherman GG, Bland RM, Rehle TM, Dorrington RE, Newell ML. The effect of early initiation of antiretroviral treatment in infants on pediatric AIDS mortality in South Africa: a model-based analysis. Pediatr Infect Dis J. 2012 May;31(5):474-80. doi: 10.1097/INF.0b013e3182456ba2.
• Background Marston M, Becquet R, Zaba B, Moulton LH, Gray G, Coovadia H, Essex M, Ekouevi DK, Jackson D, Coutsoudis A, Kilewo C, Leroy V, Wiktor S, Nduati R, Msellati P, Dabis F, Newell ML, Ghys PD. Net survival of perinatally and postnatally HIV-infected children: a pooled analysis of individual data from sub-Saharan Africa. Int J Epidemiol. 2011 Apr;40(2):385-96. doi: 10.1093/ije/dyq255. Epub 2011 Jan 18.
• Background Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, Bhagavathy S, Venkatesan P, Sekar L, Mahilmaran A, Ravichandran N, Paramesh P. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother. 2004 Nov;48(11):4473-5. doi: 10.1128/AAC.48.11.4473-4475.2004.
• Background McIlleron H, Ren Y, Nuttall J, Fairlie L, Rabie H, Cotton M, Eley B, Meyers T, Smith PJ, Merry C, Maartens G. Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis. Antivir Ther. 2011;16(3):417-21. doi: 10.3851/IMP1757.
• Background Zanoni BC, Phungula T, Zanoni HM, France H, Feeney ME. Impact of tuberculosis cotreatment on viral suppression rates among HIV-positive children initiating HAART. AIDS. 2011 Jan 2;25(1):49-55. doi: 10.1097/QAD.0b013e32833f9e04.
• Background Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008 Nov 20;359(21):2233-44. doi: 10.1056/NEJMoa0800971.
• Background Reitz C, Coovadia A, Ko S, Meyers T, Strehlau R, Sherman G, Kuhn L, Abrams EJ. Initial response to protease-inhibitor-based antiretroviral therapy among children less than 2 years of age in South Africa: effect of cotreatment for tuberculosis. J Infect Dis. 2010 Apr 15;201(8):1121-31. doi: 10.1086/651454.
• Background Coovadia A, Abrams EJ, Stehlau R, Meyers T, Martens L, Sherman G, Hunt G, Hu CC, Tsai WY, Morris L, Kuhn L. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1082-90. doi: 10.1001/jama.2010.1278.
• Background Saez-Llorens X, Violari A, Deetz CO, Rode RA, Gomez P, Handelsman E, Pelton S, Ramilo O, Cahn P, Chadwick E, Allen U, Arpadi S, Castrejon MM, Heuser RS, Kempf DJ, Bertz RJ, Hsu AF, Bernstein B, Renz CL, Sun E. Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2003 Mar;22(3):216-24. doi: 10.1097/01.inf.0000055061.97567.34.
• Background Verweel G, Burger DM, Sheehan NL, Bergshoeff AS, Warris A, van der Knaap LC, Driessen G, de Groot R, Hartwig NG. Plasma concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and below. Antivir Ther. 2007;12(4):453-8.
• Background Chadwick EG, Capparelli EV, Yogev R, Pinto JA, Robbins B, Rodman JH, Chen J, Palumbo P, Serchuck L, Smith E, Hughes M; P1030 team. Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS. 2008 Jan 11;22(2):249-55. doi: 10.1097/QAD.0b013e3282f2be1d.
• Background Chadwick EG, Pinto J, Yogev R, Alvero CG, Hughes MD, Palumbo P, Robbins B, Hazra R, Serchuck L, Heckman BE, Purdue L, Browning R, Luzuriaga K, Rodman J, Capparelli E; International Maternal Pediatric Adolescent Clinical Trials Group (IMPAACT) P1030 Team. Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. Pediatr Infect Dis J. 2009 Mar;28(3):215-9. doi: 10.1097/INF.0b013e31818cc053.
• Background Rakhmanina N, van den Anker J, Baghdassarian A, Soldin S, Williams K, Neely MN. Population pharmacokinetics of lopinavir predict suboptimal therapeutic concentrations in treatment-experienced human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2009 Jun;53(6):2532-8. doi: 10.1128/AAC.01374-08. Epub 2009 Mar 2.
• Background Elsherbiny D, Ren Y, McIlleron H, Maartens G, Simonsson US. Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children. Eur J Clin Pharmacol. 2010 Oct;66(10):1017-23. doi: 10.1007/s00228-010-0847-9. Epub 2010 Jun 16.
