• Pharmacokinetics;
  • ritonavir;
  • saquinavir


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References


To determine the correlation between ritonavir (RTV) dose and the degree of enhancement of saquinavir (SQV) exposure.


Combined analysis of pharmacokinetic data at steady state obtained from two open-label, randomized, parallel-group, multiple-dose, single-centre studies involving healthy volunteers. Plasma samples for SQV assay were obtained from 97 healthy subjects following multiple dosing of a range of SQV (400–1800 mg) plus RTV (100–400 mg) dosages for 13–14 days. The pharmacokinetics of SQV were derived by model-independent, noncompartmental methods. Data were analysed by multivariate regression of log transformed Cmin and Cmax (geometric means) of SQV dosage as the dependent variable and independent variables of SQV and RTV dosage. Ritonavir was fitted as both a continuous and a categorical variable.


There is a strong effect of any dose of RTV on Cmax and Cmin of SQV (P < 0.0001 for both parameters), but no greater effect of higher vs. lower RTV dosages on either parameter (Cmax: P=0.4373; Cmin: P=0.3393). Higher SQV dosage correlates linearly with higher Cmax (P=0.0093) and Cmin (P=0.0010), but the effects of increasing SQV dosages are less than with the addition of any RTV dose.


RTV enhances SQV concentrations to increase Cmax and Cmin. This effect is similar for RTV dosages of 100–400 mg twice daily. Based on this concept of ‘mini-dose’ RTV, once-daily dosing of 1600 mg SQV/100 mg RTV and twice-daily 1000 mg SQV/100 mg RTV are currently being evaluated in clinical trials.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Although saquinavir (SQV) is a potent and specific HIV protease inhibitor (PI) [1,2], its usage relative to other PIs was initially limited by the low bioavailability (< 4%) of the original hard gel capsule (HGC) formulation (Invirase®) [3]. However, administering SQV in a soft gelatine capsule (SGC) formulation (Fortovase®) substantially increases plasma levels [4] and significantly improves antiretroviral activity [5]. The improved pharmacokinetic profile apparently allows twice-daily administration of SQV-SCG, with a triple therapy regimen incorporating 1600 mg twice daily providing equivalent efficacy at 48 weeks to a triple therapy regimen incorporating 1200 mg three times daily [6].

The efficacy of SQV is closely related to its plasma drug concentration [7,8]. However, although the introduction of the SGC formulation has increased the absorption of SQV, further increases are still limited by extensive first-pass metabolism, particularly by the cytochrome P450 enzyme CYP3A4 present in the gut wall and liver [9,10]. The PI ritonavir (RTV) has potent inhibitory effects on the CYP3A enzyme system [9]; coadministration of SQV and RTV leads to substantial increases in the bioavailability of SQV (illustrated by significant increases in Cmax), irrespective of whether the SGC or HGC formulation is used [11–13]. This interaction is presumably mediated through inhibition of CYP3A4 by RTV, leading to inhibition of SQV first-pass metabolism by this enzyme. Pharmacokinetic interactions may also involve RTV-induced reductions in P-glycoprotein-mediated transport of SQV in the gut [14,15]. Co-administration of SQV and RTV appears to have limited effects on the systemic metabolism of SQV, as there are relatively small alterations in the clearance rate of SQV in vivo[16].

The ‘boosted’ PI combination of SQV/RTV is now frequently employed at a dose of 400 mg RTV plus 400 mg SQV twice daily, and provides potent and sustained clinical activity [13,17]. However, particularly from the perspective of tolerability and patient compliance, it may be beneficial to maximize the plasma exposure to SQV, a relatively well tolerated drug [18], while minimizing the recognized dose-related toxicity of RTV [19]. Strategies have therefore investigated the combination of ‘mini-doses’ of RTV with SQV in an attempt to obtain the enhancement of SQV exposure with lower doses of RTV [16,19,20]. However, the optimal RTV dose to achieve this pharmacokinetic enhancement is unknown and a variety of dosages are used in clinical practice.

In two dose-ranging clinical pharmacology studies, combined administration of RTV and SQV (given twice daily in one study and once daily in the second) led to several-fold increases in SQV exposure [16,21]. These increases were also associated with reductions in intersubject variability in the pharmacokinetics of SQV compared with those seen following the administration of SQV alone [16,22]. Although trough SQV levels were substantially higher than the EC50, the combination regimens were well tolerated, with those employing lower doses of RTV being associated with fewer adverse events [16,22].

