Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years

Sharon Nachman; Nan Zheng; Edward P. Acosta; Hedy Teppler; Brenda Homony; Bobbie Graham; Terence Fenton; Xia Xu; Larissa Wenning; Stephen A. Spector; Lisa M. Frenkel; Carmelita Alvero; Carol Worrell; Edward Handelsman; Andrew Wiznia; Harry Moultrie; Gurpreet Kindra; Margaret Ann Sanders; Ruth Williams; Jennifer Jensen; Midnela Acevedo; Lizbeth Fabregas; Andrea Jurgrau; Marc Foca; Alice Higgins; Jaime G. Deville; Karin Nielsen-Saines; Michele F. Carter; John Swetnam; Joan Wilson; Margaret Donnelly; Siham Akleh; Mona Rigaud; Aditya Kaul; Nehali Patel; Aditya Gaur; L. Jill Utech; Edmundo Cardoso; Ana Maria Moreira; Breno Santos; Raziya Bobat; Rosie Mngqibisa; Marlene Burey; Jacob Abadi; Michael Rosenberg; Katherine Luzuriaga; Donna Picard; Jessica Pagano-Therrien; Sylvia Dittmer; Hilda Ntatule Ndiweni; Amisha Patel; Michelle Delrey; Chivon McMullen-Jackson; Mary E. Paul; Ann Melvin; Corry Venema-Weiss; Jenna Lane; Christy Beneri; Denise Ferraro; Erin Infanzon; James B. McAuley; Mariam Aziz; Maureen McNichols; Stephen Pelton; Deb McLaud; Diana Clarke; Steven Zeichner; Arezou Akar; Deidre Thompson; Steven D. Douglas; Richard M. Rutstein; Carol A. Vincent; Mary Elizabeth Vachon; Martha Cavallo; Murli Udharam Purswani; Gaerolwe Masheto; Anthony Ogwu; Tebogo Kakhu; Rolando M. Viani; Anita Darcey; Kimberly Norris; Sandra K. Burchett; Catherine Kneut; Nancy Karthas; Denise Casey; Patricia Emmanuel; Jorge Lujan-Zilbermann; Sohail Rana; Patricia Houston; Mulu Mengistab; Mobeen Rathore; Ayesha Mirza; Tabetha Gayton; Emily Barr; Jennifer Dunn; Kerry Hahn; Zulma Eysallenne; F. Sholar Howard; Kathleen Graham; Marinella Della Negra; Wladimir Queiroz; Yu Ching Lian; Diane Wara; Ted Ruel; Russell Vandyke; Patricia Reilly; Sheila Bradford; Anita Janse Van Rensburg; Els Dobbels; Marietjie Bester; Mahrukh Bamji; Santa Paul; Mirala Sarza; Andrea Kovacs; James Homans; Lashonda Spencer; Cristna Hofer; Thalita Abreu; Ricardo Oliveira; Esau C. Joao; Jorge Pinto; Flavia Ferreira; Fabiana Kakehasi; Maria Celia Cervi; Marcia De Lima Isaac; Marcelo H. Losso; Erica Stankievich; Irene Foradori; Diane Tucker; Joseph Church; Marvin Belzer; Johns Hopkins; Jonathan Ellen; Allison Agwu; Borkovic Laurel

