title: Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics, tolerance, safety and antiviral activity of the HIV protease inhibitor, saquinavir, formulated as soft gelatin capsules (SQV-SGC), given in combination with nucleoside antiretroviral agents (NRTIs) with or without nelfinavir in HIV-infected children.
  
  
  METHODS
  This was an open label study of HIV-infected children ages 3 to 16 years, conducted in two parts. In Part 1 of the study 14 children were treated orally with SQV-SGC (initially given in three 33-mg/kg doses daily; dosage adjusted to 50 mg/kg three times daily based on initial pharmacokinetics) and two NRTIs. Addition of nelfinavir was permitted for children who did not achieve a predetermined steady state target plasma saquinavir exposure. In Part 2 a new group of 13 children received SQV-SGC (33 mg/kg three times daily) in combination with nelfinavir and one or two NRTIs. Pharmacokinetics were assessed after the first dose and 4 weeks into treatment (steady state). Patients were treated for 72 and 48 weeks in Parts 1 and 2, respectively.
  
  
  RESULTS
  Most adverse events were mild; the most commonly reported were diarrhea, abdominal discomfort and headache. Two children were withdrawn from the study because of adverse events (one each of nausea and dysphagia) related to the study treatment. There were no deaths or serious adverse events attributed to the study medication. Steady state saquinavir area under the plasma concentration vs. time curves (AUC24) were 6,210 and 11,010 ng/h/ml for Parts 1 and 2, respectively. Compared with baseline measurements median changes in plasma HIV RNA concentrations were -2.12 log10 copies/ml [5 of 14 (36%) with HIV RNA <50 copies/ml) (Week 72)] and -2.58 log10 copies/ml [8 of 13 (62%) <50 copies/ml) (Week 48)] in Parts 1 and 2, respectively. The median changes in CD4+ lymphocyte count were +292 and +154 cells/microl for Parts 1 and 2, respectively. Genotypic resistance assays revealed a low frequency of saquinavir-associated resistance mutations after 48 weeks of therapy, with only 2 of 27 children having substitutions at positions 48V and/or 90M.
  
  
  CONCLUSIONS
  Combination therapy with SQV-SGC was well-tolerated and safe in HIV-infected children, and antiviral activity was observed. Saquinavir plasma concentrations were lower than expected, particularly for Part 1 (SQV-SGC plus NRTIs), but addition of nelfinavir increased saquinavir exposures.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston 77030, USA. mkline@texaschildrenshospital.org
authors.forename: M W
authors.initials: MW
authors.lastname: Kline
authors.forename: R C
authors.initials: RC
authors.lastname: Brundage
authors.forename: C V
authors.initials: CV
authors.lastname: Fletcher
authors.forename: H
authors.initials: H
authors.lastname: Schwarzwald
authors.forename: N R
authors.initials: NR
authors.lastname: Calles
authors.forename: N E
authors.initials: NE
authors.lastname: Buss
authors.forename: P
authors.initials: P
authors.lastname: Snell
authors.forename: P
authors.initials: P
authors.lastname: DeLora
authors.forename: M
authors.initials: M
authors.lastname: Eason
authors.forename: K
authors.initials: K
authors.lastname: Jorga
authors.forename: C
authors.initials: C
authors.lastname: Craig
authors.forename: F
authors.initials: F
authors.lastname: Duff
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D002214:Capsules; D002648:Child; D002675:Child, Preschool; D005260:Female; D005780:Gelatin; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D019888:Nelfinavir / Q000627:therapeutic use; D011379:Prognosis; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019258:Saquinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D002214:Capsules; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D005780:Gelatin; D019888:Nelfinavir; D019258:Saquinavir