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Once Daily Saquinavir/r: pharmacokinetcs (drug levels) and bioequivalence of new 500 mg Invirase tablet
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Reported by Jules Levin
The pharmacokinetics of SQV/r taken as a once daily PI regimen have been evaluated and results were presented at the 9th European AIDS Conference (October 2003). Two such studies were reported at the European Conference. The aim of the studies is to compare the pharmacokinetics of the HIV protease inhibitor SQV/r in three different dose regimens – 1000/100 mg BID vs. 1600/100 mg OD vs. 2000/100 mg OD – in HIV-1 infected subjects. QD=once daily. BID=twice daily. AUC is the total drug concentration or amount in the blood over dosing period (12 or 24 hours depending if drug is taken once or twice daily). Cmin is the drug concentration in the blood at the end of the dose period. Cmax is the peak dose concentration in the blood several hours after taking the drug.
Summary. The results from the two studies are similar. On SQV/r 2000/100 mg QD mean AUC was 50% higher than for the standard 1000/100 mg BID dose; Cmin was 50% lower for the 2000/100 mg QD dose compared to the 1000/100 mg BID dose; Cmax was 130% higher for the QD 2000/100 mg dose compared to the 1000/100 mg BID dose. Central to this approach is the need to maintain PI trough concentrations above the minimum effective concentration in order to maximize ARV activity and minimize the selection of drug-resistant viruses. On the basis of pharmacokinetic (PK) studies evaluating non-boosted SQV dosing regimens, the proposed SQV MEC is 0.05 mg/l. MEC is minimum effective concentration. Cmin on day 7 of PK study for 2000/100 mg OD dose was 0.46 mg/l, and for 1000/100 mg BID dose Cmin was 1.02 mg/l. The 2000/100 QD dose is a candidate for clinical trials of QD SQV.
At EACS there was a poster reporting results from a pilot bioequivalence study comparing the current 200 mg capsule of Invirase to the new 500 mg pill. The study authors concluded the new formulation exhibits similar bioavailability to Invirase. Based on the results of this pilot study, a pivotal bioequivalence study will be performed comparing Invirase/r with SQV tablet/r. Roche is planning to use the new 500 mg tablet in the future.
Background
Currently, ritonavir-boosted saquinavir (SQV/r) is approved in Europe at a dosage of SQV/r 1000/100 mg twice daily (BID) (either Fortovase or Invirase) in combination with other antiretroviral agents. This dosage has shown clinical efficacy in both the MaxCmin1 (vs. indinavir/r) and MaxCmin2 (vs. lopinavir/r) trials.
However, since it has been shown that the favourable pharmacokinetic (PK) profile associated with SQV/r allows for once-daily (OD) dosing, a regimen of SQV/r 1600/100 mg OD in combination with at least two HIV nucleoside reverse transcriptase inhibitors (NRTIs) has been studied extensively in clinical trials. This regimen, which is widely used in Thailand, offers the convenience of both once-daily administration and a reduced pill count, and thus may improve patient adherence to therapy – a key driver of virological response to protease inhibitor treatment.
The pharmacokinetics of both SQV/r 1000/100 mg BID and 1600/100 mg OD dosing have been described before. However, a formal intrapatient comparison of these two boosted regimens has not yet been conducted. The daily SQV dose in the 1600 mg OD regimen is less than that in the 1000 mg BID regimen, possibly leading to suboptimal exposure to SQV. It is important that drug trough concentrations are maintained above the minimum effective concentration (MEC), in order to maximize antiviral activity and minimize the likelihood of drug-resistant HIV strains.
On the basis of pharmacokinetic (PK) studies evaluating non-boosted SQV dosing regimens, the proposed SQV MEC is 0.05 mg/l.
A new 500 mg formulation of SQV is currently being developed that is compatible with the SQV/r 1000/100 mg BID regimen but would necessitate a change in the once-daily dosing regimen to SQV/r 1500/100 mg or 2000/100 mg OD. An SQV/r 2000/100 mg OD regimen would standardize the daily dosing of SQV in the BID and OD regimens and would be expected to result in higher SQV plasma concentrations than the 1500/100 mg or 1600/100 mg OD regimens. With the new formulation, a reduction in daily pill count from nine pills to five pills once a day could also be achieved with this regimen.
