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Saquinavir

A Review of its Use in Boosted Regimens for Treating HIV Infection

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Summary

Abstract

Protease inhibitor boosting involves concurrent administration of a protease inhibitor, such as saquinavir, plus a potent inhibitor of cytochrome P450 (CYP) 3A4, usually ritonavir in subtherapeutic doses. Since protease inhibitors are extensively metabolised by CYP3A4, this results in a marked increase in systemic exposure of saquinavir or other protease inhibitors boosted by ritonavir. As with traditional protease inhibitor regimens, boosted regimens are typically used in combination with nucleoside reverse transcriptase inhibitors (NRTIs).

In protease inhibitor-experienced and -naive patients with HIV infection, twice-daily and once-daily boosted saquinavir regimens achieved good rates of viral suppression, improved CD4+ cell counts and were generally well tolerated in clinical trials. Encouraging results have also been reported in a number of small studies in heavily pretreated HIV-infected patients who received salvage therapy comprising double-boosted regimens of saquinavir plus lopinavir with subtherapeutic doses of ritonavir, along with other agents.

The largest clinical trials have been multicentre, randomised comparisons of twice-daily boosted saquinavir versus twice-daily boosted indinavir (MaxCminl) or lopinavir (MaxCmin2) regimens. In the MaxCmin1 study, >90% of patients in both groups had an undetectable viral load (<400 copies/mL) after 48 weeks of therapy in the on-treatment analysis. However, viral suppression was achieved in significantly more saquinavir than indinavir recipients in the intention-to-treat analysis, which appeared to be due to the significantly greater percentage of patients in the indinavir group who switched from randomised therapy because of adverse events. Interim 24-week results of the MaxCmin2 trial indicate that 90% of patients in both groups combined had plasma HIV RNA levels <400 copies/ mL; final results at 48 weeks will report data separately for the boosted regimens of saquinavir and lopinavir.

Conclusion: Boosted protease inhibitor regimens (including two NRTIs) are recommended as a first-line option in current HIV treatment guidelines and are used extensively in clinical practice. The convenient administration schedule and good pharmacokinetic profile associated with boosted saquinavir regimens have the potential to increase adherence to therapy and improve antiretroviral effects through increased drug exposure. Twice-daily boosted saquinavir is one of the most extensively evaluated boosted protease inhibitor regimens and has been shown to have good efficacy on surrogate markers of HIV disease as well as significant tolerability advantages over boosted indinavir. Once-daily boosted saquinavir regimens may be most suitable for HIV-infected patients with busy lifestyles and those who would benefit from directly observed therapy.

Overview of Pharmacodynamic Properties

Inhibition of human HIV protease by saquinavir results in the formation of immature, noninfectious virus particles. In vitro studies have shown that saquinavir is highly active against HIV in human cells that are acutely or chronically infected with the virus. When saquinavir was combined with one or two other antiretrovirals, including nucleoside reverse transcriptase inhibitors (NRTIs) and/or the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, additive to synergistic activity against HIV was demonstrated in vitro without cytotoxic effects in host cells. Synergistic activity was also shown when saquinavir was combined with lopinavir, whereas additive effects were generally shown when other protease inhibitors were combined with lopinavir. The principal protease gene mutations that confer resistance to saquinavir are L90M and G48V. Resistance to saquinavir is dependent upon both the specific mutations present and the number of mutations present. Studies have shown that patients whose virus contains up to four or five mutations in protease are still likely to achieve a clinical response with boosted saquinavir (saquinavir soft-gel capsule [SGC] 1000mg plus ritonavir 100mg twice daily and NRTIs). Cross resistance occurs between saquinavir and other protease inhibitors, but is variable and often difficult to predict.

Pharmacokinetics of Saquinavir in Boosted Regimens

Protease inhibitor boosting (or pharmacoenhancement) typically involves the use of subtherapeutic doses of ritonavir, a potent inhibitor of cytochrome P450 (CYP) 3A4, administered concurrently with therapeutic doses of other protease inhibitors such as saquinavir, which are metabolised by CYP3A4. When boosted saquinavir regimens are administered to healthy volunteers or patients with HIV infection, systemic exposure to saquinavir is increased several-fold, generally without an increase in adverse events. In comparative studies of boosted versus nonboosted regimens of saquinavir SGC, mean area under the concentration-time curve (AUC) of saquinavir was typically about 5-fold (range 3-to 9-fold) greater with boosted regimens; trough (Cmin) and peak plasma concentrations of saquinavir were usually increased by a similar magnitude. Inter-individual variability in saquinavir kinetics, although still substantial, is reduced when the drug is used in boosted regimens. In dose-ranging pharmacokinetic interaction studies in which healthy volunteers received saquinavir SGC and ritonavir concurrently, ritonavir doses of 100mg once daily to 400mg twice daily had broadly similar effects at increasing systemic exposure to saquinavir.

