Skip to main content
Log in

Saquinavir Soft-Gel Capsule Formulation

A Review of its Use in Patients with HIV Infection

  • Adis Drug Evaluation
  • Published:
Drugs Aims and scope Submit manuscript

Summary

Synopsis

Saquinavir is an HIV protease inhibitor which, formulated as a hard-gel capsule (HGC), was the first drug of its class to become available for the treatment of patients with HIV infection.

Despite the beneficial effects that saquinavir HGC-containing combination regimens have shown in the treatment of patients with HIV infection, the HGCformulation has limited oral bioavailability and has shown only modest antiviral activity in vivo. To overcome this limitation (with the aim of improving antiviral efficacy), a soft-gel capsule (SGC) formulation of the drug has been developed. At the recommended dosage of 1200mg 3 times daily, the SGC formulation of saquinavir achieves plasma concentrations >8 times higher than those in patients receiving saquinavir HGC 600mg 3 times daily.

Initial results of trials evaluating the therapeutic efficacy of saquinavir SGC-containing combination therapy in patients with moderate to advanced HIV infection are promising. In patients who were previously antiretroviral therapynaive or — experienced, short term (≤ 36 weeks) treatment with saquinavir SGC incombination with ≥ 2 nucleoside reverse transcriptase inhibitors (NRTIs), or nelfinavir, or 2 NRTIs plus nelfinavir led to marked improvements in virological and immunological markers of HIV disease. In comparative trials, saquinavir SGC showed improved antiviral activity compared with the HGC formulation in terms of reducing viral load. Furthermore, saquinavir SGC in combination with 2 NRTIs was as effective as indinavir plus 2 NRTIs in antiretroviral-naive or — experienced patients. Available data suggest that saquinavir SGC-containing combination therapy may be of greatest benefit in patients naive to previous antiretroviral therapy.

The SGC formulation of saquinavir appears to be generally well tolerated by adults with HIV infection. Gastrointestinal adverse events, notably diarrhoea, abdominal discomfort, nausea and dyspepsia, are the most common adverse events occurring during treatment with the drug.

Initial results of several trials that used surrogate markers to assess treatment efficacy indicate that the SGC formulation of saquinavir, administered in combination with other antiretroviral drugs, is an effective and well-tolerated treatment for patients with moderate or advanced HIV infection. Although further data are required before definitive conclusions can be drawn regarding the comparative efficacy and tolerability of the SGC and HGC formulations, it appears likely that the SGC formulation will replace the conventional formulation as a component of combination regimens for the treatment of patients with HIV infection.

Rationale for Developing a Soft-Gel Formulation

Because the hard-gel capsule (HGC) formulation of saquinavir HGC has low oral bioavailability, as a result of limited absorption and extensive first-pass metabolism, its therapeutic efficacy is less than optimal. To address this problem, saquinavir has been reformulated as a soft-gel capsule (SGC) which provides greater systemic exposure to the drug.

Overview of Pharmacodynamic Properties

Saquinavir is a selective inhibitor of HIV protease and a transition-state mimetic of the phenylalanine-proline (Phe-Pro) peptide cleavage site. Its antiviral activity is achieved by competitive inhibition of HIV protease-mediated cleavage of gag and gagpol polyproteins, thus preventing post-translational viral processing. At therapeutic concentrations, saquinavir does not appear to inhibit the activity of mammalian proteases.

In vitro, saquinavir shows activity against HIV-1, including zidovudine-resistant strains; concentrations required to produce 50% inhibition of various strains of HIV-1 ranged from 1 to 30 nmol/L (≈0.77 to 23.1 μg/L). Additive or synergistic in vitro antiviral activity occurs with saquinavir in combination with most nucleoside reverse transcriptase inhibitors (NRTIs) and/or other drugs with anti-HIV-1 activity.

