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Saquinavir (SQV) is a well-established component of current highly active antiretroviral therapy (HAART) regimens and has demonstrated potent and sustained viral load suppression, and is well tolerated [1–3]. More recently, the acceptance of pharmacokinetic enhancement, or boosting, as a means to increase protease inhibitor (PI) exposures has resulted in clinical trials investigating boosted SQV/ritonavir (RTV) 1000 mg/100 mg twice-daily (BID) and 1600 mg/100 mg once-daily regimens. Preliminary results, such as those from the 24-week interim analysis of the ongoing MaxCmin I trial, have shown that these boosted SQV/RTV regimens provide potent virological suppression and appear to be well tolerated [4–7].
Saquinavir is available in two formulations; the original hard gelatin capsule (HGC) formulation, Invirase®, and the soft-gelatin capsule (SGC) formulation, Fortovase®. Unboosted, the bioavailability of SQV with the HGC formulation is lower, around 4% when administered as a single 600 mg dose, than that observed with the SGC formulation (relative bioavailability of 3331%) [8,9]. This difference in bioavailability is mainly due to the fact that the glyceride excipient component of the SGC formulation, capmul, allows SQV to dissolve and disperse rapidly upon administration . However, when SQV is boosted with the PI RTV, the pharmacokinetic parameters of SQV are increased such that twice- and once-daily dosing of SQV are possible , and the bioavailability of SQV from either of these formulations (SGC and HGC) becomes much more comparable [4,11,12].
Since the capmul component of the SGC formulation of SQV is associated with potential adverse events such as diarrhoea, it may be beneficial for patients in some circumstances to use the HGC formulation in a boosted regimen. To verify this improvement in bioavailability with RTV boosting, a pilot bioequivalence study was initially conducted in HIV-1-infected patients. Encouragingly, the pharmacokinetic data showed that the boosted SQV/RTV 1000 mg/100 mg BID combination produced comparable SQV exposures with either the SGC or HGC formulation . However, there was some baseline imbalance in this initial pilot study. Patients taking the HGC formulation had lower plasma exposures to SQV at the early pharmacokinetic assessment time points, while at 12 h SQV plasma levels appeared to be similar for the two formulations. This difference is thought to be due to the time the last dose of medication was administered; patients were not observed taking their medication the evening before their planned hospital visit for pharmacokinetic assessments . Hence, it was difficult compare the pharmacokinetic data obtained in this initial pilot study. Therefore, a second, randomized, bioequivalence study with a more stringent methodological protocol was undertaken in healthy volunteers, to confirm these earlier findings. The results of this second study to assess the pharmacokinetic and tolerability profile of a boosted SQV/RTV 1000 mg/100 mg BID combination given as either the SGC or HGC formulation, in healthy volunteers, are presented here.
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Overall, this study in healthy male volunteers shows that improved SQV exposures were obtained when SQV/RTV 1000 mg/100 mg BID was administered using the HGC formulation compared with the SGC formulation. In addition, the SQV-HGC/RTV combination appeared to be the better tolerated combination in terms of gastrointestinal system disorders.
Although unboosted the bioavailability of SQV with the HGC formulation is lower than that with the SGC formulation, several studies, including the pilot bioequivalence study in HIV-infected patients, have indicated that boosting with RTV results in increased SQV exposures [4,11–13]. Further investigations undertaken in this study show that SQV exposures with the boosted HGC are slightly, but significantly, higher than those with the boosted SGC formulation. The HGC formulation provided higher SQV exposures for all the pharmacokinetic parameters assessed. In particular, a mean AUC0−24 h-value of 15.798 µg/mL/h was reported for the HGC formulation compared with 11.655 µg/mL/h for the SGC formulation (P = 0.0043).
The improvement in SQV exposure presented here with RTV boosting of the HGC compared with the SGC formulation is similar to that reported in a pharmacokinetic study in 13 HIV-1-infected patients receiving SQV/RTV 1600 mg/100 mg once-daily . A median AUC0-24 h-value of 50 µg/mL/h was reported for the boosted SQV-HGC formulation compared with 35.5 µg/mL h for the boosted SQV-SGC formulation (P = 0.056) . Although these AUC0−24 values in HIV infected patients were slightly higher than those reported in our study, this is a well-recognized phenomenon, with differences in pharmacokinetic values seen between healthy volunteers and HIV-infected patients [16,17].
In addition, the improvement in SQV exposure with the boosted HGC reported here was not seen in the initial pilot study in HIV-infected patients . This may have been due to the baseline imbalance observed in the initial pilot study, which was probably seen because patients were not monitored taking their study medication the evenings prior to their hospital visit. However, in our study in healthy volunteers, adherence to study medication was closely monitored throughout the entire study period.