doi:10.1093/cid/cit696

Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years

Sharon Nachman, Nan Zheng, Edward P. Acosta, Hedy Teppler, Brenda Homony, Bobbie Graham, Terence Fenton, Xia Xu, Larissa Wenning, Stephen A. Spector, Lisa M. Frenkel, Carmelita Alvero, Carol Worrell, Edward Handelsman, Andrew Wiznia, Harry Moultrie, Gurpreet Kindra, Margaret Ann Sanders, Ruth Williams, Jennifer JensenMidnela Acevedo, Lizbeth Fabregas, Andrea Jurgrau, Marc Foca, Alice Higgins, Jaime G. Deville, Karin Nielsen-Saines, Michele F. Carter, John Swetnam, Joan Wilson, Margaret Donnelly, Siham Akleh, Mona Rigaud, Aditya Kaul, Nehali Patel, Aditya Gaur, L. Jill Utech, Edmundo Cardoso, Ana Maria Moreira, Breno Santos, Raziya Bobat, Rosie Mngqibisa, Marlene Burey, Jacob Abadi, Michael Rosenberg, Katherine Luzuriaga, Donna Picard, Jessica Pagano-Therrien, Sylvia Dittmer, Hilda Ntatule Ndiweni, Amisha Patel, Michelle Delrey, Chivon McMullen-Jackson, Mary E. Paul, Ann Melvin, Corry Venema-Weiss, Jenna Lane, Christy Beneri, Denise Ferraro, Erin Infanzon, James B. McAuley, Mariam Aziz, Maureen McNichols, Stephen Pelton, Deb McLaud, Diana Clarke, Steven Zeichner, Arezou Akar, Deidre Thompson, Steven D. Douglas, Richard M. Rutstein, Carol A. Vincent, Mary Elizabeth Vachon, Martha Cavallo, Murli Udharam Purswani, Gaerolwe Masheto, Anthony Ogwu, Tebogo Kakhu, Rolando M. Viani, Anita Darcey, Kimberly Norris, Sandra K. Burchett, Catherine Kneut, Nancy Karthas, Denise Casey, Patricia Emmanuel, Jorge Lujan-Zilbermann, Sohail Rana, Patricia Houston, Mulu Mengistab, Mobeen Rathore, Ayesha Mirza, Tabetha Gayton, Emily Barr, Jennifer Dunn, Kerry Hahn, Zulma Eysallenne, F. Sholar Howard, Kathleen Graham, Marinella Della Negra, Wladimir Queiroz, Yu Ching Lian, Diane Wara, Ted Ruel, Russell Vandyke, Patricia Reilly, Sheila Bradford, Anita Janse Van Rensburg, Els Dobbels, Marietjie Bester, Mahrukh Bamji, Santa Paul, Mirala Sarza, Andrea Kovacs, James Homans, Lashonda Spencer, Cristna Hofer, Thalita Abreu, Ricardo Oliveira, Esau C. Joao, Jorge Pinto, Flavia Ferreira, Fabiana Kakehasi, Maria Celia Cervi, Marcia De Lima Isaac, Marcelo H. Losso, Erica Stankievich, Irene Foradori, Diane Tucker, Joseph Church, Marvin Belzer, Johns Hopkins, Jonathan Ellen, Allison Agwu, Borkovic Laurel

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth.Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log₁₀ reduction between baseline and week 24.Results. The targeted pharmacokinetic parameters (AUC_0-12h and C_12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/μL (4.6%).Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses.

Original language	English (US)
Pages (from-to)	413-422
Number of pages	10
Journal	Clinical Infectious Diseases
Volume	58
Issue number	3
DOIs	https://doi.org/10.1093/cid/cit696
State	Published - Feb 2014
Externally published	Yes

Keywords

adverse event
pediatric HIV
pharmacokinetics
raltegravir

ASJC Scopus subject areas

Microbiology (medical)
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/cid/cit696

Cite this

Nachman, S., Zheng, N., Acosta, E. P., Teppler, H., Homony, B., Graham, B., Fenton, T., Xu, X., Wenning, L., Spector, S. A., Frenkel, L. M., Alvero, C., Worrell, C., Handelsman, E., Wiznia, A., Moultrie, H., Kindra, G., Sanders, M. A., Williams, R., ... Laurel, B. (2014). Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clinical Infectious Diseases, 58(3), 413-422. https://doi.org/10.1093/cid/cit696