This paper reports a combined analysis of the pharmacokinetic data from the two dose-ranging studies discussed above [16,22]. The aims were to further explore the impact of RTV on the pharmacokinetics of SQV, utilizing the larger combined sample size in order to determine the correlation between RTV dosage and the degree of enhancement of SQV levels. This should help provide information regarding the optimal combined twice-daily dosing regimen for use in future clinical trials. However, conclusions may be generally applicable to other dosage regimens, such as once-daily administration of SQV.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Study design

This was a combined analysis of the pharmacokinetic data obtained from two studies (study 1 and study 2), the details of which are published elsewhere (study 1 [22]; study 2 [16]). Briefly, the two studies were open-label, randomized, parallel-group, multiple-dose, single-centre studies involving healthy (HIV-uninfected) volunteers. Subjects were randomized to receive a regimen involving SQV-SGC alone or in combination with RTV. This analysis involved seven of the eight regimens employed in study 1 (excluding a RTV alone regimen) and the five regimens employed in study 2 (Table 1).

Table 1.  Treatment regimens in studies 1 [22] and 2 [16]
RegimenTreatment (bid)
  • SQV-SGC, saquinavir-soft gel capsule; bid, twice daily; qd, once daily; tid, three-times daily; RTV, ritonavir.

  • *

    The RTV dose in groups F and G was escalated such that subjects received 300 mg on day 1, 300 mg bid on day 2, and 400 mg bid on days 3–14. Subjects in regimens D, E and F received SQV-SGC 600 mg on day 1, 600 mg bid on day 2, and 800 mg bid on days 3–14. For other regimens, the maximum required dose was administered from day 1.

Study 1*
A800 mg SQV-SGC
B400 mg SQV-SGC + 400 mg RTV
C600 mg SQV-SGC + 300 mg RTV
D800 mg SQV-SGC + 200 mg RTV
E800 mg SQV-SGC + 300 mg RTV
F800 mg SQV-SGC + 400 mg RTV
G600 mg SQV-SGC + 400 mg RTV
Study 2
A1200 mg SQV-SGC tid
B1200 mg SQV-SGC + 100 mg RTV (both qd)
C1600 mg SQV-SGC + 100 mg RTV (both qd)
D1800 mg SQV-SGC + 100 mg RTV (both qd)
E1200 mg SQV-SGC + 200 mg RTV (both qd)

In study 1, all subjects received a single dose of treatment on day 1, followed by twice-daily dosing (i.e. a dose every 12 h) for a further 13 days. All treatment doses were taken within approximately 15 min of completing a standardized meal. In study 2, all subjects received a single dose of treatment on the evening of day 1, followed by daily dosing for a further 12 days (once daily except for SQV-SCG monotherapy, which was administered three times daily). All treatment doses were taken within approximately 45 min of starting and within 15 min of completing a standardized meal. The objectives of the combined pharmacokinetic analysis were to determine the effects of RTV and SQV dosage on the pharmacokinetics of SQV at steady state.


Inclusion/exclusion criteria are outlined in detail elsewhere [16,22]. Briefly, healthy male or female subjects aged 18–50 years (study 1) or 18–45 years (study 2) were enrolled in the studies. Subjects were given a thorough health assessment prior to day 1 of treatment and were only included if they had no known significant pre-existing medical conditions. The studies were performed in accordance with the Declaration of Helsinki and its amendments. All patients gave their informed consent.

A previously published abstract [23] indicated that 120 subjects were involved in the study, when in fact the combined number of subjects was 110. Of those 110, a total of five subjects did not complete the previous protocols (and therefore did not reach the time points analysed in this manuscript) and eight subjects were enrolled in the RTV-only arm. Thus, this manuscript reflects the 97 subjects who completed the previous studies while receiving dual PI regimens.