In general, pharmacokinetic analyses conducted with boosted saquinavir regimens have shown wide interpatient variation in the pharmacokinetics of saquinavir, although saquinavir Cmin values were consistently above 50 μg/L and/ or the 90% or 95% inhibitory concentration (IC90 or IC95) against HIV. Saquinavir, like most protease inhibitors, is highly bound to plasma proteins, and adjustment for plasma protein binding is required when determining ratios such as Cmin/IC. The majority of pharmacokinetic analyses in adults with HIV infection have evaluated saquinavir SGC 1000mg plus ritonavir 100mg twice daily; saquinavir SGC 1600mg plus ritonavir 100mg once daily; and double-boosted regimens (e.g. saquinavir SGC 1000mg plus lopinavir/ritonavir twice daily). Patients also received at least two NRTIs/NNRTIs.

In nonboosted regimens, the relative bioavailability of saquinavir hard-gel capsule (HGC) is several-fold lower than that of saquinavir SGC. However, in healthy volunteers and patients with HIV infection, boosted regimens with saquinavir HGC achieved similar or greater systemic exposure of saquinavir compared with boosted regimens using saquinavir SGC.

In double-boosted regimens (therapeutic doses of saquinavir and lopinavir plus subtherapeutic doses of ritonavir, usually with two or more NRTIs) in patients with HIV infection, the addition of saquinavir to lopinavir/ritonavir therapy had minimal effect on the plasma concentrations of these protease inhibitors. Other pharmacokinetic drug interaction studies in healthy volunteers or patients with HIV infection found no clinically significant interactions between boosted saquinavir regimens at steady state and single-dose didanosine or multiple doses of efavirenz or the HIV-1 fusion inhibitor enfuvirtide. The addition of rifampicin (rifampin) decreased the AUC of saquinavir by approximately 50% at steady state in HIV-infected patients with tuberculosis receiving a once-daily boosted regimen of saquinavir. In general, concurrent ritonavir administration also appears to preserve saquinavir exposure in the presence of the enzyme inducer rifabutin, although saquinavir/ritonavir dosages used in boosted regimens have not been evaluated.

Therapeutic Use of Saquinavir in Boosted Regimens

Clinical efficacy results from studies evaluating boosted or double-boosted regimens of saquinavir in adult patients with HIV infection have focused on changes in plasma HIV RNA levels. In addition, modest improvements in CD4+ cell counts were observed with boosted or double-boosted saquinavir regimens across all of the studies.

Twice-daily regimens: All clinical trials of twice-daily boosted saquinavir regimens have used saquinavir (SGC or HGC) 1000mg plus ritonavir 100mg twice daily with two or more NRTIs/NNRTIs. Comparator boosted protease inhibitor regimens also included two or more NRTIs/NNRTIs.

In the MaxCmin1 study, a multicentre randomised comparison between twice-daily boosted saquinavir SGC and boosted indinavir (indinavir/ritonavir 800/100mg twice daily) in 306 protease inhibitor-experienced or -naive patients, significantly more saquinavir than indinavir recipients had an undetectable viral load (plasma HIV RNA <400 copies/mL) at 48 weeks in the intention-to-treat (ITT) analysis (68% vs 53%, p = 0.014). The difference appeared to be the result of significantly fewer patients in the boosted saquinavir group who switched therapy because of adverse effects (a switch was considered to be a treatment failure in the ITT analysis). The on-treatment (OT) analysis at 48 weeks showed that both regimens were similarly effective at achieving an undetectable viral load (94% vs 90%).

Final results are not yet available from the MaxCmin2 trial, a large (n = 326) randomised multicentre study comparing twice-daily boosted saquinavir SGC versus boosted lopinavir (lopinavir/ritonavir 400/100mg twice-daily) regimens in a mixed patient population. Interim 24-week results combining data from patients in both treatment arms showed that 77% and 90% of patients had an undetectable viral load (<400 copies/mL) in the ITT and OT analyses, respectively.

