Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors
Brian L Robbins, Edmund V Capparelli, Ellen G Chadwick, Ram Yogev, Leslie Serchuck, Carol Worrell, Mary Elizabeth Smith, Carmelita Alvero, Terence Fenton, Barbara Heckman, Stephen I Pelton, Grace Aldrovandi, William Borkowsky, John Rodman, Peter L Havens, PACTG 1038 Team, Charles Rose, Michael Bates, Malte Schutz, Marisol Martinez, Kenneth McIntosh, Sandra K Burchett, Nancy Karthas, Catherine Catherine Kneut, Audra Deveikis, Jagmohan Batra, Susan Marks, Nancy Hutton, Andrea Ruff, Mary Beth Griffith, Margaret Donnelly, Juliana Simonetti, Carole Mathison, Opemipo Johnson, Elaine Abrams, Susan Champion, Maxine Frere, Kamali Swaminathan, Pat Flynn, Aditya Gaur, Nehali Patel, Jill Utech, Brian L Robbins, Edmund V Capparelli, Ellen G Chadwick, Ram Yogev, Leslie Serchuck, Carol Worrell, Mary Elizabeth Smith, Carmelita Alvero, Terence Fenton, Barbara Heckman, Stephen I Pelton, Grace Aldrovandi, William Borkowsky, John Rodman, Peter L Havens, PACTG 1038 Team, Charles Rose, Michael Bates, Malte Schutz, Marisol Martinez, Kenneth McIntosh, Sandra K Burchett, Nancy Karthas, Catherine Catherine Kneut, Audra Deveikis, Jagmohan Batra, Susan Marks, Nancy Hutton, Andrea Ruff, Mary Beth Griffith, Margaret Donnelly, Juliana Simonetti, Carole Mathison, Opemipo Johnson, Elaine Abrams, Susan Champion, Maxine Frere, Kamali Swaminathan, Pat Flynn, Aditya Gaur, Nehali Patel, Jill Utech
Abstract
Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m(2) orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m(2) p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m(2) p.o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years (range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of >0.75 log(10), with a median maximal decrease in viral load of -1.57 log(10) copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 (range, 62.8 to 305.5) microg x h/ml and median LPV trough concentration (C(trough)) of 10.8 (range, 4.1 to 25.3) microg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) microg x h/ml and the median SQV C(trough) was 2.1 (range, 0.2 to 4.1) microg/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach.
Trial registration: ClinicalTrials.gov NCT00084058.
Figures
Source: PubMed