Nachman, S, Zheng, N, Acosta, EP, Teppler, H, Homony, B, Graham, B, Fenton, T, Xu, X, Wenning, L, Spector, SA, Frenkel, LM, Alvero, C, Worrell, C, Handelsman, E, Wiznia, A, Moultrie, H, Kindra, G, Sanders, MA, Williams, R, Jensen, J, Acevedo, M, Fabregas, L, Jurgrau, A, Foca, M, Higgins, A, Deville, JG, Nielsen-Saines, K, Carter, MF, Swetnam, J, Wilson, J, Donnelly, M, Akleh, S, Rigaud, M, Kaul, A, Patel, N, Gaur, A, Utech, LJ, Cardoso, E, Moreira, AM, Santos, B, Bobat, R, Mngqibisa, R, Burey, M, Abadi, J, Rosenberg, M, Luzuriaga, K, Picard, D, Pagano-Therrien, J, Dittmer, S, Ndiweni, HN, Patel, A, Delrey, M, McMullen-Jackson, C, Paul, ME, Melvin, A, Venema-Weiss, C, Lane, J, Beneri, C, Ferraro, D, Infanzon, E, McAuley, JB, Aziz, M, McNichols, M, Pelton, S, McLaud, D, Clarke, D, Zeichner, S, Akar, A, Thompson, D, Douglas, SD, Rutstein, RM, Vincent, CA, Vachon, ME, Cavallo, M, Purswani, MU, Masheto, G, Ogwu, A, Kakhu, T, Viani, RM, Darcey, A, Norris, K, Burchett, SK, Kneut, C, Karthas, N, Casey, D, Emmanuel, P, Lujan-Zilbermann, J, Rana, S, Houston, P, Mengistab, M, Rathore, M, Mirza, A, Gayton, T, Barr, E, Dunn, J, Hahn, K, Eysallenne, Z, Howard, FS, Graham, K, Negra, MD, Queiroz, W, Lian, YC, Wara, D, Ruel, T, Vandyke, R, Reilly, P, Bradford, S, Van Rensburg, AJ, Dobbels, E, Bester, M, Bamji, M, Paul, S, Sarza, M, Kovacs, A, Homans, J, Spencer, L, Hofer, C, Abreu, T, Oliveira, R, Joao, EC, Pinto, J, Ferreira, F, Kakehasi, F, Cervi, MC, Isaac, MDL, Losso, MH, Stankievich, E, Foradori, I, Tucker, D, Church, J, Belzer, M, Hopkins, J, Ellen, J, Agwu, A & Laurel, B 2014, 'Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years', Clinical Infectious Diseases, vol. 58, no. 3, pp. 413-422. https://doi.org/10.1093/cid/cit696

@article{205cf27aa062461c93c9ccd3e8b66147,

title = "Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years",

abstract = "Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth.Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction between baseline and week 24.Results. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/μL (4.6%).Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses.",

keywords = "adverse event, pediatric HIV, pharmacokinetics, raltegravir",

author = "Sharon Nachman and Nan Zheng and Acosta, {Edward P.} and Hedy Teppler and Brenda Homony and Bobbie Graham and Terence Fenton and Xia Xu and Larissa Wenning and Spector, {Stephen A.} and Frenkel, {Lisa M.} and Carmelita Alvero and Carol Worrell and Edward Handelsman and Andrew Wiznia and Harry Moultrie and Gurpreet Kindra and Sanders, {Margaret Ann} and Ruth Williams and Jennifer Jensen and Midnela Acevedo and Lizbeth Fabregas and Andrea Jurgrau and Marc Foca and Alice Higgins and Deville, {Jaime G.} and Karin Nielsen-Saines and Carter, {Michele F.} and John Swetnam and Joan Wilson and Margaret Donnelly and Siham Akleh and Mona Rigaud and Aditya Kaul and Nehali Patel and Aditya Gaur and Utech, {L. Jill} and Edmundo Cardoso and Moreira, {Ana Maria} and Breno Santos and Raziya Bobat and Rosie Mngqibisa and Marlene Burey and Jacob Abadi and Michael Rosenberg and Katherine Luzuriaga and Donna Picard and Jessica Pagano-Therrien and Sylvia Dittmer and Ndiweni, {Hilda Ntatule} and Amisha Patel and Michelle Delrey and Chivon McMullen-Jackson and Paul, {Mary E.} and Ann Melvin and Corry Venema-Weiss and Jenna Lane and Christy Beneri and Denise Ferraro and Erin Infanzon and McAuley, {James B.} and Mariam Aziz and Maureen McNichols and Stephen Pelton and Deb McLaud and Diana Clarke and Steven Zeichner and Arezou Akar and Deidre Thompson and Douglas, {Steven D.} and Rutstein, {Richard M.} and Vincent, {Carol A.} and Vachon, {Mary Elizabeth} and Martha Cavallo and Purswani, {Murli Udharam} and Gaerolwe Masheto and Anthony Ogwu and Tebogo Kakhu and Viani, {Rolando M.} and Anita Darcey and Kimberly Norris and Burchett, {Sandra K.} and Catherine Kneut and Nancy Karthas and Denise Casey and Patricia Emmanuel and Jorge Lujan-Zilbermann and Sohail Rana and Patricia Houston and Mulu Mengistab and Mobeen Rathore and Ayesha Mirza and Tabetha Gayton and Emily Barr and Jennifer Dunn and Kerry Hahn and Zulma Eysallenne and Howard, {F. Sholar} and Kathleen Graham and Negra, {Marinella Della} and Wladimir Queiroz and Lian, {Yu Ching} and Diane Wara and Ted Ruel and Russell Vandyke and Patricia Reilly and Sheila Bradford and {Van Rensburg}, {Anita Janse} and Els Dobbels and Marietjie Bester and Mahrukh Bamji and Santa Paul and Mirala Sarza and Andrea Kovacs and James Homans and Lashonda Spencer and Cristna Hofer and Thalita Abreu and Ricardo Oliveira and Joao, {Esau C.} and Jorge Pinto and Flavia Ferreira and Fabiana Kakehasi and Cervi, {Maria Celia} and Isaac, {Marcia De Lima} and Losso, {Marcelo H.} and Erica Stankievich and Irene Foradori and Diane Tucker and Joseph Church and Marvin Belzer and Johns Hopkins and Jonathan Ellen and Allison Agwu and Borkovic Laurel",