HIV-1 resistance to saquinavir has been documented in vitro and in vivo. The key mutations conferring viral resistance to the drug are at codons 90 (Leu → Met) [L90M] and 48 (Gly → Val) [G48V]. In clinical isolates from patients treated with either the SGC or HGC formulation of saquinavir, the L90M mutation predominates. Although systemic exposure to saquinavir (and therefore selective pressure) is greater with the saquinavir SGC than with the HGC, available data suggest that the resistance profiles of the 2 formulations are the same or similar.

Although the mutations in HIV protease characterising resistance to saquinavir differ from those seen in patients receiving treatment with ritonavir, indinavir and nelfinavir, additional mutations may occur during long term treatment. These mutations may lead to resistance to other protease inhibitors.

Overview of Pharmacokinetic Properties

Mean maximum plasma concentration (Cmax) values of saquinavir ranged from 301.2 to 2181 μg/L in patients with HIV infection after doses of saquinavir SGC 400, 800 or 1200mg given 3 times daily. A lower saquinavir Cmax occurred in HIV-infected patients who received saquinavir HGC 600mg 3 times daily. The area under the plasma concentration-time curve (indicating the extent of systemic exposure to saquinavir) was >8 times higher in recipients of saquinavir SGC 1200mg 3 times a day (the recommended dosage) than after saquinavir HGC 600mg 3 times daily. Absorption of saquinavir from the SGC is enhanced by the presence of food.

Saquinavir has a large volume of distribution (about 700L) and is highly bound (about 97%) to plasma proteins. It is metabolised by the cytochrome P450 3A4 (CYP3A4) isoenzyme to mono- and di-hydroxylated metabolites, which have negligible antiviral activity.

Drugs that induce [e.g. rifampicin (rifampin), rifabutin, phenobarbital, phenytoin, carbamazepine] the CYP3A4 isoenzyme have the potential to cause an interactive decrease in the bioavailability of saquinavir. Conversely, administration of saquinavir with drugs that inhibit CYP3A4 (such as the protease inhibitors ritonavir, nelfinavir and indinavir) results in an interactive increase in the bioavailability of saquinavir.

Therapeutic Efficacy

The efficacy of saquinavir SGC has been investigated in several hundred adults with moderate or advanced HIV infection. Efficacy assessments were based on surrogate marker data (changes in plasma HIV RNA levels and in CD4+ cell counts); clinical end-point data are not yet available.

In a dose-ranging trial (NV 15107), the reduction in plasma HIV RNA levels was greater in HIV-infected patients who received saquinavir SGC 1200mg 3 times daily for 8 weeks than in recipients of saquinavir SGC 400 or 800mg 3 times daily or saquinavir HGC 600mg 3 times daily. The maximum median reduction in plasma HIV RNA in the saquinavir SGC 1200mg treatment group was 1.43 log10 copies/ml.

In trials of saquinavir SGC in combination with ≥2 NRTIs conducted in antiretroviral therapy-experienced adults with moderate to advanced HIV infection, plasma HIV RNA levels decreased by approximately 2.8 logio copies/ml after 16 or 36 weeks of treatment. HIV RNA levels became undetectable (limit of detection <400 copies/ml) in 43 to 80% of patients. Increases in CD4+ cell counts also occurred. Marked improvements in plasma HIV RNA levels and CD4+ cell counts were also evident in antiretroviral therapy-naive patients with HIV infection who received saquinavir SGC 1200mg 3 times daily in combination with zidovudine 300mg twice daily and lamivudine 150mg twice daily.

In addition, saquinavir SGC in combination with 2 NRTIs improved virological and immunological markers of HIV infection in a small number of antiretro viral therapy-experienced children with HIV infection.

Improvements in virological and immunological markers also occurred in antiretroviral therapy-experienced adults with HIV infection who received combination therapy with saquinavir SGC 1200mg 3 times daily plus nelfinavir 750mg 3 times daily.

In comparative trials, saquinavir SGC 1200mg 3 times daily in combination with 2 NRTIs was as effective as indinavir 800mg 3 times daily plus 2 NRTIs. Decreases in plasma HIV RNA levels were greater in patients who received saquinavir SGC in combination with either 2 NRTIs plus nelfinavir or 2 NRTIs than in patients treated with either saquinavir SGC plus nelfinavir or nelfinavir plus 2 NRTIs. Patients who were antiretroviral therapy-naive gained the most benefit from 4-drug combination therapy.

