Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection

Mark W. Kline, Richard C. Brundage, Courtney V Fletcher, Heidi Schwarzwald, Nancy R. Calles, Neil E. Buss, Paul Snell, Patricia Delora, Monica Eason, Karin Jorga, Charles Craig, Frank Duff

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objectives. 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 (NR-TIs) with or without nelfinavir in HIV-infected children. Methods. This was an open label study of HIVinfected 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 Two children were withdrawn from the study because of adverse events (one each of nausea and dysphagia) related to the study treatment.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 6210 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/μl 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.

Original languageEnglish (US)
Pages (from-to)666-671
Number of pages6
JournalPediatric Infectious Disease Journal
Volume20
Issue number7
DOIs
StatePublished - Jul 26 2001
Externally publishedYes

Fingerprint

Saquinavir
Virus Diseases
Gelatin
Capsules
HIV
Nelfinavir
Therapeutics
Pharmacokinetics
Antiviral Agents
RNA
Anti-Retroviral Agents
HIV Protease Inhibitors
CD4 Lymphocyte Count
Deglutition Disorders
Nucleosides
Nausea
Headache
Diarrhea

Keywords

  • Human immunodeficiency virus infection
  • Nelfinavir
  • Saquinavir soft gelatin capsules

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection. / Kline, Mark W.; Brundage, Richard C.; Fletcher, Courtney V; Schwarzwald, Heidi; Calles, Nancy R.; Buss, Neil E.; Snell, Paul; Delora, Patricia; Eason, Monica; Jorga, Karin; Craig, Charles; Duff, Frank.

In: Pediatric Infectious Disease Journal, Vol. 20, No. 7, 26.07.2001, p. 666-671.

Research output: Contribution to journalArticle

Kline, MW, Brundage, RC, Fletcher, CV, Schwarzwald, H, Calles, NR, Buss, NE, Snell, P, Delora, P, Eason, M, Jorga, K, Craig, C & Duff, F 2001, 'Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection', Pediatric Infectious Disease Journal, vol. 20, no. 7, pp. 666-671. https://doi.org/10.1097/00006454-200107000-00006
Kline, Mark W. ; Brundage, Richard C. ; Fletcher, Courtney V ; Schwarzwald, Heidi ; Calles, Nancy R. ; Buss, Neil E. ; Snell, Paul ; Delora, Patricia ; Eason, Monica ; Jorga, Karin ; Craig, Charles ; Duff, Frank. / Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection. In: Pediatric Infectious Disease Journal. 2001 ; Vol. 20, No. 7. pp. 666-671.
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abstract = "Objectives. 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 (NR-TIs) with or without nelfinavir in HIV-infected children. Methods. This was an open label study of HIVinfected 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 6210 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/μl 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.",
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AU - Kline, Mark W.

AU - Brundage, Richard C.

AU - Fletcher, Courtney V

AU - Schwarzwald, Heidi

AU - Calles, Nancy R.

AU - Buss, Neil E.

AU - Snell, Paul

AU - Delora, Patricia

AU - Eason, Monica

AU - Jorga, Karin

AU - Craig, Charles

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N2 - Objectives. 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 (NR-TIs) with or without nelfinavir in HIV-infected children. Methods. This was an open label study of HIVinfected 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 6210 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/μl 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.

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