note = "Funding Information: Participating sites and site personnel include: Shandukani Research (Harry Moultrie, MD MSc; Angela Oosthuizen, BPharm; Gurpreet Kindra, MD PhD); Chicago Children{\textquoteright}s (Margaret Ann Sanders, MPH; Ruth Williams, RN; Jennifer Jensen, PNP); San Juan City Hospital PR NICHD (Midnela Acevedo, MD; Lizbeth Fabregas, MS); Columbia IMPAACT (Andrea Jurgrau, PNP; Marc Foca, MD; Alice Higgins, RN); UCLA–Los Angeles/Brazil AIDS Consortium (Jaime G. Deville, MD; Karin Nielsen-Saines, MD; Michele F. Carter, RN); DUMC Pediatric (John Swetnam, MD; Joan Wilson, RN, BSN; Margaret Donnelly, PA-C); NYU NY NICHD, supported in part by grant UL1 TR000038 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) (Siham Akleh, RN; Mona Rigaud, MD; Aditya Kaul, MD); St Jude/UTHSC (Nehali Patel, MD; Aditya Gaur, MD; L. Jill Utech, RN, MSN); Hospital Nossa Senhora da Con-ceicao (Edmundo Cardoso, MD; Ana Maria Moreira, MD; Breno Santos, MD); Durban Pediatric HIV (Raziya Bobat, MD; Rosie Mngqibisa, MS); Jacobi Medical Center Bronx NICHD (Marlene Burey, PNP; Jacob Abadi, MD; Michael Rosenberg, MD); WNE Maternal Pediatric Adolescent AIDS (Katherine Luzuriaga, MD; Donna Picard, RN; Jessica Pagano-Therrien, RN, PNP; CTSI: UL1TR000161); Soweto IMPAACT (Sylvia Dittmer, MBBCH, DCH; Hilda Ntatule Ndiweni, BC, Ed ET Admin; Amisha Patel, BPharm); Texas Children{\textquoteright}s Hospital (Michelle DelRey, RN; Chivon McMullen-Jackson, RN, BSN, CCRP; Mary E. Paul, MD); Seattle Children{\textquoteright}s Hospital (Ann Melvin, MD, MPH; Corry Venema-Weiss, ARNP; Jenna Lane, ARNP). This publication was supported by the NCATS of the NIH under Award Number UL1TR000423); SUNY Stony Brook NICHD (Christy Beneri, DO; Denise Ferraro, FNP; Erin Infanzon); Rush University Cook County Hospital Chicago NICHD (James B McAuley, MD, MPH; Mariam Aziz, MD; Maureen McNichols, RN, MSN, CCRC); Boston Medical Center Pediatric HIV Program NICHD (Stephen Pelton, MD; Deb McLaud, RN; Diana Clarke, PharmD); Children{\textquoteright}s National Medical Center Washington DC NICHD (Steven Zeichner, MD, PhD; Arezou Akar, MPH; Deidre Thompson, RN); The Children{\textquoteright}s Hospital of Philadelphia IMPAACT (Steven D. Douglas, MD, Richard M. Rutstein, MD, Carol A. Vincent, PhD, CRNP); Bronx-Lebanon Hospital IMPAACT (Mary Elizabeth Vachon, MPH; Martha Cavallo, NP; Murli Udharam Purswani, MD); Gaborone Prevention/Treatment Trials (Gaerolwe Masheto, MD; Anthony Ogwu, MD, MPH; Tebogo Kakhu, BS, RN); University of California San Diego Maternal, Child, and Adolescent HIV (Rolando