Saquinavir SGC 1200mg 3 times daily in combination with 2 NRTIs was more effective than saquinavir HGC 600mg plus 2 NRTIs in terms of reducing viral load in antiretroviral therapy-naive patients with HIV infection; plasma HIV RNA levels decreased to below the limit of detection (<400 copies/ml) in 80 and 43% of the SGC and HGC recipients, respectively, (p = 0.001) after 16 weeks.

Tolerability

Saquinavir SGC, given in combination with NRTIs and/or nelfinavir, is generally well tolerated in antiretroviral therapy-naive and -experienced adults with HIV infection. Limited data indicate that saquinavir SGC combination therapy is also well tolerated in children.

Gastrointestinal disturbances, including diarrhoea, abdominal discomfort, nausea and dyspepsia, were the most common events that occurred in HIV-infected patients receiving the drug in clinical trials. These events were typically mild in intensity. In a comparative trial, the incidence of adverse events was slightly higher in recipients of saquinavir SGC combination therapy than in patients treated with HGC combination therapy. Serious adverse events occurred in 5.6 and 2.5% of SGC and HGC recipients, respectively. 21 (5%) of 442 HIV-infected patients treated with saquinavir SGC combination therapy discontinued treatment because of adverse events in another trial.

Dosage and Administration

The recommended dosage of saquinavir SGC for patients with HIV infection is 1200mg 3 times daily in combination with NRTIs, taken ≤2 hours after a meal. Dosage reduction is required when saquinavir SGC is coadministered with the protease inhibitors ritonavir or nelfinavir, although formal recommendations are not yet available. Saquinavir SGC should not be given as monotherapy.

Patients should be monitored for biochemical abnormalities before and during treatment with saquinavir SGC. Since there are no data on the use of saquinavir SGC in patients with hepatic impairment, caution should be applied when administering the drug in this group. Drugs which are contraindicated in patients receiving saquinavir SGC therapy include terfenadine, astemizole, cisapride, triazolam, midazolam and ergot derivatives.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Noble S, Faulds D. Saquinavir: a review of its pharmacology and clinical potential in the management of HIV infection. Drugs 1996 Jul; 52: 93–112

    Article  PubMed  CAS  Google Scholar 

  2. Moyle G. Saquinavir: a review of its development, pharmacological properties and clinical use. Expert Opin Invest Drug 1996 Feb; 5: 155–67

    Article  CAS  Google Scholar 

  3. Hoetelmans RMW, Meenhorst PL, Mulder JW, et al. Clinical pharmacology of HIV protease inhibitors: focus on saquinavir, indinavir, and ritonavir. Pharm World Sci 1997 Aug; 19: 159–75

    Article  PubMed  CAS  Google Scholar 

  4. Bartlett JG. Protease inhibitors for HIV infection. Ann Intern Med 1996 Jun 15; 124: 1086–8

    PubMed  CAS  Google Scholar 

  5. Deeks SG, Smith M, Holodniy M, et al. HIV-1 protease inhibitors: a review for clinicians. JAMA 1997 Jan 8; 277: 145–53

    Article  PubMed  CAS  Google Scholar 

  6. Collier AC, Coombs RW, Schoenfeld DA, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine and zalcitabine. N Engl J Med 1996; 334: 1011–7

    Article  PubMed  CAS  Google Scholar 

  7. Vella S, Lazzarin A, Carosi G, et al. A randomized controlled trial of a protease inhibitor (saquinavir) in combination with zidovudine in previously untreated patients with advanced HIV infection. Antiviral Ther 1996 Aug; 1: 129–40

    CAS  Google Scholar 

  8. Clumek N et al. Clinical benefits of saquinavir (SQV) + zalcitabine (ddC) + zidovudine (ZDV) in untreated/minimally treated HIV-infected patients [abstract no. LB4]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1: Toronto