In both MaxCmin1 and MaxCmin2, saquinavir was switched from the SGC to the HGC formulation if adverse gastrointestinal disturbances occurred.

In general, the clinical efficacy demonstrated with twice-daily boosted saquinavir in comparative trials is supported by data from noncomparative studies in protease inhibitor-experienced patients.

Once-daily regimens: All clinical trials with once-daily boosted saquinavir regimens have used the SGC formulation of saquinavir, and most have used a regimen of saquinavir SGC 1600mg plus ritonavir 100mg once daily with two NRTIs. This was the regimen used in the largest trial (FOCUS), which compared boosted saquinavir versus efavirenz 600mg once daily plus two NRTIs in 152 antiretroviral-naive patients. In general, the saquinavir and efavirenz regimens were similarly effective at achieving an undetectable viral load (<400 copies/mL) at 48 weeks in both the ITT (59% vs 73%) and the OT analysis (83% vs 93%), although statistical analysis was not provided in the abstract report. Interim data at 24 weeks showed that, at the <50 copies/mL level, there was a significant difference favouring the efavirenz group (60% vs 78%, p = 0.008).

In the largest noncomparative trial with once-daily boosted saquinavir (HIVNAT 001.3), 69 patients who had an undetectable viral load (<50 copies/mL) for 2 years while receiving saquinavir SGC 1400mg twice daily plus two NRTIs had their saquinavir SGC regimen switched to 1600mg once daily given concurrently with ritonavir 100mg once daily. After 48 weeks in the ITT analysis, 91% of patients maintained an undetectable viral load, and this was accompanied by a statistically significant improvement in CD4+ cell count. Other, smaller noncomparative trials with once-daily boosted saquinavir regimens have primarily been conducted in patients with prior exposure to protease inhibitors. In most of these trials an undetectable viral load was achieved in the majority of patients at interim or final analysis.

Double-boosted regimens: Although several studies have been conducted with double-boosted saquinavir regimens as salvage therapy, none has evaluated more than 50 patients. The most frequently used regimen has been saquinavir SGC 1000mg twice daily plus lopinavir/ritonavir 400mg/100mg twice daily, usually in combination with two or more NRTIs, and patients typically had HIV infection resistant to all three drug classes. In general, results have been encouraging. In a representative study in 46 patients with multiclass drug resistance, approximately one-third to one-half of patients had an undetectable viral load (<80 copies/mL) in the ITT analysis at 24 weeks. In approximately half of the patients, the double-boosted regimen was preceded by a 3-month antiretroviral drug holiday; results in this group were similar to those in patients whose antiretroviral therapy was not temporarily interrupted. In a nonrandomised single-centre study (n = 42), double-boosted saquinavir achieved plasma HIV RNA levels <500 copies/mL in 39% of patients at 48 weeks in the ITT analysis compared with 21% of those who received a double-boosted amprenavir regimen (statistical analysis not provided). In these and other studies with double-boosted saquinavir regimens, somewhat better results were demonstrated in OT than ITT analyses, as would be expected.

Tolerability of Boosted Saquinavir

In general, saquinavir in boosted or double-boosted regimens was well tolerated in clinical trials of up to 48 weeks’ duration in adult patients with HIV infection. The vast majority of trials involved concomitant use of at least two NRTIs (some regimens included NNRTIs).

Twice-daily regimens: In the MaxCmin1 trial, there was a significantly lower rate of withdrawal from the study (28% vs 42%, p = 0.025) and withdrawal because of adverse events (15% vs 28%, p = 0.006) with saquinavir than indinavir in twice-daily boosted regimens over 48 weeks. In the MaxCmin2 trial, 24-week data showed that the tolerability profile of twice-daily boosted saquinavir was similar to that of a twice-daily boosted lopinavir regimen. Saquinavir was initially administered as the SGC formulation in both MaxCmin1 and MaxCmin2 but was switched to the HGC formulation for patients who experienced gastrointestinal disturbances.