M. Viani, MD, MTP; Anita, Darcey, RN; Kimberly Norris, RN, BSN); Children{\textquoteright}s Hospital of Boston NICHD (Sandra K. Burchett, MD, MS; Catherine Kneut, RN, MS, CPNP; Nancy Karthas, RN, MS, CPNP); University of South Florida–Tampa NICHD (Denise Casey, RN; Patricia Emmanuel, MD; Jorge Lujan-Zilbermann, MD); Howard University, Washington DC, NICHD (Sohail Rana, MD; Patricia Houston, MS; Mulu Mengistab, Pharm D); University of Florida College of Medicine, Jacksonville NICHD (Mobeen Rathore, MD; Ayesha Mirza, MD; Tabetha Gayton, MS, RN, FNP; The UF CTSI is supported in part by the NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award UL1 RR029890); University of Colorado Denver NICHD (Emily Barr, CPNP, CNM, MSN; Jennifer Dunn, FNP-C; Kerry Hahn, BS, CCRP); South Florida CDC Fort Lauderdale NICHD (Zulma Eysallenne, RN; F. Sholar Howard, ARNP; Kathleen Graham, Pharm D); Instituto de Infectologia Em{\'i}lio Ribas Sao Paulo Brazil NICHD (Marinella Della Negra, MD, PhD; Wladimir Queiroz, MD, MSc; Yu Ching Lian, MD, MSc); University of California, San Francisco NICHD (Diane Wara, MD; Ted Ruel, MD; This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131); Tulane University New Orleans NICHD (Russell VanDyke, MD; Patricia Reilly, RN; Sheila Bradford, RN); Stellenbosch University (Anita Janse van Rensburg, RN; Els Dobbels, MD; Marietjie Bester, RN); Metropolitan Hospital NICHD (Mahrukh Bamji, MD; Santa Paul, MD; Mirala Sarza, MS); USC LA NICHD (Andrea Kovacs, MD; James Homans, MD; LaShonda Spencer, MD); Inst of Pediatrics Fed Univ Rio de Janeiro NICHD (Cristna Hofer, MD, PhD; Thalita Abreu, MD; Ricardo Oliveira, MD); Hospital Federal dos Servi-dores do Estado Rio de Janeiro NICHD (Esau C. Joao, MD, PhD); SOM Federal University Minas Gerais Brazil NICHD (Jorge Pinto, MD; Flavia Fer-reira, MD; Fabiana Kakehasi, MD); University of Sao Paulo Brazil NICHD (Maria Celia Cervi; Marcia De Lima Isaac); Hospital General de Agudos Buenos Aires Argentina NICHD (Marcelo H. Losso, MD; Erica Stankievich, MD; Irene Foradori, MD); Children{\textquoteright}s Hospital of Los Angeles NICHD (Diane Tucker, MSN; Joseph Church, MD; Marvin Belzer, MD, FACP, FSAM); and Johns Hopkins University Baltimore NICHD (Jonathan Ellen MD; Allison Agwu MD; Laurel Borkovic MS ED). Funding Information: Financial support. Overall support for the IMPAACT Group was provided by the NIAID (grant number U01 AI068632), the NICHD, and the National Institute of Mental Health (grant number AI068632). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C), and by Merck & Co Inc.",