  9. F. Hoffmann-La Roche. Fortivase™ (saquinavir) soft gelatin capsules. Prescribing information, 1997. (Data on file)

  10. Gieschke R, Fotteler B, Buss N, et al. Relationship between exposure to saquinavir and surrogate markers of efficacy/toxicity in therapeutic study NV 15107. F Hoffmann-La Roche, Research Report B-162305, 1997 Mar 12. (Data on file)

  11. Beattie D, Bieska G, Buss N, et al. A randomized, parallel, open-label study comparing saquinavir hard gelatin formulation (600mg t.i.d.) to saquinavir soft gelatin formulation [(400 mg, 800 mg, 1200 mg) t.i.d.] x 8 weeks in HIV infected patients. F Hoffmann-La Roche, Research Report W-144981/ 30, 1996 Sep 30. (Data on file)

  12. Fischer L. Saquinavir SGC dose-ranging study. F Hoffmann-La Roche, 1998. (Data on file)

  13. F Hoffmann-La Roche (Welwyn), 1998. (Data on file)

  14. Hill G. ‘Fortovase’: optimising the benefits of saquinavir. Inpharma 1997; 1112 (13)

  15. Moyle G, Gazzard B. Current knowledge and future prospects for the use of HIV protease inhibitors. Drugs 1996 May; 51: 701–12

    Article  PubMed  CAS  Google Scholar 

  16. American Hospital Formulary Service Drug Information. Saquinavir Mesylate, 1997

  17. Perry CM, Benfield P. Nelfinavir. Drugs 1997 Jul; 54: 81–7

    Article  PubMed  CAS  Google Scholar 

  18. Lea AP, Faulds D. Ritonavir. Drugs 1996 Oct; 52: 541–6

    Article  PubMed  CAS  Google Scholar 

  19. Moyle G. Saquinavir in the management of HIV infection. Br J Hosp Med 1997 Jun 4; 57: 560–4

    PubMed  CAS  Google Scholar 

  20. Perno C-F, Aquaro S, Rosenwirth B, et al. In vitro activity of inhibitors of late stages of the replication of HIV in chronically infected macrophages. J Leukoc Biol 1994; 56: 381–6

    PubMed  CAS  Google Scholar 

  21. Bilello JA, Bilello PA, Pritchard M, et al. Reduction in the in vitro activity of A77003, an inhibitor of human immunodeficiency virus protease, by serum α1 acid glycoprotein. J Infect Dis 1995; 171: 546–51

    Article  PubMed  CAS  Google Scholar 

  22. Mosby’s Complete Drug Reference Physicians GenRX. St Louis: Mosby, 1997

  23. Demine CA, Bechtold CM, Stock D, et al. Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. Antimicrob Agents Chemother 1996 Jun; 40: 1346–51

    Google Scholar 

  24. Bloom LA, Boritzki TJ, Patick AK. Evaluation of the antiviral activity and cytotoxicity of nelfinavir in combination with reverse transcriptase and protease inhibitors in an in vitro acute HIV-1 infection model [abstract]. Antiviral Res 1997 Apr; 34: 58

    Article  Google Scholar 

  25. Oh M-d, Merrill DP, Sutton L, et al. Sequential versus simultaneous combination antiretroviral regimens for the treatment of human immunodeficiency virus type 1 infection in vitro. J Infect Dis 1997 Aug; 176: 510–4

    Article  PubMed  CAS  Google Scholar 

  26. Bold G, Capraro HG, Cozens R, et al. Profile of CGP 61755 a novel and potent HIV-1 protease inhibitor that acts synergistically with saquinavir and AZT in vitro: consequences of clinical use [abstract]. Schweiz Med Wochenschr 1996; 126 Suppl. 74/II: 54

    Google Scholar 

  27. Merrill DP, Manion DJ, Chou T-C, et al. Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro. J Infect Dis 1997 Jul; 176: 265–8

    Article  PubMed  CAS  Google Scholar 

  28. Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. Drugs 1996 Aug; 52: 168–85