• Background Urien S, Firtion G, Anderson ST, Hirt D, Solas C, Peytavin G, Faye A, Thuret I, Leprevost M, Giraud C, Lyall H, Khoo S, Blanche S, Treluyer JM. Lopinavir/ritonavir population pharmacokinetics in neonates and infants. Br J Clin Pharmacol. 2011 Jun;71(6):956-60. doi: 10.1111/j.1365-2125.2011.03926.x.
• Background Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers T, Bwakura-Dangarembizi M, Chi BH, Musoke P, Kamthunzi P, Schimana W, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Violari A. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 2010 Oct 14;363(16):1510-20. doi: 10.1056/NEJMoa1000931.
• Background Moorthy A, Kuhn L, Coovadia A, Meyers T, Strehlau R, Sherman G, Tsai WY, Chen YH, Abrams EJ, Persaud D. Induction therapy with protease-inhibitors modifies the effect of nevirapine resistance on virologic response to nevirapine-based HAART in children. Clin Infect Dis. 2011 Feb 15;52(4):514-21. doi: 10.1093/cid/ciq161. Epub 2011 Jan 22.
• Background Eley BS, Meyers T. Antiretroviral therapy for children in resource-limited settings: current regimens and the role of newer agents. Paediatr Drugs. 2011 Oct 1;13(5):303-16. doi: 10.2165/11593330-000000000-00000.
• Background McIlleron H, Willemse M, Werely CJ, Hussey GD, Schaaf HS, Smith PJ, Donald PR. Isoniazid plasma concentrations in a cohort of South African children with tuberculosis: implications for international pediatric dosing guidelines. Clin Infect Dis. 2009 Jun 1;48(11):1547-53. doi: 10.1086/598192.
• Background Schaaf HS, Willemse M, Cilliers K, Labadarios D, Maritz JS, Hussey GD, McIlleron H, Smith P, Donald PR. Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis. BMC Med. 2009 Apr 22;7:19. doi: 10.1186/1741-7015-7-19.
• Background Thee S, Detjen A, Wahn U, Magdorf K. Pyrazinamide serum levels in childhood tuberculosis. Int J Tuberc Lung Dis. 2008 Sep;12(9):1099-101.
• Background Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendations. Int J Tuberc Lung Dis. 2006 Dec;10(12):1318-30.
• Background Thee S, Seddon JA, Donald PR, Seifart HI, Werely CJ, Hesseling AC, Rosenkranz B, Roll S, Magdorf K, Schaaf HS. Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations. Antimicrob Agents Chemother. 2011 Dec;55(12):5560-7. doi: 10.1128/AAC.05429-11. Epub 2011 Oct 3.
• Background Berenguer J, Perez-Elias MJ, Bellon JM, Knobel H, Rivas-Gonzalez P, Gatell JM, Miguelez M, Hernandez-Quero J, Flores J, Soriano V, Santos I, Podzamczer D, Sala M, Camba M, Resino S; Spanish Abacavir, Lamivudine, and Zidovudine Cohort Study Group. Effectiveness and safety of abacavir, lamivudine, and zidovudine in antiretroviral therapy-naive HIV-infected patients: results from a large multicenter observational cohort. J Acquir Immune Defic Syndr. 2006 Feb 1;41(2):154-9. doi: 10.1097/01.qai.0000194231.08207.8a.
• Background Shey M, Kongnyuy EJ, Shang J, Wiysonge CS. A combination drug of abacavir-lamivudine-zidovudine (Trizivir) for treating HIV infection and AIDS. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD005481. doi: 10.1002/14651858.CD005481.pub2.
• Background la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP, Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2004 May;48(5):1553-60. doi: 10.1128/AAC.48.5.1553-1560.2004.
• Background Decloedt EH, McIlleron H, Smith P, Merry C, Orrell C, Maartens G. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Antimicrob Agents Chemother. 2011 Jul;55(7):3195-200. doi: 10.1128/AAC.01598-10. Epub 2011 May 2.
• Background Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers TM, Smith PJ, Maartens G, McIlleron HM. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):566-9. doi: 10.1097/QAI.0b013e3181642257.
• Background Frohoff C, Moodley M, Fairlie L, Coovadia A, Moultrie H, Kuhn L, Meyers T. Antiretroviral therapy outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis treatment. PLoS One. 2011 Feb 23;6(2):e17273. doi: 10.1371/journal.pone.0017273.
• Background Rae JM, Johnson MD, Lippman ME, Flockhart DA. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther. 2001 Dec;299(3):849-57.
• Background Zhang C, McIlleron H, Ren Y, van der Walt JS, Karlsson MO, Simonsson US, Denti P. Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children. Antivir Ther. 2012;17(1):25-33. doi: 10.3851/IMP1915.
• Background Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303-32. doi: 10.1146/annurev.pharmtox.48.113006.094708.
