Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Pharmaco-therapeutic group: Antiviral agent
ATC code: J05AE01
The HIV protease is an essential viral enzyme required for the specific cleavage of viral gag and gag-pol polyproteins. Saquinavir selectively inhibits the HIV protease, thereby preventing the creation of mature infectious virus particles.
The effects of therapeutic (1000/100 mg twice daily) and supra-therapeutic (1500/100 mg twice daily) doses of Invirase/ritonavir on the QT interval were evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg) study in healthy male and female volunteers aged 18 to 55 years old (N=59). On Day 3 of dosing, ECG measurements were done over a period of 20 hours. The Day 3 timepoint was chosen since the pharmacokinetic exposure was maximum on that day in a previous 14-day multiple dose pharmacokinetic study. On Day 3, mean Cmax values were approximately 3-fold and 4-fold higher with the therapeutic and supra-therapeutic doses, respectively, relative to the mean Cmax observed at steady state with the therapeutic dose administered to HIV patients. On Day 3, the upper 1-sided 95% confidence interval of the maximum mean difference in pre-dose baseline-corrected QTcS (study specific heart rate corrected QT) between the active drug and placebo arms was >10 msec for the two ritonavir-boosted Invirase treatment groups (see results in Table 3). While the supra-therapeutic dose of Invirase/ritonavir appeared to have a greater effect on the QT interval than the therapeutic dose of Invirase/ritonavir, it is not sure if maximum effect for both doses has been observed. In the therapeutic and the supra-therapeutic arm 11% and 18% of subjects, respectively, had a QTcS between 450 and 480 msec. There was no QT prolongation >500 msec and no torsade de pointes in the study (see also section 4.4).
Table 3. Maximum mean of ddQTcS† (msec) on day 3 for therapeutic dose of Invirase/ritonavir, supra-therapeutic dose of Invirase/ritonavir and active control moxifloxacin in healthy volunteers in Thorough QT (TQT) Study:
| Treatment | Post-Dose Time Point | Mean ddQTcS | Standard Error | Upper 95%-CI of ddQTcS |
|---|---|---|---|---|
| Invirase/ritonavir 1,000/100 mg BID | 12 hours | 18.86 | 1.91 | 22.01 |
| Invirase/ritonavir 1,500/100 mg BID | 20 hours | 30.22 | 1.91 | 33.36 |
| Moxifloxacin^ | 4 hours | 12.18 | 1.93 | 15.36 |
† Derived difference of pre-dose baseline corrected QTcS between active treatment and placebo arms
^ 400 mg was administered only on Day 3
Note: QTcS in this study was QT/RR0.319 for males and QT/RR0.337 for females, which are similar to Fridericia’s correction (QTcF=QT/RR0.333).
In this study, PR interval of >200 msec was also observed in 40% and 47% of subjects receiving Invirase/ritonavir 1000/100 mg twice daily and 1500/100 mg twice daily, respectively, on Day 3. PR intervals of >200 msec were seen in 3% of subjects in the active control group (moxifloxacin) and 5% in the placebo arm. The maximum mean PR interval changes relative to the pre-dose baseline value were 25 msec and 34 msec in the two ritonavir-boosted Invirase treatment groups, 1000/100 mg twice daily and 1500/100 mg twice daily, respectively (also see section 4.4).
Events of syncope/presyncope occurred at a higher than expected rate and were seen more frequently under treatment with saquinavir (11 of 13). The clinical relevance of these findings from this study in healthy volunteers to the use of Invirase/ritonavir in HIV-infected patients is unclear, but doses exceeding Invirase/ritonavir 1000/100 mg twice daily should be avoided.