year = "2014",

month = feb,

doi = "10.1093/cid/cit696",

language = "English (US)",

volume = "58",

pages = "413--422",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

T1 - Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years

AU - Nachman, Sharon

AU - Zheng, Nan

AU - Acosta, Edward P.

AU - Teppler, Hedy

AU - Homony, Brenda

AU - Graham, Bobbie

AU - Fenton, Terence

AU - Xu, Xia

AU - Wenning, Larissa

AU - Spector, Stephen A.

AU - Frenkel, Lisa M.

AU - Alvero, Carmelita

AU - Worrell, Carol

AU - Handelsman, Edward

AU - Wiznia, Andrew

AU - Moultrie, Harry

AU - Kindra, Gurpreet

AU - Sanders, Margaret Ann

AU - Williams, Ruth

AU - Jensen, Jennifer

AU - Acevedo, Midnela

AU - Fabregas, Lizbeth

AU - Jurgrau, Andrea

AU - Foca, Marc

AU - Higgins, Alice

AU - Deville, Jaime G.

AU - Nielsen-Saines, Karin

AU - Carter, Michele F.

AU - Swetnam, John

AU - Wilson, Joan

AU - Donnelly, Margaret

AU - Akleh, Siham

AU - Rigaud, Mona

AU - Kaul, Aditya

AU - Patel, Nehali

AU - Gaur, Aditya

AU - Utech, L. Jill

AU - Cardoso, Edmundo

AU - Moreira, Ana Maria

AU - Santos, Breno

AU - Bobat, Raziya

AU - Mngqibisa, Rosie

AU - Burey, Marlene

AU - Abadi, Jacob

AU - Rosenberg, Michael

AU - Luzuriaga, Katherine

AU - Picard, Donna

AU - Pagano-Therrien, Jessica

AU - Dittmer, Sylvia

AU - Ndiweni, Hilda Ntatule

AU - Patel, Amisha

AU - Delrey, Michelle

AU - McMullen-Jackson, Chivon

AU - Paul, Mary E.

AU - Melvin, Ann

AU - Venema-Weiss, Corry

AU - Lane, Jenna

AU - Beneri, Christy

AU - Ferraro, Denise

AU - Infanzon, Erin

AU - McAuley, James B.

AU - Aziz, Mariam

AU - McNichols, Maureen

AU - Pelton, Stephen

AU - McLaud, Deb

AU - Clarke, Diana

AU - Zeichner, Steven

AU - Akar, Arezou

AU - Thompson, Deidre

AU - Douglas, Steven D.

AU - Rutstein, Richard M.

AU - Vincent, Carol A.

AU - Vachon, Mary Elizabeth

AU - Cavallo, Martha

AU - Purswani, Murli Udharam

AU - Masheto, Gaerolwe

AU - Ogwu, Anthony

AU - Kakhu, Tebogo

AU - Viani, Rolando M.

AU - Darcey, Anita

AU - Norris, Kimberly

AU - Burchett, Sandra K.

AU - Kneut, Catherine

AU - Karthas, Nancy

AU - Casey, Denise

AU - Emmanuel, Patricia

AU - Lujan-Zilbermann, Jorge

AU - Rana, Sohail

AU - Houston, Patricia

AU - Mengistab, Mulu

AU - Rathore, Mobeen

AU - Mirza, Ayesha

AU - Gayton, Tabetha

AU - Barr, Emily

AU - Dunn, Jennifer

AU - Hahn, Kerry

AU - Eysallenne, Zulma

AU - Howard, F. Sholar

AU - Graham, Kathleen

AU - Negra, Marinella Della

AU - Queiroz, Wladimir

AU - Lian, Yu Ching

AU - Wara, Diane

AU - Ruel, Ted

AU - Vandyke, Russell

AU - Reilly, Patricia

AU - Bradford, Sheila

AU - Van Rensburg, Anita Janse

AU - Dobbels, Els

AU - Bester, Marietjie

AU - Bamji, Mahrukh

AU - Paul, Santa

AU - Sarza, Mirala

AU - Kovacs, Andrea

AU - Homans, James

AU - Spencer, Lashonda

AU - Hofer, Cristna

AU - Abreu, Thalita

AU - Oliveira, Ricardo

AU - Joao, Esau C.

