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Antimicrobial Agents and Chemotherapy, September 2008, p. 3276-3283, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00224-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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{triangledown} ,{dagger}

Brian L. Robbins,1 Edmund V. Capparelli,2 Ellen G. Chadwick,3 Ram Yogev,3 Leslie Serchuck,4,{ddagger} Carol Worrell,4 Mary Elizabeth Smith,5,§ Carmelita Alvero,6 Terence Fenton,6 Barbara Heckman,7 Stephen I. Pelton,8 Grace Aldrovandi,9 William Borkowsky,10 John Rodman,1 Peter L. Havens,11* for the PACTG 1038 Team

St. Jude Children's Research Hospital, Memphis, Tennessee,1 University of California San Diego, San Diego, California,2 Children's Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, Illinois,3 National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland,4 Division of AIDS, National Institutes of Health, Bethesda, Maryland,5 Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts,6 Frontier Science and Technology Research Foundation, Amherst, New York,7 Boston University Schools of Medicine and Public Health, Boston, Massachusetts,8 Children's Hospital of Los Angeles, Los Angeles, California,9 New York School of Medicine, New York, New York,10 Medical College of Wisconsin, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin,11

Received 17 February 2008/ Returned for modification 13 April 2008/ Accepted 16 June 2008

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/m2 orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m2 p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m2 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 log10, with a median maximal decrease in viral load of –1.57 log10 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) µg·h/ml and median LPV trough concentration (Ctrough) of 10.8 (range, 4.1 to 25.3) µg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) µg·h/ml and the median SQV Ctrough was 2.1 (range, 0.2 to 4.1) µg/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.

* Corresponding author. Mailing address: Suite C450, Pediatric Infectious Diseases, Children's Hospital of Wisconsin, P.O. Box 1997, Milwaukee, WI 53201-1997. Phone: (414) 337-7070. Fax: (414) 337-7093. E-mail: phavens{at}mcw.edu

{triangledown} Published ahead of print on 14 July 2008.

{dagger} This is PACTG study P1038.

{ddagger} Present address: 2118 Pine Street, Philadelphia, PA 19103.

§ Present address: National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3276-3283, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00224-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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