Pharmacokinetic assessments

Details of the assessments are provided elsewhere [16,22]. In study 1, samples for assessment of drug concentrations were obtained before drug administration on days 1, 11, and 14, and at regular intervals up to 12 h after drug administration on these days. In addition, on days 1 and 14 only, blood samples were taken at 14, 16, 20, and 24 h after drug administration and additionally, for day 14 only, at 13, 15, 17, 18, 22, 26, 30, 34, 38, 42, and 48 h after drug administration. Plasma samples for SQV assay were analysed by a sensitive radioimmunoassay (RIA) with a lower limit of quantification of 0.5 ng/mL for the assay of undiluted samples and 25 ng/mL for samples diluted 1 in 50 with blank plasma. In study 2, blood samples for assessment of trough drug concentrations (observed Cmin) were obtained following the standardized evening meal but prior to administration of study drugs on days 2, 7, 11, and 12. Intensive pharmacokinetic assessment of drug concentrations was performed on day 13 predose and at 1, 2, 3, 4, 6, 8, 12, 18, and 24 h post-dose. SQV plasma concentration was assayed using a validated SCIEXIII–Plus API liquid chromatography extraction method with a mass spectrophotometric (LC-MS) detection system. The method was validated for a range of 5.0–3000 ng/mL SQV based on a 0.05 mL sample volume.

Pharmacokinetic evaluation

In both studies, the pharmacokinetic parameters Cmax and Cmin of SQV were derived by model-independent (noncompartmental) methods [24]. For this analysis, the pharmacokinetics at steady state (day 14 in study 1, evening day 13 and for the following 12 h in study 2) were of primary interest.

For study 1 (twice-daily dosing), the parameters of primary interest were the maximum plasma concentration (Cmax) and end of dose interval (12-h) plasma concentration (observed Cmin) on day 14.

For study 2 (once-daily dosing), the pharmacokinetic profiles obtained during the first 12 h after the evening dose on day 13 were used to estimate Cmax and Cmin for the equivalent dosage administered twice daily. Although once-daily dosing of this dual PI regimen is also currently under investigation, our primary objective was to evaluate potential twice-daily dosing regimens for future studies. This may produce an underestimate of the true values seen with twice-daily dosing since the plasma levels associated with a given dosage of drug might be expected to reach a lower Cmin following once-daily compared with twice-daily dosing.

Due to the intersubject variation in the pharmacokinetics seen with SQV (subject to positive skew) [11], the geometric means of Cmax and Cmin for each SQV monotherapy or SQV/RTV dosage combination were used in the statistical analyses.

Statistical evaluation

Data were analysed by multivariate regression of log transformed Cmax or Cmin (geometric means) of SQV as the dependent variable and independent variables of SQV and RTV dosage. RTV dosage was fitted as both a categorical variable (i.e. whether RTV was included or not, irrespective of dosage) and a continuous variable (i.e. the dosage of RTV used).

The data were derived from two clinical studies. However, as the two sources provided data on nonoverlapping ranges of SQV dosages, the inclusion of the data source as a dummy binary variable would make analysis unstable. The data source (study 1 or study 2) was therefore not included as a variable in the analyses, but extra attention was paid to the potential limitations of the fitted model to ensure that this was satisfactory.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

In study 1, it was planned that 56 healthy subjects would receive SQV or SQV/RTV combinations. Eight subjects were randomized to each treatment group, but two subjects withdrew (two females, one each from regimens B and F) and were replaced by two other subjects (one male and one female). Data at steady state were available from these 56 subjects.

In study 2, 45 subjects were eligible for inclusion in the study, although one subject (randomized into group C) dropped out of the study for personal reasons without ever receiving study medication. Although a total of 44 subjects received study medication, three of these dropped out of the study prior to the determination of steady state pharmacokinetics (patient disposition is described in more detail in [16]). Pharmacokinetic data at steady state were therefore available from 97 healthy subjects (56 in study 1 and 41 in study 2). The subjects were primarily male (73%) and Caucasian (74%). The mean age was 29.9 years (range 18–50), mean weight was 72.7 kg (range 47.7–103) and mean height was 173 cm (range 155–193).

Pharmacokinetic data

The Cmin and Cmax of SQV (geometric mean) according to the dosage of SQV and RTV used are shown in Table 2.

Table 2.  Pharmacokinetic parameters according to the dosage of saquinavir and ritonavir used (geometric means and 95% CIs)
RegimennCmax (ng/mL) (95% CI)Cmin (ng/mL) (95% CI)
  • SQV-SGC, saquinavir-soft gel capsule; bid, twice daily; qd, once daily; tid, three times daily; RTV, ritonavir.

  • *

    Derived by exploratory analyses from concentration–time profiles at steady state.