    Article  PubMed  CAS  Google Scholar 

  29. Boucher C. Rational approaches to resistance: using saquinavir. AIDS 1996 Nov; 10 Suppl. 1: S15–19

    PubMed  CAS  Google Scholar 

  30. Roberts NA. Drug-resistance patterns of saquinavir and other HIV proteinase inhibitors. AIDS 1995 Dec; 9 Suppl. 2: 27–32

    PubMed  Google Scholar 

  31. Maschera B, Darby G, Palu G, et al. Human immunodeficiency virus: mutations in the viral protease that confer resistance to saquinavir increase the dissociation rate constant of the protease-saquinavir complex. J Biol Chem 1996 Dec 27; 271: 33231–5

    Article  PubMed  CAS  Google Scholar 

  32. F Hoffmann-La Roche. Study of proteinase genotypes after 16 weeks therapy with two formulations of saquinavir in combination with NRTI of choice. F Hoffmann-La Roche, 1997. (Data on file)

  33. F Hoffmann-La Roche. SQV-SGC and HIV proteinase genotype in clinical trials. F. Hoffmann-La Roche, 1997. (Data on file)

  34. Race E, Gilbert SM, Sheldon JG, et al. Low occurrence of reduced sensitivity to saquinavir in antiviral combination: results from a phase III clinical trial (NV14256) [abstract]. AIDS 1996 Nov; 10 Suppl. 2: 22

    Google Scholar 

  35. Race E, Gilbert SM, Tomlinson PW, et al. Long term treatment with saquinavir (invirase), does not lead to a significant reduction in sensitivity to MK-639 [abstract]. 1 lth International Conference on AIDS; 1996 Jul 7–12; Vancouver, 285–6

  36. Tomlinson PW, Craig JC, Moffatt AR, et al. HIV-1 from patients in a phase II clinical trial with the proteinase inhibitor (PI) saquinavir (SQV) taken in combination with RT inhibitors (RTIs) exhibits very little reduced sensitivity to other PI’s [abstract]. AIDS 1996 Nov; 10 Suppl. 2: S21

    Google Scholar 

  37. Race E, Gilbert SM, Sheldon JG, et al. An overview of drug resistance during saquinavir treatment. AIDS 1996 Nov; 10 Suppl. 2: 11

    Google Scholar 

  38. Kaye S, Pym AS, Galpin S, et al. Changes in virological markers during prolonged saquinavir monotherapy [abstract]. AIDS 1996 Nov; 10 Suppl. 2: S22

    Google Scholar 

  39. Craig C, Race E, Sheldon J, et al. Key amino acid substitutions in HIV proteinase remain unaltered during increased exposure to saquinavir (SQV-SGC): results from preliminary clinical trials [abstract]. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg, 30

  40. Duncan IB, Patick AK, Gilbert S, et al. Genotypic analysis of HIV protease in patients undergoing combination therapy with saquinavir and nelfinavir [abstract]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28; St Petersburg (FL)

  41. Deeks S, Eastman S, Horton C, et al. Addition of saquinavir-soft gel capsule to existing ARV therapy: virologic predictors of response [abstract]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28; St Petersburg (FL)

  42. Craig C, Race E, O’Sullivan E, et al. Increased exposure to the HIV protease inhibitor saquinavir (SGV) does not alter the nature of key resistance mutations [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago

  43. Kravcik S, Sahai J, Kerr B, et al. Protease gene mutations and long term follow-up of HIV-infected patients treated with nelfinavir mesylate (NFV) plus saquinavir-soft gel capsule (SQV-SGC). 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto, 278

  44. Kravcik S, Farnsworth A, Patrick A, et al. Long term follow-up of combination protease inhibitor therapy with nelfinavir and saquinavir (soft gel) in HIV infection [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago

  45. Schmit JC, Ruiz L, Clotet B, et al. Resistance-related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538). AIDS 1996 Aug; 10: 995–9

    Article  PubMed  CAS  Google Scholar 

  46. Shapiro J. HAART: planning for the future [oral presentation at Roche satellite symposium]. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg

  47. Schapiro JM, Winters M, Lawrence J, et al. Clinical and genotypic cross resistance between the protease inhibitors saquinavir and indinavir [abstract]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28; St Petersburg (FL)

  48. Eastman PS, Duncan IB, Gee C, et al. Acquisition of genotypic mutations associated with reduced susceptibility to protease inhibitors during saquinavir monotherapy [abstract]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28; St Petersburg (FL)

  49. Lawrence J, Schapiro J, Pesano R, et al. Clinical response and genotypic resistance patterns of sequential therapy with nelfinavir followed by indinavir plus nevirapine in saquinavir/reverse transcriptase inhibitor-experienced patients [abstract]. International Workshop in HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28; St Petersburg (FL)

  50. Para MF, Collier A, Coombs R, et al. ACTG 333: antiviral effects of switching from saquinavir hard capsule (SQVhc) to saquinavir soft gelatin capsule (SQVsgc) vs. switching to indinavir (IDV) after prior saquinavir [abstract]. Infectious Diseases Society of America Annual Meeting; 1997 Sep 13–16; San Francisco

  51. Bodsworth N, Slade M, Ewan J, et al. RTV and IND therapy at 28 weeks after 32 weeks’ SQV therapy — influence of HIV-1 protease mutations [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago

  52. F Hoffmann La-Roche (Basel), 1998. (Data on file)

  53. Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistannt to multiple protease inhibitors. Nature 1995; 374: 569–79

    Article  PubMed  CAS  Google Scholar 

  54. Craig JC, Duncan IB, Hockley D, et al. Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Res 1991; 16: 295–305

    Article  PubMed  CAS  Google Scholar 

  55. Craig JC, Whittaker LN, Duncan IB, et al. In vitro anti-HIV and cytotoxicological evaluation of the triple combination: AZT and ddC with HIV proteinase inhibitor saquinavir (Ro 31-8959). Antiviral Chem Chemother 1994; 5: 380–6

    CAS  Google Scholar 

  56. Galpin S, Roberts NA, O’Connor T. Antiviral properties of the HIV-1 proteinase inhibitor RO-31-8959. Antiviral Chem Chemother 1994; 5: 43–5

    CAS  Google Scholar 

  57. Roberts NA, Martin JA, Kinchington D, et al. Rational design of peptide-based HIV proteinase inhibitors. Science 1990; 248: 358–61

    Article  PubMed  CAS  Google Scholar 

  58. Buss N, Gieschke R, Massarella J, et al. Summary of the human bioavailability, pharmacokinetics and pharmacodynamics of saquinavir. F. Hoffmann-La Roche. Research Report W-144010, 1997 Feb 14. (Data on file)

  59. Buss N on behalf of the FSG. Saquinavir soft gel capsule (Fortovase): pharmacokinetics and drug interactions [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago, S16

  60. Conway B. The activity and safety of two formulations of saquinavir combined with two nucleosides in treatment-naive patients [abstract]. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg, 923

  61. Merry C, Barry M, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in patients with HIV disease. AIDS 1996 Nov; 10 Suppl. 2: 13

    Google Scholar 

  62. Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV-infected patients. AIDS 1997; 11(15): F117–20

    Article  PubMed  CAS  Google Scholar 

  63. Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease: clinically important pharmacokinetic considerations. Clin Pharmacokinet 1997 Mar; 32: 194–209

    Article  PubMed  CAS  Google Scholar 

  64. Moyle GJ, Sadler M, Hawkins D, et al. Correlation between plasma and CSF viral load in patients on saquinavir containing regimens. Pharmacokinetics (PK) of saquinavir at steady state in CSF and plasma. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg

  65. Lazdins JK, Mestan J, Goutte G, et al. In vitro effect of α1-acid glycoprotein on the anti-human immunodeficiency virus (HIV) activity of the protease inhibitor CGP 61755: a comparative study with other relevant HIV protease inhibitors. J Infect Dis 1997 May; 175: 1063–70