The effect of treatment initiation with a dosing regimen of Invirase/ritonavir 500/100 mg twice daily in combination with 2 NRTIs for the first 7 days of treatment followed by Invirase/ritonavir 1000/100 mg twice daily in combination with 2 NRTIs in the subsequent 7 days on QTc interval, PK, and viral load was evaluated in an open-label 2-week observational study in 23 HIV-1 infected, treatmentnaïve patients initiating Invirase/ritonavir therapy. ECG and PK measurements were collected on Days 3, 4, 7, 10, and 14 of treatment with the modified Invirase/ritonavir treatment. The primary study variable was maximal change from dense predose baseline in QTcF (ΔQTcFdense). The modified Invirase/ritonavir regimen reduced mean maximum ΔQTcFdense in the first week of treatment compared with the same value in healthy volunteers receiving the standard Invirase/ritonavir dosing regimen in the TQT study on Day 3, (Table 4) based on cross-study comparison in a different population. Only 2/21 (9%) patients across all study days had maximum QTcF change from dense predose baseline ≥ 30 ms following administration of the modified Invirase/ritonavir regimen in the treatment-naïve HIV-1 infected patient population; and the maximum mean change from dense predose baseline in QTcF was <10 ms across all study days. These results suggest that the QTc liability is reduced with the modified Invirase/ritonavir dosing regimen, based on a cross-study comparison in a different population (Table 4). The proportion of patients with a reported PR interval prolongation >200 ms in this study ranged from 3/22 (14%) (day 3) to 8/21 (38%) (day14).
Following the modified Invirase/ritonavir regimen, saquinavir exposure during the first week peaked on Day 3 and declined to the lowest exposure on Day 7 with ritonavir induction effects, while Day 14 saquinavir PK parameters (following full doses of Invirase/ritonavir in the second week) approached the range of historical mean values for saquinavir steady-state values in HIV-1 infected patients (Table 9). Mean Invirase Cmax with the modified Invirase/ritonavir regimen was approximately 53-83% lower across study days in the HIV-1 infected patients relative to the mean Cmax achieved in healthy volunteers in the TQT study on Day 3. Continuous declines in HIV-RNA were observed in all treatment-naïve patients receiving the modified Invirase/ritonavir dosing regimen over the 2-week treatment period, suggesting HIV viral suppression during the time of the study. No long-term efficacy was evaluated with the modified regimen.
Table 4. Summary of Electrocardiogram Parameters following administration of the Modified Invirase/ritonavir Regimen in Treatment Naïve HIV-1 infected Patients initiating treatment with Invirase/ritonavir:
| Parameter | Day 3 | Day 4 | Day 7 | Day 10 | Day 14 | Study TQT |
|---|---|---|---|---|---|---|
| 500/100 mg | 500/100 mg | 500/100 mg | 1,000/100 mg | 1,000/100 mg | Day 3* | |
| (n=22) | (n=21) | (n=21) | (n=21) | (n=21) | (n=57) | |
| Mean Maximal ΔQTcFdense ms (SD) | 3.26 ± 7.01 | 0.52 ± 9.25 | 7.13 ± 7.36 | 11.97 ± 11.55 | 7.48 ± 8.46 | 32.2 ± 13.4 |
| Patients with maximal ΔQTcFdense ≥30 ms (%) | 0 | 0 | 0 | 2/21 (9%) | 0 | 29/57 (51%) |
* Historical data from the thorough QT study conducted in healthy volunteers.
Saquinavir demonstrates antiviral activity against a panel of laboratory strains and clinical isolates of HIV-1 with typical EC50 and EC90 values in the range 1-10 nM and 5-50 nM, respectively, with no apparent difference between subtype B and non-B clades. The corresponding serum (50% human serum) adjusted EC50 ranged from 25-250 nM. Clinical isolates of HIV-2 demonstrated EC50 values in the range of 0.3-2.4 nM.
Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted saquinavir have been derived from retrospective analyses of the RESIST 1 and 2 clinical studies and analysis of a large hospital cohort (Marcelin et al 2007).
Baseline saquinavir phenotype (shift in susceptibility relative to reference, PhenoSense Assay) was shown to be a predictive factor of virological outcome. Virological response was first observed to decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the fold shift exceeded 12-fold.
Marcelin et al (2007) identified nine protease codons (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M) that were associated with decreased virological response to saquinavir/ritonavir (1000/100 mg twice daily) in 138 saquinavir naive patients. The presence of 3 or more mutations was associated with reduced response to saquinavir/ritonavir. The association between the number of these saquinavir-associated resistance mutations and virological response was confirmed in an independent clinical study (RESIST 1 and 2) involving a more heavily treatment experienced patient population, including 54% who had received prior saquinavir (p=0.0133, see Table 5). The G48V mutation, previously identified in vitro as a saquinavir signature mutation, was present at baseline in virus from three patients, none of whom responded to therapy.