800 mg SQV-SGC bid*8533 (238, 1193)41 (24, 69)
400 mg SQV-SGC + 400 mg RTV bid*82919 (2136, 3989)840 (482, 1463)
600 mg SQV-SGC + 300 mg RTV bid*83894 (2700, 5616)735 (389, 1390)
800 mg SQV-SGC + 200 mg RTV bid*84518 (3479, 5868)785 (465, 1328)
800 mg SQV-SGC + 300 mg RTV bid*85299 (3733, 7523)1160 (855, 1574)
800 mg SQV-SGC + 400 mg RTV bid*84828 (3561, 6545)1476 (879, 2477)
600 mg SQV-SGC + 400 mg RTV bid*84779 (3651, 6255)1407 (904, 2191)
1200 mg SQV-SGC tid81039 (575, 1879)49 (30,78)
1200 mg SQV-SGC + 100 mg RTV (both qd)86037 (3846, 9477)2370 (1438, 3908)
1600 mg SQV-SGC + 100 mg RTV (both qd)95704 (3033, 10725)2291 (1018, 5158)
1800 mg SQV-SGC + 100 mg RTV (both qd)87480 (5939, 9420)2408 (1473, 3935)
1200 mg SQV-SGC + 200 mg RTV (both qd)84451 (3373, 5875)1462 (962, 2307)

While the addition of RTV markedly increased Cmax and Cmin in all combination dose groups, there was no clear effect of increasing the RTV dosages above 100 mg. For example, the SQV/RTV 1200 mg/100 mg regimen led to higher Cmin values than the SQV/RTV 1200 mg/200 mg regimen, whereas the SQV/RTV 800 mg/400 mg regimen led to a higher Cmin than the SQV/RTV 800 mg/200 mg regimen.

Statistical analyses

The effects of RTV and SQV on the pharmacokinetics of SQV, as derived by multiple regression analyses, are shown in Table 3.

Table 3.  Effects of ritonavir and saquinavir on the pharmacokinetics of saquinavir – regression of log10 (Cmin) and log10 (Cmax) on drugs received
ParameterEstimate95% CIP-value
  • adj., adjusted; SQV-SGC, saquinavir-soft gel capsule; RTV, ritonavir.

  • *

    Twice-daily dose of saquinavir (hundreds of mg).

  • †0 if no ritonavir, 1 if some ritonavir.

  • ‡Twice-daily dose of ritonavir (hundreds of mg).

Cminr2 (adj.) = 0.7976
 Intercept1.18953(0.8885, 1.4905)< 0.0001
 SQV dosage*0.04611(0.0195, 0.0727)0.0010
 Any RTV1.37359(1.0881, 1.6591)< 0.0001
 RTV dosage0.04799(− 0.0499, 0.1479)0.3393
Cmaxr2 (adj.) = 0.6451
 Intercept2.57934(2.3351, 2.8236)< 0.0001
 SQV dosage*0.02923(0.0076, 0.0508)0.0093
 Any RTV0.74008(0.5084, 0.9718)< 0.0001
 RTV dosage0.03163(− 0.0478, 0.1111)0.4373

As anticipated, the presence of any RTV had a significant enhancing effect on the Cmax and Cmin of SQV compared with SQV monotherapy (P < 0.0001 for both Cmax and Cmin). However, the dosage of RTV employed did not significantly affect the magnitude of the increases in these parameters seen (P > 0.2 for both Cmax and Cmin). In fact, there was a trend toward decreasing levels at higher RTV doses.

There was an independent effect of SQV dose on Cmax (P=0.0093) and Cmin (P=0.0010), with a linear correlation between higher SQV dosage and higher parameters, as shown in Fig. 1. There was a wide variability in the values obtained for Cmax and Cmin as illustrated by the wide confidence intervals in Fig. 1.


Figure 1. Observed data and geometric mean (95% CI) regression model for Cmin for twice daily doses of saquinavir.

Download figure to PowerPoint

Estimation of the residuals of multivariate regression plots revealed no systematic difference in data obtained from the two studies.

Exploratory analyses

SQV, when administered in the oral form, has two half-lives, with the slope of the declining concentration–time curve decreasing over time in two distinct phases. An exploratory regression analysis was performed to estimate the impact of SQV dosage and the addition of any RTV on the first of these half-lives, occurring immediately post-Cmax (data not shown). This suggested that approximately 1 h was added to the half-life for every increase in SQV dosage of 700 mg twice daily, while the addition of any RTV increased the half-life by approximately 2.7 h. There was no additional effect of increasing RTV dosage on the half-life of SQV.