    Article  PubMed  CAS  Google Scholar 

  66. Washington CB, Duran GE, Sikic BI, et al. Saquinavir is a high affinity substrate for the multidrug transporter p-glycoprotein [abstract]. 98th Annual Meeting of the American Society for Clinical Pharmacology and Experimental Therapeutics; 1997 Mar 5–8: San Diego, 193

  67. Hoof T, Brandt T, Demmer A, et al. Interaction of HIV proteases inhibitors with MDR1 — competetive binding and resistance modulation. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto, I-111

  68. Fitzsimmons ME, Collins JM. Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism. Drug Metab Dispos 1997 Feb; 25: 256–66

    PubMed  CAS  Google Scholar 

  69. Sahai J, Stewart F, Swick L, et al. Rifabutin reduces saquinavir plasma levels in HIV-infected patients [abstract]. 36th Inter-science Conference on Antimicrobial Agents and Chemotherapy; 1996 Sep 15–18: New Orleans, 6

  70. Heylen R, Miller R. Adverse effects and drug interactions of medications commonly used in the treatment of adult HIV positive patients: Part 2. Genitourin Med 1997 Feb; 73: 5–11

    PubMed  CAS  Google Scholar 

  71. Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997 Aug; 44: 190–4

    Article  PubMed  CAS  Google Scholar 

  72. Inaba T, Fischer N, Riddick DS, et al. HIV protease inhibitors, saquinavir, indinavir and ritonavir: inhibition of CYP3A4-mediated metabolism of testosterone and KRM-1648 in human liver microsomes [abstract]. Pharmacologist 1997; 39(1): 21

    Google Scholar 

  73. Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother 1997 Mar; 41: 654–60

    PubMed  CAS  Google Scholar 

  74. Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS 1997 Mar 15; 11: F29–33

    Article  PubMed  CAS  Google Scholar 

  75. McCrea J, Buss N, Stone J, et al. Indinavir-saquinavir single dose pharmacokinetic study [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC

  76. Kravcik S, Sahai J, Kerr B, et al. Nelfinavir mesylate increases saquinavir-soft gel capsule exposure in HIV+ patients [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC

  77. Conway B, Kwiatkowski MB, Shillington A, et al. Pilot study of saquinavir enhanced oral formulation as adjunctive anti-retroviral therapy in advanced HIV [abstract]. Can J Infect Dis 1997 Mar-Apr; 8 Suppl. A: 45A

    Google Scholar 

  78. Fletcher CV, Kline MW, Brundage RC, et al. Saquinavir soft gel capsules combined with nucleoside antiretroviral agents in HIV-infected children. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg, 919

  79. Kline MW, Fletcher CV, Brundage RC, et al. Combination therapy including saquinavir soft gelatin capsules (SQV-SGC) in HIV-infected children [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago

  80. F Hoffmann-La Roche (Nutley), 1998. (Data on file)

  81. Gill MJ, Beall G, Beattie D, et al. Safety of saquinavir soft gelatin capsule (SQV-SGC) in combination with other antiretroviral agents: multicenter study NV15182: 24 week analysis. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto

  82. Kravcik S, Seguin I, Sahai J, et al. Long term follow-up of a cohort of HIV infected persons treated with nelfinavir and saquinavir SGC in combination [abstract]. Can J Infect Dis 1997 Mar–Apr; 8 Suppl. A: 45A

    Google Scholar 

  83. Stellbrink HJ, van Lunzen J, Albrecht H, et al. Antiviral effect of triple drug combination therapy using saquinavir soft gelatin capsules [abstract]. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg, 427

  84. Sension M, Farthing C, Siemon-Hryczyk P, et al. Saquinavir soft gel capsule (SGC) in combination wtih AZT and 3TC in treatment naive patients. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto, 1–190

  85. Sension M, Farthing C, Palmer Pattison T, et al. FortivaseTM (saquinavir soft gel capsule; SQV-SGC) in combination with AZT and 3TC in antiretroviral-naïve HIV-1 infected patients [abstract]. 5th International Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago, S19