Table 5. Virological response to saquinavir/ritonavir stratified by the number of baseline saquinavirassociated resistance mutations:
| Number of Saquinavir Associated Resistance Mutations at Baseline* | Marcelin et al (2007) | RESIST 1 & 2 | ||
|---|---|---|---|---|
| SQV Naive Population | SQV Naive/Experienced Population | |||
| N=138 | Change in Baseline Plasma HIV-1 RNA at Weeks 12-20 | N=114 | Change in Baseline Plasma HIV-1 RNA at Week 4 | |
| 0 | 35 | -2.24 | 2 | -2.04 |
| 1 | 29 | -1.88 | 3 | -1.69 |
| 2 | 24 | -1.43 | 14 | -1.57 |
| 3 | 30 | -0.52 | 28 | -1.41 |
| 4 | 9 | -0.18 | 40 | -0.75 |
| 5 | 6 | -0.11 | 17 | -0.44 |
| 6 | 5 | -0.30 | 9 | 0.08 |
| 7 | 0 | - | 1 | 0.24 |
* Saquinavir Mutation Score Mutations: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M
In the MaxCmin1 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg twice daily plus 2 NRTIs/Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) was compared to indinavir/ritonavir 800/100 mg twice daily plus 2 NRTIs/NNRTIs in over 300 (both protease inhibitor treatment naïve and experienced) subjects. The combination of saquinavir and ritonavir exhibited a superior virological activity compared with the indinavir and ritonavir arm when switch from the assigned treatment was counted as virological failure.
In the MaxCmin2 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg twice daily plus 2 NRTIs/NNRTIs was compared with lopinavir/ritonavir 400/100 mg twice daily plus 2 NRTIs/NNRTIs in 324 (both protease inhibitor treatment naïve and experienced) subjects. None of the subjects in the lopinavir/ritonavir arm had been exposed to lopinavir prior to randomisation whereas 16 of the subjects in the saquinavir/ritonavir arm had previously been exposed to saquinavir.
Table 6. Subject Demographics MaxCmin1 and MaxCmin2†:
| MaxCmin1 | MaxCmin2 | |||
|---|---|---|---|---|
| SQV/r | IDV/r | SQV/r | LPV/r | |
| N=148 | N=158 | N=161 | N=163 | |
| Sex Male | 82% | 74% | 81% | 76% |
| Race (White/Black/Asian)% | 86/9/1 | 82/12/4 | 75/19/1 | 74/19/2 |
| Age, median, yrs | 39 | 40 | 40 | 40 |
| CDC Category C (%) | 32% | 28% | 32% | 31% |
| Antiretroviral naïve (%) | 28% | 22% | 31% | 34% |
| PI naïve (%) | 41% | 38% | 48% | 48% |
| Median Baseline HIV-1 RNA, log10 copies/ml (IQR) | 4.0 (1.7-5.1) | 3.9 (1.7-5.2) | 4.4 (3.1-5.1) | 4.6 (3.5-5.3) |
| Median Baseline CD4+ Cell Count, cells/mm³ (IQR) | 272 (135-420) | 280 (139-453) | 241 (86-400) | 239 (95-420) |
† data from clinical study report
Table 7. Outcomes at Week 48 MaxCmin1 and MaxCmin2†
| Outcomes | MaxCmin1 | MaxCmin2 | ||
|---|---|---|---|---|
| SQV/r | IDV/r | SQV/r | LPV/r | |
| Initiated assigned treatment, n (%) | 148 (94%) | 158 (99%) | 161 (94%) | 163 (98%) |
| Discontinued assigned treatment, n (%) | 40 (27%) | 64 (41%) | 48 (30%) | 23 (14%) |
| P=0.01 | P=0.001 | |||
| Virological failure ITT/e*# | 36/148 (24%) | 41/158 (26%) | 53/161 (33%) | 29/163 (18%) |
| P=0.76 | P=0.002 | |||
| Proportion with VL <50 copies/ml at week 48, ITT/e# | 97/144 (67%) | 106/154 (69%) | 90/158 (57%) | 106/162 (65%) |
| P>0.05‡ | P=0.12 | |||
| Proportion with VL <50 copies/ml at week 48, On Treatment | 82/104 (79%) | 73/93 (78%) | 84/113 (74%) | 97/138 (70%) |
| P>0.05‡ | P=0.48 | |||
| Median increase in CD4 cell count at week 48 (cells/mm³) | 85 | 73 | 110 | 106 |
* For both studies: For patients entering study with VL <200 copies/ml, VF defined as ≥200 copies/ml. MaxCmin1: For those entering with VL ≥200 copies/ml, VF defined as any increase ≥0.5 logs and/or VL ≥50,000 copies/ml at week 4, ≥5,000 copies/ml at week 12, or ≥200 copies/ml at week 24 or thereafter. MaxCmin2: any rise ≥0.5 log at a specific visit; ≤0.5 log reduction if VL ≥200 copies/ml at week 4; ≤1.0 log reduction from base line if VL ≥200 copies/ml at week 12; and a VL ≥200 copies/ml at week 24.