It has been postulated that the increased SQV exposure obtained with the boosted SQV-HGC/RTV (1000 mg/100 mg BID) combination may be related to the order of dissolution of the RTV and SQV capsules. The SQV-SGC formulation may dissolve rapidly, being absorbed and metabolized before RTV has an opportunity to act on the P-glycoprotein transport and cytochrome P450 systems. In contrast, the SQV-HGC formulation may dissolve slowly, thus providing time for RTV itself to dissolve and to inhibit P-glycoprotein transport and the cytochrome P450 metabolic pathway before SQV is released, thus facilitating SQV absorption and distribution. However, if this is the case, it is unclear why Tmax for SQV-SGC is reached at a later time point than for the SGV-HGC [Fig. 1], and further investigations are required to confirm this hypothesis.
A potential drawback of the study was that a significant treatment sequence effect was observed for the pharmacokinetic parameters Cmin 0−12 and Cmin 0−24. This observation may be explained by both the lack of a washout period and the time taken to achieve steady-state inhibition of CYP3A4 by RTV.
Inhibition of metabolism by RTV is generally highest during the first few days of drug administration, leading to the highest plasma concentrations of saquinavir. However, after an initial adaptation process, some of the inhibition effect of RTV on the metabolism of saquinavir is compensated for and the effect of RTV on saquinavir plasma concentrations, although still apparent, is less pronounced. This adaptation process involves autoinduction of the 3A4 enzymes of cytochrome P450 system, and reaches a steady state 10–14 days after the start of RTV administration . This steady state may, therefore, have not been achieved until the second PK evaluation (at 20 days).
Both SQV formulations were well tolerated. Overall, the incidence and severity of adverse events reported were in accordance with the side-effect profile of SQV, where gastrointestinal disorders were the most commonly observed. The SQV-HGC/RTV combination was better tolerated in terms of gastrointestinal adverse events than the SQV-SGC/RTV combination, with a lower incidence of diarrhoea and vomiting. The differences observed in the tolerability profile of the two SQV formulations were comparable with those in a study of 171 antiretroviral-naïve, HIV-1 infected patients . Mitsuyasu et al. showed that dyspepsia, vomiting and abdominal pain were all more frequently observed with SQV-SGC .
The increased incidence of adverse events reported here with the SQV-SGC/RTV combination may be due to capmul, the glyceride excipient component of the capsule formulation of SQV . This hypothesis is supported by the fact that, in this study, there was no significant correlation between SQV plasma drug levels and the incidence of diarrhoea or abdominal symptoms (P > 0.05 for both comparisons) reported. It has also been postulated that the nonabsorbed portion of the drug may be responsible for the diarrhoea. Hence, a negative correlation with plasma drug levels may exist, although this was not examined in our study.
Furthermore, an ongoing study in 69 antiretroviral-experienced patients who previously received SQV-SGC 1400 mg BID plus two nucleoside reverse transcriptase inhibitors (NRTIs) for 162 weeks, and were switched to a SQV-SGC/RTV 1600 mg/100 mg once-daily regimen, showed that at 48 weeks, this regimen was well tolerated . Despite the increased SQV exposures obtained, no increase in the incidence of gastrointestinal disorders was reported [6,21]. Adverse events are usually related to the drug dose; however, this study illustrates that toxic effects can also arise from the excipient components of drug formulations.
Long-term HIV antiretroviral therapy is associated with changes in fat distribution and metabolism . In one such study, the effect of different NRTIs on fasting lipid levels revealed that patients receiving stavudine had significantly elevated triglyceride levels compared with those receiving zidovudine and lamivudine in combination with indinavir, over a period of 48 weeks . Furthermore, a switch study involving 23 patients receiving SQV/RTV 400 mg/400 mg BID who switched to a SQV/RTV 1000 mg/100 mg as part of a four-drug BID regimen, showed reductions in fasting triglyceride levels and cholesterol levels following the switch over 6 months . Changes in triglycerides with SQV/RTV combinations containing RTV doses of 200 mg and above have been reported as early as three days after the initiation of therapy in healthy volunteers . Importantly, the findings presented here show that the SQV/RTV 1000 mg/100 mg BID combination did not appear to have any effect on triglycerides and total cholesterol values, over a 20-day period.
In conclusion, in healthy volunteers, RTV boosting of SQV with the HGC formulation produced improved SQV plasma levels at least as high as that achieved with the SGC formulation. In addition, it appears that in terms of gastrointestinal system disorders, the HGC may be the better-tolerated formulation of SQV. This would suggest that RTV boosting of the HGC formulation may be considered to be as acceptable as the boosted SGC formulation for inclusion in HIV-treatment regimens. Furthermore, the HGC formulation may be a better therapeutic option for those patients who experience problems with the SGC formulation, including those who are particularly vulnerable to gastrointestinal disorders, or have difficulties with the larger size of the soft gelatin capsules or their need for refrigeration. Importantly, the findings presented here in healthy volunteers may be of clinical relevance and warrant further evaluation in HIV-infected individuals.