Evaluation of potential dosages for a twice-daily SQV/RTV combination

Since the statistical analyses suggested that RTV had a significant effect on SQV exposure, but increasing the RTV dose above 100 mg did not provide further benefit, Cmin and Cmax values were plotted according to the dosage of SQV used and irrespective of the dosage of RTV employed.

The actual and predicted Cmin and Cmax data for twice-daily doses of SQV are shown in Fig. 2. Twice-daily dosages of SQV/RTV 800 mg/100 mg, 1000 mg/100 mg and 1200 mg/100 mg would be predicted to provide geometric mean Cmin values of 1005 ng/mL (95% CI 314–4436), 1387 ng/mL (95% CI 369–5208) and 1629 ng/mL (95% CI 434–6138), respectively, with corresponding values for the geometric mean Cmax of 4420 ng/mL (95% 1511–12927), 4887 ng/mL (95% CI 1675–14289) and 5410 ng/mL (95% CI 1849–15827), respectively.


Figure 2. Actual and predicted Cmin and Cmax for twice daily doses of saquinavir.

Download figure to PowerPoint


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

These retrospective analyses of pharmacokinetic data from 97 healthy volunteers further characterize the interaction between RTV and SQV. These results show for the first time that the pharmacokinetic enhancement of SQV exposure provided by RTV is not significantly affected by the dose of RTV when dosages ranging from 100 to 400 mg twice daily are employed. Recently, further data from 271 patients treated either with SQV-SGC or combinations of SQV (SGC or HGC) plus RTV have confirmed that SQV exposure is related to the dose of SQV and not the dose of RTV (100–400 mg twice daily) used [25].

In the present investigation, for regression analyses generated from pharmacokinetic data, the r2 values for both the Cmax and Cmin models were high, indicating that the variables assessed (SQV dosage, any RTV and RTV dosage) account for most of the variability in the data. While once-daily regimens are also under investigation, it remains to be verified that this is a reliable dosing strategy in HIV-infected patients. A potential limitation of our approach to evaluating potential twice-daily dose regimens is that some of the data were derived from a study involving once-daily dosing. However, this factor would be expected to underestimate rather than overestimate the potential exposure to SQV seen with twice-daily dosing. In addition, estimation of the residuals of multivariate regression plots revealed no systematic difference in measurements between the data obtained from once- and twice-daily studies.

The results suggest that a dose of 100 mg RTV is sufficient to achieve enhancement of SQV levels. At this dose, RTV is not expected to have a significant antiviral effect (600 mg twice daily being the licensed dose). However, as RTV shows a dose-related toxicity [19,26], it is likely that the lowest dose of RTV will have the most favourable toxicity profile. Indeed, in one of the two studies from which the data used in this analysis were derived, although all the combinations assessed were generally well tolerated, the least number of adverse events was recorded for the SQV/RTV 800 mg/200 mg regimen (200 mg RTV was the lowest dose of RTV used in that study) [22].

In certain patients it may be appropriate to consider adding RTV at a therapeutic dose (400 mg twice daily or greater) [27]. The advantage of this approach would be to put additional selective pressure on the virus and potentially decrease the likelihood of the selection of RTV- and/or SQV-related mutations. Another approach that has been increasingly studied is to use the mini-dose of RTV to boost two PIs simultaneously such as SQV and lopinavir (unpublished data). This may have additional advantages of better tolerability compared to regimens including high-dose RTV.

The pharmacokinetic profiles seen with PIs when coadministered with RTV as part of pharmacokinetic enhancement strategies can loosely be divided into two categories: (1) bioavailability increases, but the rate of clearance remains similar; and (2) bioavailability is relatively unaffected, but the rate of clearance is reduced. The pharmacokinetic profile of SQV boosted with RTV falls into the first of these categories. Large increases in the bioavailability of SQV are likely to reflect the combination of a reduction in first-pass metabolism (due to inhibition of CYP3A4 in the intestine and liver by RTV) [9,10], and increased absorption of SQV (due to inhibition by RTV of P-glycoprotein transport) [14,15]. Lopinavir (ABT-378), when boosted with RTV, also falls into the first of these categories, with a large increase in bioavailability seen with doses of RTV as low as 50 mg [28]. By contrast, indinavir and amprenavir fall into the second of these categories, with the rate of clearance being reduced, leading to significant increases in the plasma half-life [29–31].