# ITT/e = Intent-to-treat/exposed
† Data from clinical study report
‡ Data from MaxCmin1 publication
The pharmacokinetics, safety and activity of saquinavir have been evaluated in an open label, multicenter study in 18 children aged 4 months to less than 6 years old in which saquinavir (50 mg/kg bid up to the adult dose of 1000 mg bid) was administered in combination with ritonavir oral solution (3 mg/kg bid for body weight from 5 to <15 kg, 2.5 mg/kg bid for body weight from 15 to 40 kg and 100 mg bid for body weight >40 kg) plus ≥2 background ARVs. The infants and young children were stratified into 2 groups: Group A “Low Age Group” 4 months to less than 2 years old (n=5) and Group B “High Age Group” children 2 years to less than 6 years old (n=13).
In the “High Age Group”, the number of patients with a viral load <400 copies/mL at week 48 was 11 of 13. The number of patients with viral load <50 copies/mL was 9 of 13 for the same period. The CD4 lymphocyte count expressed as percentage mean CD4 increased by a mean of 2.97% over the same 48 week period. The size of the study was too small to allow conclusions on clinical benefit.
Saquinavir is essentially completely metabolised by CYP3A4. Ritonavir inhibits the metabolism of saquinavir, thereby increasing (“boosting”) the plasma levels of saquinavir.
In HIV-infected adult patients, Invirase in combination with ritonavir at doses of 1,000/100 mg twice daily provides saquinavir systemic exposures over a 24-hour period similar to or greater than those achieved with saquinavir soft capsules 1200 mg tid (see Table 8). The pharmacokinetics of saquinavir is stable during long-term treatment.
Table 8. Mean (% CV) AUC, Cmax and Cmin of saquinavir in patients following multiple dosing of Invirase, saquinavir soft capsules, Invirase/ritonavir, and saquinavir soft capsules/ritonavir:
| Treatment | N | AUCτ (ng·h/ml) | AUC(0-24) (ng·h/ml)† | Cmax (ng/ml) | Cmin (ng/ml) |
|---|---|---|---|---|---|
| Invirase (hard capsule) 600 mg tid | 10 | 866 (62) | 2,598 | 197 (75) | 75 (82) |
| saquinavir soft capsule 1,200 mg tid | 31 | 7,249 (85) | 21,747 | 2,181 (74) | 216 (84) |
| Invirase (tablet) 1,000 mg bid plus ritonavir 100 mg bid* (fasting condition) | 22 | 10,320 (2,530-30,327) | 20,640 | 1,509 (355-4,101) | 313 (70-1,725)†† |
| Invirase (tablet) 1,000 mg bid plus ritonavir 100 mg bid* (high fat meal) | 22 | 34,926 (11,826-105,992) | 69,852 | 5,208 (1,536-14,369) | 1,179 (334-5,176)†† |
τ = dosing interval, i.e. 8 hour for tid and 12 h for bid dosing.
Cmin = the observed plasma concentration at the end of the dose interval.
bid = twice daily
tid = three times daily
* results are geometric mean (min – max)
† derived from tid or bid dosing schedule
†† Ctrough values
Absolute bioavailability averaged 4% (CV 73%, range: 1% to 9%) in 8 healthy volunteers who received a single 600 mg dose (3 × 200 mg hard capsule) of Invirase following a heavy breakfast. The low bioavailability is thought to be due to a combination of incomplete absorption and extensive firstpass metabolism. Gastric pH has been shown to be only a minor component in the large increase in bioavailability seen when given with food. The absolute bioavailability of saquinavir co-administered with ritonavir has not been established in humans.
In combination with ritonavir, bioequivalence of Invirase hard capsules and film-coated tablets was demonstrated under fed conditions.
Effective therapy in treatment naïve patients is associated with a Cmin of approximately 50 ng/ml and an AUC0-24 of about 20,000 ng·h/ml. Effective therapy in treatment experienced patients is associated with a Cmin of approximately 100 ng/ml and an AUC0-24 of about 20,000 ng·h/ml.
