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A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the Who Pediatric Weight Band Dosing Guidelines

Pinto, Jorge A. MD, DSc; Capparelli, Edmund V. PharmD; Warshaw, Meredith MSS, MA; Zimmer, Bonnie MS; Cressey, Tim R. PhD; Spector, Stephen A. MD; Qin, Min PhD; Smith, Betsy MD; Siberry, George K. MD; Mirochnick, Mark MD; for the IMPAACT P1083 Team
The Pediatric Infectious Disease Journal: Post Acceptance: October 28, 2017
doi: 10.1097/INF.0000000000001817
HIV Reports: PDF Only

Background:

The World Health Organization (WHO) recommends weight band dosing of antiretrovirals for children. Data are limited describing drug exposure/safety of lopinavir/ritonavir (LPV/r) using WHO weight-band dosing.

Methods:

IMPAACT P1083 was a phase II/III trial assessing the pharmacokinetics (PK) and short-term safety, tolerance, and efficacy of LPV/r in HIV-infected children 3 to 25 kg dosed according to WHO weight bands, with liquid solution or meltrex extrusion tablets. The main PK target was an area under the curve (AUC0-24) of 80-320 mcg*hr/mL.

Results:

Of 97 enrolled participants, median age 2.5 years, 89 (91.8%) completed the protocol. Median LPV dose was 303 mg/m2. The geometric mean (90% confidence limits) LPV PK AUC0-24 was 196 (177, 217) mcg*hr/mL and Cmin was 2.47 (1.52, 4.02) mcg/mL. AUC0-24 was within the target range for 79% of participants. The median (Q1, Q3) difference between individual observed PK parameters and those expected if FDA dosing guidelines were followed was 30.7 (7.9, 54.3) for AUC0-24 and 0.56 (0, 1.27) for Cmin. Ten (10%) participants had grade 3 or 4 events deemed related to study treatment, mostly asymptomatic laboratory abnormalities. Three participants died of unrelated study treatment causes. At week 24, 57/79 (72%) of participants reached viral suppression and the median increase in CD4% (n=83) was 6.0 (p<0.0001).

Conclusions:

WHO weight band dosing guidelines in children achieved adequate LPV plasma exposure but was higher than that expected with FDA dosing guidelines. Despite the higher LPV exposure the treatment was well tolerated and the 24-week efficacy data were favorable.

Presented in part at the Conference on Retrovirus and Opportunistic Infections (CROI), Boston, MA, February 2013.

Funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632, UM1AI068616 and UM1AI106716, with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH)

Acknowledgements The authors thank the patients and families who participated in this trial. In addition to the authors, members of the P1083 protocol team include Vincent Carey, Ph.D. (Harvard School of Public Health, Boston, MA), Kulkanya Chokephaibulkit, M.D. (Mahidol University, Bangkok, Thailand), James Tutko, B.S. (Frontier Science & Technology Research Foundation, Inc., Buffalo, NY), Marisol Martinez-Tristani, M.D. (AbbVie Pharmaceuticals, Lake County, IL). AbbVie Pharmaceuticals provided the lopinavir/ritonavir (Kaletra®) used in this study. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Corresponding author: Jorge A. Pinto, MD, DSc, Department of Pediatrics, Faculdade de Medicina, Universidade Federal de Minas Gerais. Av. Alfredo Balena 190, room # 161, Belo Horizonte, MG, 30130-100, Brasil. Telephone: (55 31) 3409 9822 Fax: (55 31) 3273 0422, e-mail: jpinto@medicina.ufmg.br

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