AU - Pinto, Jorge

AU - Ferreira, Flavia

AU - Kakehasi, Fabiana

AU - Cervi, Maria Celia

AU - Isaac, Marcia De Lima

AU - Losso, Marcelo H.

AU - Stankievich, Erica

AU - Foradori, Irene

AU - Tucker, Diane

AU - Church, Joseph

AU - Belzer, Marvin

AU - Hopkins, Johns

AU - Ellen, Jonathan

AU - Agwu, Allison

AU - Laurel, Borkovic

N1 - Funding Information: Participating sites and site personnel include: Shandukani Research (Harry Moultrie, MD MSc; Angela Oosthuizen, BPharm; Gurpreet Kindra, MD PhD); Chicago Children’s (Margaret Ann Sanders, MPH; Ruth Williams, RN; Jennifer Jensen, PNP); San Juan City Hospital PR NICHD (Midnela Acevedo, MD; Lizbeth Fabregas, MS); Columbia IMPAACT (Andrea Jurgrau, PNP; Marc Foca, MD; Alice Higgins, RN); UCLA–Los Angeles/Brazil AIDS Consortium (Jaime G. Deville, MD; Karin Nielsen-Saines, MD; Michele F. Carter, RN); DUMC Pediatric (John Swetnam, MD; Joan Wilson, RN, BSN; Margaret Donnelly, PA-C); NYU NY NICHD, supported in part by grant UL1 TR000038 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) (Siham Akleh, RN; Mona Rigaud, MD; Aditya Kaul, MD); St Jude/UTHSC (Nehali Patel, MD; Aditya Gaur, MD; L. Jill Utech, RN, MSN); Hospital Nossa Senhora da Con-ceicao (Edmundo Cardoso, MD; Ana Maria Moreira, MD; Breno Santos, MD); Durban Pediatric HIV (Raziya Bobat, MD; Rosie Mngqibisa, MS); Jacobi Medical Center Bronx NICHD (Marlene Burey, PNP; Jacob Abadi, MD; Michael Rosenberg, MD); WNE Maternal Pediatric Adolescent AIDS (Katherine Luzuriaga, MD; Donna Picard, RN; Jessica Pagano-Therrien, RN, PNP; CTSI: UL1TR000161); Soweto IMPAACT (Sylvia Dittmer, MBBCH, DCH; Hilda Ntatule Ndiweni, BC, Ed ET Admin; Amisha Patel, BPharm); Texas Children’s Hospital (Michelle DelRey, RN; Chivon McMullen-Jackson, RN, BSN, CCRP; Mary E. Paul, MD); Seattle Children’s Hospital (Ann Melvin, MD, MPH; Corry Venema-Weiss, ARNP; Jenna Lane, ARNP). This publication was supported by the NCATS of the NIH under Award Number UL1TR000423); SUNY Stony Brook NICHD (Christy Beneri, DO; Denise Ferraro, FNP; Erin Infanzon); Rush University Cook County Hospital Chicago NICHD (James B McAuley, MD, MPH; Mariam Aziz, MD; Maureen McNichols, RN, MSN, CCRC); Boston Medical Center Pediatric HIV Program NICHD (Stephen Pelton, MD; Deb McLaud, RN; Diana Clarke, PharmD); Children’s National Medical Center Washington DC NICHD (Steven Zeichner, MD, PhD; Arezou Akar, MPH; Deidre Thompson, RN); The Children’s Hospital of Philadelphia IMPAACT (Steven D. Douglas, MD, Richard M. Rutstein, MD, Carol A. Vincent, PhD, CRNP); Bronx-Lebanon Hospital IMPAACT (Mary Elizabeth Vachon, MPH; Martha Cavallo, NP; Murli Udharam Purswani, MD); Gaborone Prevention/Treatment Trials (Gaerolwe Masheto, MD; Anthony Ogwu, MD, MPH; Tebogo Kakhu, BS, RN); University of California San Diego Maternal, Child, and Adolescent HIV (Rolando M. Viani, MD, MTP; Anita, Darcey, RN; Kimberly Norris, RN, BSN); Children’s Hospital of Boston NICHD (Sandra K. Burchett, MD, MS; Catherine Kneut, RN, MS, CPNP; Nancy Karthas, RN, MS, CPNP); University of South Florida–Tampa NICHD (Denise Casey, RN; Patricia Emmanuel, MD; Jorge Lujan-Zilbermann, MD); Howard University, Washington DC, NICHD (Sohail Rana, MD; Patricia Houston, MS; Mulu