In treatment-naïve HIV-1 infected patients initiating Invirase/ritonavir treatment with a modified Invirase/ritonavir dosing regimen of Invirase 500 mg two times daily with ritonavir 100 mg two times daily for the first 7 days of treatment and increased to Invirase 1,000 mg two times daily with ritonavir 100 mg two times daily in the subsequent 7 days, saquinavir systemic exposures generally approached or exceeded the range of historical steady-state values with the standard Invirase/ritonavir 1,000 mg/100 mg bid dosing regimen across study days (see Tables 9 and 8).
Table 9. Mean (CV%) PK Parameters following administration of the Modified Invirase/ritonavir Regimen in Treatment Naïve HIV-1 infected Patients initiating treatment with Invirase/ritonavir:
| Parameter | Day 3 | Day 4 | Day 7 | Day 10 | Day 14 |
|---|---|---|---|---|---|
| 500/100 mg | 500/100 mg | 500/100 mg | 1,000/100 mg | 1,000/100 mg | |
| (n=22) | (n=21) | (n=21) | (n=21) | (n=21) | |
| AUC0-12 (ng*hr/ml) | 27,100 (35.7) | 20,300 (39.9) | 12,600 (54.5) | 34,200 (48.4) | 31,100 (49.6) |
| Cmax (ng/ml) | 4,030 (29.1) | 2,960 (40.2) | 1,960 (53.3) | 5,300 (36.0) | 4860 (46.8) |
| C12 (ng/ml) | 899 (64.9) | 782 (62.4) | 416 (98.5) | 1,220 (91.6) | 1120 (80.9) |
In vitro studies have shown that saquinavir is a substrate for P-glycoprotein (P-gp).
In a cross-over study in 22 HIV-infected patients treated with Invirase/ritonavir 1,000 mg/100 mg twice daily and receiving three consecutive doses under fasting conditions or after a high-fat, high-calorie meal (46 g fat, 1,091 Kcal), the AUC0-12, Cmax and Ctrough values of saquinavir under fasting conditions were about 70 per cent lower than with a high-fat meal. All but one of the patients achieved Ctrough values of saquinavir above the therapeutic threshold (100 ng/ml) in the fasted state. There were no clinically significant differences in the pharmacokinetic profile of ritonavir in fasting and fed conditions but the ritonavir Ctrough (geometric mean 245 vs. 348 ng/ml) was lower in the fasting state compared to the administration with a meal. Invirase/ritonavir should be administered with or after food.
Saquinavir partitions extensively into the tissues. The mean steady-state volume of distribution following intravenous administration of a 12 mg dose of saquinavir was 700 l (CV 39%). It has been shown that saquinavir is approximately 97% bound to plasma proteins up to 30 µg/ml. In two patients receiving Invirase 600 mg three times daily, cerebrospinal fluid concentrations of saquinavir were negligible when compared to concentrations from matching plasma samples.
In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90% of the hepatic metabolism. Based on in vitro studies, saquinavir is rapidly metabolised to a range of mono- and di-hydroxylated inactive compounds. In a mass balance study using 600 mg 14C-saquinavir (n=8), 88% and 1% of the orally administered radioactivity, was recovered in faeces and urine, respectively, within 4 days of dosing. In an additional four subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in faeces and urine, respectively, within 4 days of dosing. 13% of circulating saquinavir in plasma was present as unchanged compound after oral administration and the remainder as metabolites. Following intravenous administration 66% of circulating saquinavir was present as unchanged compound and the remainder as metabolites, suggesting that saquinavir undergoes extensive first pass metabolism. In vitro experiments have shown that the hepatic metabolism of saquinavir becomes saturable at concentrations above 2 µg/ml.
Systemic clearance of saquinavir was high, 1.14 l/h/kg (CV 12%), slightly above the hepatic plasma flow, and constant after intravenous doses of 6, 36 and 72 mg. The mean residence time of saquinavir was 7 hours (n=8).
A gender difference was observed with females showing higher saquinavir exposure than males (AUC on average 56% higher and Cmax on average 26% higher) in the bioequivalence study comparing Invirase 500 mg film coated tablets with Invirase 200 mg hard capsules both in combination with ritonavir. There was no evidence that age and body-weight explained the gender difference in this study. Limited data from controlled clinical studies with the approved dosage regimen do not indicate a major difference in the efficacy and safety profile between men and women.