This pharmacokinetic analysis can be used to assist in the selection of an appropriate twice-daily dosage of SQV/RTV to take forward for further clinical study. The analysis shows that 100 mg twice-daily RTV is sufficient to achieve pharmacokinetic enhancement while limiting the toxicity associated with this agent. Irrespective of the dosage of RTV over the range 100–400 mg twice daily, there was a consistent rise in the Cmin and Cmax of SQV for each increase in SQV dosage.

Clear exposure–response relationships based on Cmin and area under curve (AUC) have been established for SQV-SGC administered as monotherapy in HIV PI-naive adults, and an in vivo EC50 of 50 ng/mL for SQV-SGC monotherapy has been calculated based on Cmin[7]. The EC50 for SQV in combination therapy may be lower due to synergies between antiretroviral agents [32]. Based on these data, a target Cmin of 100 ng/mL has been suggested to ensure an optimal response among PI-naive patients [33]. However, few data are currently available to suggest target pharmacokinetic parameters in patients who have previously experienced virological failure while receiving PI-containing combinations, and who are likely to harbour a diverse population of viruses with a range of susceptibilities to the various antiretroviral agents in the new regimen.

In selecting an appropriate SQV dosage, several considerations need to be balanced. Maximizing SQV exposure and Cmin provides the greatest theoretical probability of completely inhibiting the replication of virus strains exhibiting a range of decreased susceptibilities to SQV. However, a high level of adherence to medications has been shown to be essential for complete and durable viral suppression [34], and compliance is affected by both the dosing regimen and tolerability.

The Cmin values obtained with SQV dosages of at least 800 mg twice daily in association with mini-dose RTV were at least nine-fold above the in vivo monotherapy EC50, even at the lower extent of the 95% confidence interval. Nearly all patients receiving at least 800 mg SQV-SGC plus mini-dose RTV are therefore likely to maintain drug levels throughout the dosage interval that are adequate to suppress virus with moderately reduced susceptibility to SQV. However, higher dosages of SQV would increase further the confidence that all patients will attain adequate trough drug concentrations to suppress virus strains with substantially reduced SQV susceptibility.

The observation that drug exposure following the 1200 mg/200 mg SQV/RTV regimen was actually lower than the 1200 mg/100 mg SQV/RTV regimen was unexpected. While no definitive answer for this apparently counterintuitive result is currently available, there appears to be at least two theoretical answers. First, and perhaps most likely, is that this is a reflection of intrinsic pharmacokinetic variability. It might be argued that had the sample size been larger, this anomaly would not have been observed. Alternatively, this observation may uncover differences in the dose–response relationship for RTV-related enzyme induction and inhibition. It is theoretically possible that the 100 mg dose of RTV is predominantly associated with the cytochrome P450-related inhibition commonly associated with RTV, whereas at the slightly higher dose of 200 mg the P450-inducing effect of RTV results in a net reduction in inhibition relative to the 100 mg dose. At higher RTV doses there may be a net shift back towards greater P450-related inhibition.

Based on these considerations, a dosage of SQV-SGC/RTV 1000 mg/100 mg, which provides an estimated Cmin of 1387 ng/mL (95% CI 369–5208), has been selected for further clinical investigation. This dosage has been successfully employed in a study assessing the safety and efficacy of a five-drug regimen including efavirenz in patients who failed conventional highly active antiretroviral therapy (HAART) including indinavir or RTV [19,35]. At 24 weeks, 71% of patients achieved a plasma viral load < 500 copies/mL and 45% achieved a viral load < 50 copies/mL [19]. At 48 weeks, these figures were 61% and 58%, respectively [35]. Although efavirenz has been reported to reduce the exposure to SQV when administered as a sole PI [36], it had no marked effect on SQV plasma exposure when SQV was administered in combination with RTV at a dose of 400 mg/400 mg [37]. Limited data suggest that a SQV/RTV 1000 mg/100 mg combination enables the coadministration of efavirenz [38]; however, this needs to be confirmed in clinical trials.