Once-daily regimens: During the 48-week HIVNAT 001.3 trial, none of the 69 patients (who had switched from a traditional saquinavir SGC-containing antiretroviral regimen to a once-daily boosted saquinavir SGC regimen) discontinued therapy because of adverse events. Severe (grade 3 or 4) adverse events (4%) and laboratory abnormalities (12%) were reported during the first 24 weeks of the trial, and lipodystrophy (a common adverse effect of antiretroviral therapy) was newly reported in 19% of patients. During the 24-week period before and after switching to the boosted regimen, a significant reduction in nausea and vomiting was reported following the switch to the boosted regimen.

In the FOCUS trial comparing once-daily boosted saquinavir SGC versus efavirenz (both with two NRTIs), moderate to severe nausea (22.2% vs 3.8%) and vomiting (6.2% vs 0%) were more frequently reported in the saquinavir group at 48 weeks, and more patients in the saquinavir group discontinued therapy because of adverse gastrointestinal events. Although a modest increase in serum lipid levels is commonly reported with boosted saquinavir (and other antiretroviral) regimens, the FOCUS trial found that the strongest predictor of increases in serum triglyceride and cholesterol levels was concurrent treatment with stavudine as one of the NRTIs.

Double-boosted regimens: Half of the 28 patients who received double-boosted therapy in the PIE study required temporary dosage reductions of saquinavir SGC, primarily because of gastrointestinal disturbances. Saquinavir SGC dosage was gradually increased back to the target level of 1000mg twice daily in all 14 patients. Grade 3 or 4 diarrhoea occurred in 18% of patients, myalgia/arthralgia in 8% and nausea in 7%. In this and a similar-sized study of double-boosted saquinavir, approximately 10% of patients withdrew from therapy because of adverse events. Interestingly, no significant gastrointestinal adverse effects were noted in the similar-sized trial.

Dosage and Administration

In Europe, saquinavir (SGC or HGC) 1000mg plus ritonavir 100mg twice daily is approved for use in HIV infection, and an application for this boosted regimen is pending in the US. Once-daily boosted saquinavir regimens are not yet approved in Europe or the US for saquinavir SGC or HGC. In clinical trials with boosted or double-boosted saquinavir regimens, the most frequently used combinations have been as follows: saquinavir SGC or HGC 1000mg twice daily plus ritonavir 100mg twice daily (with at least two NRTIs/NNRTIs); saquinavir SGC 1600mg once daily plus ritonavir 100mg once daily (in combination with at least two NRTIs); and saquinavir 1000mg SGC twice daily plus lopinavir and ritonavir 400/ 100mg twice daily (in combination with at least two NRTIs).

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  1. Tradenames are included for identification purposes and do not imply product endorsement.

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Various sections of the manuscript reviewed by: R.C. Brundage, Graduate Program in Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA; P.J. Carey, Sunderland Royal Infirmary, Sunderland, England; B. Conway, Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada; V. Joly, Hôpital Bichat-Claude Bernard and Xavier-Bichat Medical School, Paris, France; A.D.M. Kashuba, School of Pharmacy and UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; J. Mallolas, Department of Infectious Diseases, Institut D’Investigacions Biomediques August Pi I Sunyer (IDIBAPS) Fundacio Clinic, Barcelona, Spain; S.R. Penzak, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Maryland, USA; R.P.G. van Heeswijk, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, Ontario, Canada; C. Zala, Clinical Research, Fundacion Huesped, Buenos Aires, Argentina.

Data Selection

Sources: Medical literature published in any language since 1980 on saquinavir, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘saquinavir and boosted’ or ‘saquinavir and pharmacoenhancement’ or ‘saquinavir and protease inhibitors’ or ‘saquinavir and HIV infections’. EMBASE search terms were ‘saquinavir and boosted’ or ‘saquinavir and pharmacoenhancement’ or ‘saquinavir and protease inhibitors’ or ‘saquinavir and HIV infections’. AdisBase search terms were ‘saquinavir and boosted’ or ‘saquinavir and protease-inhibitors’ or ‘saquinavir and HIV-infections’. Searches were last updated 15 April 2003.

Selection: Studies in patients with HIV infection who received boosted saquinavir regimens. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Saquinavir, boosted regimens, pharmacoenhancement, pharmacodynamics, pharmacokinetics, pharmacokinetic enhancement, drug interactions, therapeutic use, tolerability, HIV infection.

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Plosker, G.L., Scott, L.J. Saquinavir. Drugs 63, 1299–1324 (2003). https://doi.org/10.2165/00003495-200363120-00007

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