The effect of hepatic impairment on the steady state pharmacokinetics of saquinavir/ritonavir (1,000 mg/100 mg twice daily for 14 days) was investigated in 7 HIV-infected patients with moderate liver impairment (Child Pugh Grade B score 7 to 9). The study included a control group consisting of 7 HIV-infected patients with normal hepatic function matched with the hepatically impaired patients for age, gender, weight and tobacco use. The mean (% coefficient of variation in parentheses) values for saquinavir AUC0-12 and Cmax were 24.3 (102%) µg·hr/ml and 3.6 (83%) µg/ml, respectively, for HIV-infected patients with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) µg·hr/ml and 4.3 (68%) µg/ml. The geometric mean ratio (ratio of pharmacokinetic parameters in hepatically impaired patients to patients with normal liver function) (90% confidence interval) was 0.7 (0.3 to 1.6) for both AUC0-12 and Cmax, which suggests approximately 30% reduction in the pharmacokinetic exposure in patients with moderate hepatic impairment. Results are based on total concentrations (protein-bound and unbound). Concentrations unbound at steady-state were not assessed. No dosage adjustment seems warranted for patients with moderate hepatic impairment based on limited data. Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is recommended due to increased variability of the exposure in this population (see sections 4.2 and 4.4).
Steady state pharmacokinetic information is available from HIV-infected paediatric patients from study NV20911. In this study, 5 patients were <2 years and 13 between 2 to <6 years and received 50 mg/kg saquinavir bid (not to exceed 1,000 mg bid) boosted with ritonavir at 3 mg/kg for patients with body weight ranging from 5 to <15 kg or 2.5 mg/kg for patients with body weight ranging from 15 to 40 kg (not to exceed 100 mg bid). Sixteen of 18 children could not swallow Invirase hard capsules and received medication by opening the capsules and mixing the contents with different vehicles. The pharmacokinetic exposure parameters for the “High Age Group” are listed in Table 10. Results of the “Low Age Group” are not shown as data are limited due to the small size of the group.
Table 10. Pharmacokinetic parameters of saquinavir at steady-state in HIV-infected pediatric patients:
| Mean ± SD Saquinavir (%CV) Pharmacokinetic Parameters* | |||||
|---|---|---|---|---|---|
| Study | Age Group (Years) | N | AUC0-12h (ng•h/mL) | Ctrough (ng/mL) | Cmax (ng/mL) |
| NV20911 | 2 to <6 years | 13 | 38,000 ± 18,100 (48%) | 1,860 ± 1,060 (57%) | 5,570 ± 2,780 (50%) |
* All parameters normalized to a 50 mg/kg dose.
Steady state saquinavir exposures observed in paediatric trials were substantially higher than historical data in adults where dose- and exposure-dependent QTc and PR prolongation were observed (see section 4.4).
Saquinavir was well tolerated in oral acute and chronic toxicity studies in mice, rats, dogs and marmosets.
Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have shown that saquinavir has no mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells (Chinese hamster lung V79/HPRT test). Saquinavir does not induce chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis test.
There was no evidence of carcinogenic activity after the administration of saquinavir mesilate for 96 to 104 weeks to rats and mice. The plasma exposures (AUC values) in rats (maximum dose 1000 mg/kg/day) and in mice (maximum dose 2500 mg/kg/day) were lower than the expected plasma exposures obtained in humans at the recommended clinical dose of ritonavir boosted Invirase.
Fertility, peri- and postnatal development were not affected, and embryotoxic/teratogenic effects were not observed in rats or rabbits at plasma exposures lower than those achieved in humans at the recommended clinical dose of ritonavir boosted Invirase. Distribution studies in these species showed that the placental transfer of saquinavir is low (less than 5% of maternal plasma concentrations).
Cloned human cardiac potassium channel (hERG) trafficking in vitro was inhibited by 75% at 30μM of saquinavir. Saquinavir inhibited both hERG current and L-type Ca++ channel current with respective IC50 of 4.7 and 6.3 μM. In a myocardial distribution study in the rat an approximately 2-fold accumulation of saquinavir was observed in the heart compared to plasma after coadministration of saquinavir and ritonavir. The clinical relevance of these preclinical results are unknown, however cardiac conduction and repolarisation abnormalities in humans have been observed with saquinavir and ritonavir combination therapy (see section 4.4 and 5.1).
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