Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus- Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377 Leslie Carstensen Floren, PharmD*; Andrew Wiznia, MD‡; Sandra Hayashi, PharmD*; Anura Jayewardene, PhD*; Kenneth Stanley, PhD§; George Johnson, MD; Sharon Nachman, MD¶; Paul Krogstad, MD#; Francesca T. Aweeka, PharmD*; and the Pediatric ACTG 377 Protocol Team ABSTRACT. Objective. Pharmacokinetic data ob- tained from children who have human immunodefi- ciency virus (HIV) infection are essential for the safe and effective use of antiretroviral agents in pediatric popula- tions. The objective of this study was to assess the impact of body weight on the pharmacokinetic disposition of nelfinavir (NFV) in the absence and presence of nevirap- ine (NVP) and compare the pharmacokinetic profiles of twice-daily (BID) and three-times-daily (TID) NFV regi- mens. Methods. This was an intensive pharmacokinetic substudy nested in a phase II, multicenter, randomized, open-label trial. Forty-five HIV-infected children receiv- ing NFV 30 mg/kg TID and 6 HIV-infected children receiving NFV 55 mg/kg BID were enrolled in this study and assigned to 1 of 4 stavudine-containing regimens, 3 containing NFV and 2 containing NVP. Area under the plasma concentration-time curves from 0 to 8 hours (AUC 0 – 8 hours ) and from 0 to 12 hours (AUC 0 –12 hours ) for the TID and BID regimens, respectively, were deter- mined. For comparative purposes, the AUC 0 –24 hours was also calculated for each regimen. Results. NFV exposure in the absence of NVP was decreased in children who were <25 kg compared with those who were >25 kg (a 2.6-fold difference in median AUC 0–8 hours ). NFV pharmacokinetics in the presence of NVP did not differ between the <25 kg and >25 kg groups. The AUC 0 –24 hours for children who were <30 kg and on NFV BID was comparable to the AUC 0 –24 hours for children who were >25 kg and on NFV TID but was 2.7-fold greater than AUC 0 –24 hours for children who were <25 kg and on NFV TID. Conclusions. NFV in the absence of NVP resulted in less than half the drug exposure in children who were <25 kg compared with children who were >25 kg. NFV dosed at 55 mg/kg BID in children who are <30 kg provides comparable exposure to that measured in chil- dren who are >25 kg and receiving NFV 30 mg/kg TID. Pediatrics 2003;112: e 220–e 227. URL: http://www. pediatrics.org/cgi/content/full/112/3/e220; pharmacokinet- ics, nelfinavir, children, HIV, protease inhibitor, nevira- pine. ABBREVIATIONS. PI, protease inhibitor; HIV, human immuno- deficiency virus; NFV, nelfinavir; TID, three times daily; NNRTI, nonnucleoside reverse transcriptase inhibitor; NVP, nevirapine; BID, twice daily; NRTI, nucleoside reverse transcriptase inhibitor; PACTG, Pediatric AIDS Clinical Trials Group; d4T, stavudine; 3TC, lamivudine; AUC, area under the plasma concentration-time curve; CL/F, apparent clearance; C min , minimum plasma concen- tration. P rotease inhibitors (PIs) for human immunode- ficiency virus (HIV-1) have become an impor- tant and commonly used component of highly active antiretroviral therapy to treat HIV infection in adults and children. 1 To date, data regarding the disposition and drug interactions of nelfinavir (NFV) and other PIs in the pediatric population are limit- ed. 2–7 We report the unique pharmacokinetic param- eters of NFV dosed at a target of 27 to 33 mg/kg orally three times daily (TID), in the absence and presence of the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP), and dosed at a target of 55 mg/kg twice daily (BID) in clinically stable, antiretroviral-experienced patients who were aged 8 months to 16 years and enrolled in a large Pediatric AIDS Clinical Trials Group Protocol (PACTG) 377. PACTG 377 was designed to evaluate new combinations of potent antiretroviral agents. As most enrollees had already had extensive exposure to nucleoside analog reverse transcriptase inhibitors, we designed a trial involving both of the available HIV PIs and sought to examine the benefits of using a nonnucleoside inhibitor of the viral reverse tran- scriptase. The pharmacokinetics of the NVP in younger infants were well known, and the drug was available as a liquid formulation. However, its po- tential effects on NFV metabolism in children had not been evaluated previously. NFV is an orally active aspartyl PI licensed for use, in combination with other highly active antiretrovi- ral agents, in the treatment of HIV-1 infection. In adults, NFV given in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) has sup- pressed viral replication to levels below the level of From the *Drug Research Unit, Department of Clinical Pharmacy, Univer- sity of California, San Francisco, California; ‡Jacobi Medical Center, Bronx, New York; §Harvard School of Public Health, Boston, Massachusetts; Med- ical University of South Carolina, Charleston, South Carolina; ¶SUNY Health Sciences Center, Stony Brook, New York; and #University of Cali- fornia, Los Angeles, California. Drs Aweeka, Nachman, and Wiznia have served as ad hoc consultants or as speakers in programs sponsored by Abbott Laboratories, Agouron Pharma- ceuticals, GlaxoSmithKline, or Bristol-Myers Squibb, pharmaceutical firms whose products were studied. This work was presented in part at the Sixth Conference on Retroviruses and Opportunistic Infections; Chicago, IL; January 31–February 4, 1999. Received for publication Dec 23, 2002; accepted May 7, 2003. Reprint requests to (F.T.A.) University of California, San Francisco Drug Research Unit, San Francisco General Hospital, 1001 Potrero Ave, Bldg 100, Rm 157, San Francisco, CA 94110. E-mail: faweeka@sfghsom.ucsf.edu PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Acad- emy of Pediatrics. e220 PEDIATRICS Vol. 112 No. 3 September 2003 http://www.pediatrics.org/cgi/content/full/112/3/e220 by guest on September 11, 2016 Downloaded from