  86. Fischer L, Siemon-Hryczyk P, Pilson R, et al. Saquinavir soft gel capsule (SGC) in combination with AZT and 3TC in treatment naive patients [abstract]. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg, 393

  87. Borleffs JC, Boucher CA, Bravenboer B, et al. Saquinavir-soft gelatine capsules versus indinavir as part of AZT and 3TC containing triple therapy. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto, 1–92

  88. Borleffs JC et al. First comparative study of saquinavir soft gel capsules vs indinavir as part of triple therapy regimen in CHEESE [abstract]. 5th Conference of Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago, S15

  89. Pozniak A et al. Study of protease inhibitors in combination in Europe (SPICE) [abstract]. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg

  90. Opravil M et al. Study of protease inhibitor combination in Europe (SPICE); saquinavir soft gelatin capsule (SQV-SGC) and nelfinavir in HIV infected individuals [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago

  91. Beattie D, Bieska G, Leung P, et al. A randomized, parallel, open-label study comparing saquinavir hard geltain formulation (600 mg t.i.d.) to saquinavir soft gelatin formulation [(400 mg, 800 mg, 1200 mg) tid] x 8 weeks in HIV infected patients: (24 week extension data). F Hoffmann-La Roche, Research Report W-145012/6, 1996 Dec. (Data on file)

  92. Ault A. FDA warns of potential protease-inhibitor link to hyperglycaemia. Lancet 1997 Jun 21; 349: 1819

    Article  PubMed  CAS  Google Scholar 

  93. Protease inhibitors and hyperglycaemia. Curr Probl Pharmacovig 1997 Sep; 23: 10

    Google Scholar 

  94. Winter AJ, Pywell JM, Ilchyshyn A, et al. Photosensitivity due to saquinavir. Genitourin Med 1997 Aug; 73: 323

    PubMed  CAS  Google Scholar 

  95. Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society — USA Panel. JAMA 1997 Jun 25; 277: 1962–9

    Article  PubMed  CAS  Google Scholar 

  96. Gazzard BG, Moyle GJ, Weber J, et al. British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1997 Apr 12; 349: 1086–92

    Article  Google Scholar 

  97. HIV treatment: aggressive therapy may use up options and divide opinion. Pharm J 1997 Aug 23; 259: 279

  98. Department of Health and Human Services and the Henry J. Kaiser Family Foundation Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents [online]. Department of Health and Human Services and the Henry J. Kaiser Familty Foundation; 1997 Nov 5 [Accessed 1998 Jan 16]. Available as Adobe Acrobat (PDF) file from: URL: http://www.hivatis.org/guide6.pdf

  99. Double protease inhibitors — new gold standard in HIV. Scrip 1997 Oct 10(2274): 18

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Caroline M. Perry.

Additional information

Various sections of the manuscript reviewed by: M. Barry, Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, England; J.C.C. Borleffs, Department of Infectious Diseases and AIDS, University Hospital Utrecht, Utrecht, The Netherlands; C.A.B. Boucher, Department of Virology, University Hospital Utrecht, Utrecht, The Netherlands; B. Conway, St Paul’s Hospital/University of British Columbia, Vancouver, British Columbia, Canada; C.V. Fletcher, Division of Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA; M. Floridia, Retrovirus Department, Laboratory of Virology, Istituto Superiore Di Sanita, Rome, Italy; K. Gallicano, Clinical Investigation Unit, Ottawa General Hospital, Ottawa, Ontario, Canada; B.G. Gazzard, Chelsea and Westminster Hospital NHS Trust, St Stephens Centre, London, England; M. J. Gill, Southern Alberta Clinic, Calgary, Alberta, Canada; L. Naesens, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium; A.L. Pozniak, Department of Genitourinary Medicine, King’s College School of Medicine and Dentistry, King’s College, London, UK; J.-P. Routy, McGill University, Montreal, Quebec, Canada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perry, C.M., Noble, S. Saquinavir Soft-Gel Capsule Formulation. Drugs 55, 461–486 (1998). https://doi.org/10.2165/00003495-199855030-00014

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199855030-00014

Keywords

Navigation