The large increases in Cmax seen with boosted SQV regimens may lead to questions regarding tolerability. At a 1000 mg/100 mg dose, the predicted Cmax for SQV is 4962 ng/mL. These exposures are similar to those levels which have been reported to be well tolerated in healthy volunteers [22], and presumably reflect the fact that SQV is generally well tolerated. By reducing the number of SQV capsules that need to be taken using a boosted regimen, it should be possible to achieve high exposure (e.g. Cmax and Cmin) while reducing the tolerability problems often associated with the administration of multiple capsules (so called capsule toxicity). The safety of the SQV/RTV 800–1200 mg/100 mg twice-daily combination in terms of SQV tolerability is supported by the fact that doses within this range were also found to be well tolerated at both 24 and 48 weeks in PI-experienced HIV-infected patients [19,35]. Although this study involved the HGC formulation of SQV, boosting with RTV produces a similar range of exposures, irrespective of the formulation [11–13].

In conclusion, increasing the exposure to SQV using RTV appears to be similar for doses between 100 and 400 mg. Given the potential advantages of using ‘mini-dose’ RTV to enhance SQV exposure (e.g. reduced toxicity, reduced pill burden and number of daily doses, leading to potential for improved compliance), we recommend further investigation of this strategy. A regimen of 800–1200 mg SQV plus 100 mg RTV is suggested based on both pill burden and a favourable exposure profile. A large clinical trial involving HIV-infected individuals is now ongoing to further evaluate the SQV/RTV 1000 mg/100 mg combination dose regimen.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References
  • 1
    Stellbrink H-J, Hawkins DA, Clumeck N et al. Randomised, multicentre phase III study of saquinavir plus zidovudine plus zalcitabine in previously untreated or minimally pretreated HIV-infected patients. Clin Drug Invest 2000; 20: 295307.
  • 2
    Haubrich R, Lalezari J, Follansbee SE et al. Improved survival and reduced clinical progression in HIV-infected patients with advanced disease treated with saquinavir plus zalcitabine. Antiviral Ther 1998; 3: 3342.
  • 3
    Williams PEO, Sampson AP, Green CP et al. Disposition and bioavailability of the HIV-proteinase inhibitor Ro-31–8959 after single doses in healthy volunteers. Br J Clin Pharmacol 1992; 34: 155P156P.
  • 4
    Lalezari J. Selecting the optimum dose for a new soft gelatin capsule formulation of saquinavir. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19: 195196.
  • 5
    Mitsuyasu RT, Skolnik PR, Cohen SR et al. Activity of the soft gelatin formulation of saquinavir in combination therapy in antiretroviral-naive patients. AIDS 1998; 12: F103F109.
  • 6
    Lalezari J, Feinberg J, Sension M et al. TIDBID study 48 week analysis: fortovase™ (FTV) TID regimen compared with FTV BID or FTV + NFV BID regimens in HIV-1 infected patients. 13th International AIDS Conference. Durban, South Africa, 914 July 2000 Abstract TupeB2229.
  • 7
    Gieschke R, Fotteler B, Buss N, Steimer J-L. Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients. Clin Pharmacokinet 1999; 37: 7586.
  • 8
    Schapiro JM, Winters MA, Stewart F et al. The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med 1996; 124: 10391050.
  • 9
    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; 44: 190194.
  • 10
    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 Disposit 1997; 25: 256266.
  • 11
    Merry C, Barry MG, Mulcahy F et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS 1997; 11: F29F33.
  • 12
    Hsu A, Granneman GR, Cao G et al. Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir. Clin Pharmacol Ther 1998; 63: 453464.
  • 13
    Hsu A, Granneman GR, Bertz RJ. Ritonavir: clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 1998; 35: 275291.
  • 14
    Washington CB, Duran GE, Sikic BI, Blaschke TF. Saquinavir is a high affinity substrate for the multidrug transporter, P-glycoprotein. Clin Pharmacol Ther 1997; 61: 193.
  • 15
    Wacher VJ, Wu C-Y, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129134.
  • 16
    Kilby JM, Sfakianos G, Gizzi N et al. Safety and pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus mini-dose ritonavir in HIV-negative adults. Antimicrob Agents Chemother 2000; 44: 26722678.
  • 17
    Cameron DW, Japour AJ, Xu Y et al. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 1999; 13: 213234.DOI: 10.1097/00002030-199902040-00009