• Background Holford N. Dosing in children. Clin Pharmacol Ther. 2010 Mar;87(3):367-70. doi: 10.1038/clpt.2009.262. Epub 2010 Jan 20. No abstract available.
• Background Price PS, Conolly RB, Chaisson CF, Gross EA, Young JS, Mathis ET, Tedder DR. Modeling interindividual variation in physiological factors used in PBPK models of humans. Crit Rev Toxicol. 2003;33(5):469-503.
• Background Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. doi: 10.1136/bmj.39000.486400.55. Epub 2006 Nov 3.
• Background Hartkoorn RC, Kwan WS, Shallcross V, Chaikan A, Liptrott N, Egan D, Sora ES, James CE, Gibbons S, Bray PG, Back DJ, Khoo SH, Owen A. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet Genomics. 2010 Feb;20(2):112-20. doi: 10.1097/FPC.0b013e328335b02d.
• Background Chigutsa E, Visser ME, Swart EC, Denti P, Pushpakom S, Egan D, Holford NH, Smith PJ, Maartens G, Owen A, McIlleron H. The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications. Antimicrob Agents Chemother. 2011 Sep;55(9):4122-7. doi: 10.1128/AAC.01833-10. Epub 2011 Jun 27.
• Background Svard J, Spiers JP, Mulcahy F, Hennessy M. Nuclear receptor-mediated induction of CYP450 by antiretrovirals: functional consequences of NR1I2 (PXR) polymorphisms and differential prevalence in whites and sub-Saharan Africans. J Acquir Immune Defic Syndr. 2010 Dec 15;55(5):536-49. doi: 10.1097/QAI.0b013e3181f52f0c.
• Background Shimizu M, Fukami T, Kobayashi Y, Takamiya M, Aoki Y, Nakajima M, Yokoi T. A novel polymorphic allele of human arylacetamide deacetylase leads to decreased enzyme activity. Drug Metab Dispos. 2012 Jun;40(6):1183-90. doi: 10.1124/dmd.112.044883. Epub 2012 Mar 13.
• Background Nakajima A, Fukami T, Kobayashi Y, Watanabe A, Nakajima M, Yokoi T. Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine. Biochem Pharmacol. 2011 Dec 1;82(11):1747-56. doi: 10.1016/j.bcp.2011.08.003. Epub 2011 Aug 12.
• Background Wiseman CA, Gie RP, Starke JR, Schaaf HS, Donald PR, Cotton MF, Hesseling AC. A proposed comprehensive classification of tuberculosis disease severity in children. Pediatr Infect Dis J. 2012 Apr;31(4):347-52. doi: 10.1097/INF.0b013e318243e27b.
• Background Nijland HM, L'homme RF, Rongen GA, van Uden P, van Crevel R, Boeree MJ, Aarnoutse RE, Koopmans PP, Burger DM. High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets. AIDS. 2008 May 11;22(8):931-5. doi: 10.1097/QAD.0b013e3282faa71e.
• Background Dansirikul C, Silber HE, Karlsson MO. Approaches to handling pharmacodynamic baseline responses. J Pharmacokinet Pharmacodyn. 2008 Jun;35(3):269-83. doi: 10.1007/s10928-008-9088-2. Epub 2008 Apr 30.
• Background Gupta P, Hutmacher MM, Frame B, Miller R. An alternative method for population pharmacokinetic data analysis under noncompliance. J Pharmacokinet Pharmacodyn. 2008 Apr;35(2):219-33. doi: 10.1007/s10928-008-9085-5. Epub 2008 Feb 26.
• Background Zhang C, Denti P, Decloedt EH, Ren Y, Karlsson MO, McIlleron H. Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin. Br J Clin Pharmacol. 2013 Nov;76(5):741-51. doi: 10.1111/bcp.12101.
• Galileya LT, Wasmann RE, Chabala C, Rabie H, Lee J, Njahira Mukui I, Hesseling A, Zar H, Aarnoutse R, Turkova A, Gibb D, Cotton MF, McIlleron H, Denti P. Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis. PLoS Med. 2023 Nov 21;20(11):e1004303. doi: 10.1371/journal.pmed.1004303. eCollection 2023 Nov.
• Rabie H, Tikiso T, Lee J, Fairlie L, Strehlau R, Bobat R, Liberty A, McIlleron H, Andrieux-Meyer I, Cotton M, Lallemant M, Denti P. Abacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e01923-19. doi: 10.1128/AAC.01923-19. Print 2020 Apr 21.
• Rabie H, Denti P, Lee J, Masango M, Coovadia A, Pillay S, Liberty A, Simon F, McIlleron H, Cotton MF, Lallemant M. Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study. Lancet HIV. 2018 Dec 6:S2352-3018(18)30293-5. doi: 10.1016/S2352-3018(18)30293-5. Online ahead of print.

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