Mengistab, Pharm D); University of Florida College of Medicine, Jacksonville NICHD (Mobeen Rathore, MD; Ayesha Mirza, MD; Tabetha Gayton, MS, RN, FNP; The UF CTSI is supported in part by the NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award UL1 RR029890); University of Colorado Denver NICHD (Emily Barr, CPNP, CNM, MSN; Jennifer Dunn, FNP-C; Kerry Hahn, BS, CCRP); South Florida CDC Fort Lauderdale NICHD (Zulma Eysallenne, RN; F. Sholar Howard, ARNP; Kathleen Graham, Pharm D); Instituto de Infectologia Emílio Ribas Sao Paulo Brazil NICHD (Marinella Della Negra, MD, PhD; Wladimir Queiroz, MD, MSc; Yu Ching Lian, MD, MSc); University of California, San Francisco NICHD (Diane Wara, MD; Ted Ruel, MD; This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131); Tulane University New Orleans NICHD (Russell VanDyke, MD; Patricia Reilly, RN; Sheila Bradford, RN); Stellenbosch University (Anita Janse van Rensburg, RN; Els Dobbels, MD; Marietjie Bester, RN); Metropolitan Hospital NICHD (Mahrukh Bamji, MD; Santa Paul, MD; Mirala Sarza, MS); USC LA NICHD (Andrea Kovacs, MD; James Homans, MD; LaShonda Spencer, MD); Inst of Pediatrics Fed Univ Rio de Janeiro NICHD (Cristna Hofer, MD, PhD; Thalita Abreu, MD; Ricardo Oliveira, MD); Hospital Federal dos Servi-dores do Estado Rio de Janeiro NICHD (Esau C. Joao, MD, PhD); SOM Federal University Minas Gerais Brazil NICHD (Jorge Pinto, MD; Flavia Fer-reira, MD; Fabiana Kakehasi, MD); University of Sao Paulo Brazil NICHD (Maria Celia Cervi; Marcia De Lima Isaac); Hospital General de Agudos Buenos Aires Argentina NICHD (Marcelo H. Losso, MD; Erica Stankievich, MD; Irene Foradori, MD); Children’s Hospital of Los Angeles NICHD (Diane Tucker, MSN; Joseph Church, MD; Marvin Belzer, MD, FACP, FSAM); and Johns Hopkins University Baltimore NICHD (Jonathan Ellen MD; Allison Agwu MD; Laurel Borkovic MS ED). Funding Information: Financial support. Overall support for the IMPAACT Group was provided by the NIAID (grant number U01 AI068632), the NICHD, and the National Institute of Mental Health (grant number AI068632). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C), and by Merck & Co Inc.

PY - 2014/2

Y1 - 2014/2

N2 - Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth.Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction between baseline and week 24.Results. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/μL (4.6%).Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses.

AB - Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth.Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction between baseline and week 24.Results. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/μL (4.6%).Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses.

KW - adverse event

KW - pediatric HIV

KW - pharmacokinetics

KW - raltegravir

UR - http://www.scopus.com/inward/record.url?scp=84892742221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892742221&partnerID=8YFLogxK

U2 - 10.1093/cid/cit696

DO - 10.1093/cid/cit696

M3 - Article

C2 - 24145879

AN - SCOPUS:84892742221

SN - 1058-4838

VL - 58

SP - 413

EP - 422

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 3

ER -

Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this