  • 18
    Gill MJ Safety profile of soft gelatin formulation of saquinavir in combination with nucleosides in a broad patient population. AIDS 1998; 12: 14001402.
  • 19
    Piketty C, Race E, Castiel P et al. Efficacy of a five-drug combination of ritonavir, saquinavir and efavirenz in patients who failed on conventional triple drug regime: phenotypic resistance to protease inhibitors predicts outcome of therapy. AIDS 1999; 13: F71F77.
  • 20
    Kurowski M, Muller M, Donath F, Mrozikiewicz M, Mocklinghoff C. Single daily doses of saquinavir achieve HIV-inhibitory concentrations when combined with ‘baby-dose’ ritonavir. Eur J Med Res 1999; 4: 101104.
  • 21
    Jorga K, Buss NE. Pharmacokinetic (PK) drug interaction with saquinavir soft gelatin capsule. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA, 2629 September 1999 [Poster 339.
  • 22
    Buss N, Snell P, Bock J et al. Saquinavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration. Br J Clin Pharmacol 2001; 52: 255264.
  • 23
    Kilby JM, Hill AM, Buss N. The effect of ritonavir on increases in saquinavir plasma concentration is independent of ritonavir dosage. Combined analysis of 120 subjects. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1722 September 2000 [Abstract 1650.
  • 24
    Gibaldi M, Perrier D. Pharmacokinetics, 2nd edn. New York, Marcel Dekker, 1982.
  • 25
    Kurowski M, Arslan A, Moecklinghoff C, Sawyer W, Hill A. Effects of ritonavir on saquinavir plasma concentration. analysis of 271 patients in routine clinical practice. AIDS 2000; 14 (Suppl. 4): S91 [ Poster P261A.
  • 26
    Rublein JC, Eron JJ, Butts JD, Raasch R. Discontinuation rates for protease inhibitor regimens containing ritonavir 600mg versus ritonavir 400mg plus saquinavir 400mg. Ann Pharmacother 1999; 33: 899905.
  • 27
    Paredes R, Puig T, Arno A et al. High-dose saquinavir plus ritonavir: long-term efficacy in HIV-positive inhibitor-experienced patients and predictors of virologic response. J Acquir Immune Defic Syndr 1999; 22: 132138.
  • 28
    Sham HL, Kempf DJ, Molla A et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 1998; 42: 32183224.
  • 29
    Van Heeswijk RP, Velkamp AI, Hoetelmans RM et al. The steady state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals. AIDS 1999; 13: F95F99.DOI: 10.1097/00002030-199910010-00001
  • 30
    Saah A, Winchell M, Seniuk M, Deutsch P. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) and ritonavir (RTV) combinations in a once-daily regimen in healthy volunteers (Merck 089). 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 2629 September 1999 [Abstract 329.
  • 31
    Sadler BM, Piliero PJ, Preston SL, Lou Y, Sale M, Stein D. Pharmacokinetic (PK) drug interaction between amprenavir (APV) and ritonavir (RTV) in HIV-seronegative subjects after multiple oral dosing. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January2 February 2000 [Abstract 77.
  • 32
    Kline MW, Fletcher CV, Brundage RC et al. Combination therapy with saquinavir soft gelatin capsules plus nucleoside antiretroviral agents in HIV-infected children. 12th World AIDS Conference. Geneva, Switzerland, 28 June3 July 1998 [Poster 12260.
  • 33
    Gibbons SE, Reynolds HE, Tjia JF, Khoo SH, Drake J, Back J. Therapeutic drug monitoring in the management of subjects on the protease inhibitors nelfinavir and saquinavir: results of the Roche UK TDM Service. AIDS 2000; 14 (suppl. 4): S89 [ Poster P259.
  • 34
    Paterson DL, Swindells S, Mohr J et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133: 2130.
  • 35
    Piketty C, Race E, Castiel P et al. Phenotypic resistance to protease inhibitors in patients who fail on highly active antiretroviral therapy predicts the outcome at 48 weeks of a five-drug combination including ritonavir, saquinavir and efavirenz. AIDS 2000; 14: 626628.
  • 36
    Figgitt DP, Plosker GL. Saquinavir soft-gel capsule. An updated review of its use in the management of HIV infection. Drugs 2000; 60: 481516.
  • 37
    Hendrix CW, Fiske WD, Fuchs EJ et al. Pharmacokinetics of the triple combination of saquinavir, ritonavir, and efavirenz in HIV-positive patients. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA 30 January 2 February 2000 [Abstract 79.
  • 38
    Veldkamp AI, Hoetelmans RMW, Beijnen JH, Mulder JW, Meenhorst PL. Ritonavir enables combined therapy with rifampin and saquinavir. Clin Infect Dis 1999; 29: 1586.