Study Methods
This was a single-centre, open-label, pilot PK study in asymptomatic HIV-infected individuals conducted as a substudy of the STACCATO trial. Subjects had a plasma viral load below 50 copies/ml and a CD4 count of > 350 cells/mm3, and at baseline had been taking SQV/r 1600/100 mg (SQV hard gel formulation) in combination with two NRTIs for at least 4 weeks. Patients were randomized on day 1 to receive either 1000/100 mg BID or 2000/100 mg OD plus their background RTI regimen for 7 days. At the end of the study period they reverted to their original SQV/r 1600/100 mg OD regimen.
The diet (breakfast, lunch and dinner) of all subjects was standardized with no other foods allowed. SQV regimens were administered in the morning with a breakfast of approximately 500 calories (including approximately 12 grams fat).
Blood Collection and Drug Concentration Assay
On days 0 and 7, serial blood samples were drawn pre-dose, at drug intake and at 2, 4, 6, 8, 10 and 12 hours post-dose for measurement of SQV concentrations. An additional blood sample was drawn at 24 hours from those subjects randomized to the OD dosing arm. Plasma SQV and ritonavir (RTV) concentrations were measured using a validated high performance liquid chromatography assay.
Data Analysis
The SQV and RTV PK parameters that were determined included both maximum (Cmax ) and minimum (Cmin ) plasma concentration, time to Cmax (Tmax ), elimination half-life (t1/2 ) and total drug exposure, expressed as the area under the concentration–time curve (AUC0–24 or AUC0–12 ). Standard non-compartmental analyses were used to derive AUC and t1/2 for each patient over the dosing interval. PK parameters were log-transformed prior to statistical analyses. To compare treatment groups the geometric mean ratio (GMR) and associated 90% confidence interval (CI) were calculated for each PK parameter using Microsoft Excel software.
RESULTS
Twenty HIV-infected adults were enrolled in the study, with ten subjects randomized to each dosing arm. Baseline characteristics of the study participants are illustrated in Table 1.
The median plasma SQV concentration–time profiles for each of the three dosing regimens are shown in Figure 2. SQV and RTV PK parameters are summarized in Tables 2.
Table 1. Baseline Characteristics (n=20)
Age: 32
Height: 157 cm
Body weight 49.4 kg
Sex; 4 mem:16 women
Mean CD4 cell-count at screening was 383 mm3; 11/15 pts had plasma HIV-RNA<50copies/mL. No significant changes in ALT, AST, glucose, total cholesterol and triglycerides were observed.
On SQV/r 2000/100 mg QD mean AUC was 50% higher than for the standard 1000/100 mg BID dose; Cmin was 50% lower for the 2000/100 mg QD dose compared to the 1000/100 mg BID dose; Cmax was 130% higher for the QD 2000/100 mg dose compared to the 1000/100 mg BID dose. The 2000/100 QD dose is a candidate for clinical trials of QD SQV.
Table 2.
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Day 0 SQV/r |
Day 7 SQV/r |
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1600/100 QD |
2000/100 QD |
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n=10 |
n=10 |
| Cmin (mg/l) |
0.32 |
0.46 |
| AUC-0-24 (mg/l) |
53.95 |
82.00 |
| Cmax (mg/l) |
6.5 |
8.85 |
| Tmax (h) |
4.80 |
5.40 |
| T1/2 (h) |
4.68 |
4.35 |
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Day 0 SQV/r |
Day 7 SQV/r |
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1600/100 QD |
1000/100 BID |
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n=10 |
n=10 |
| Cmin (mg/l) |
0.28 |
1.02 |
| AUC-0-24 (mg/l) |
36.62 |
55.33* |
| Cmax (mg/l) |
4.09 |
3.89 |
| Tmax (h) |
5.80 |
5.20 |
| T1/2 (h) |
4.80 |
3.58 |
| *AUC-0-12 x 2 |
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Tmax for three subjects randomized to SQV/r 2000/100 mg OD increased from 4 to 6 hours, while all other subjects in this arm maintained the same Tmax observed with the1600/100 mg OD dosing (range 4 to 6 hours). In contrast, Tmax was reduced in four subjects, unchanged in five subjects and increased in one subject who switched from SQV/r 1600/100 mg OD to 1000/100 mg BID (range 4 to 8 hours).
The total daily dose of RTV administered was 100 mg for the OD regimens and 200 mg for the BID regimen. As might be expected, the BID regimen was associated with higher RTV AUC, Cmax and Cmin values than seen with the 1600 mg OD regimen.
Despite the less favorable PK parameters of the SQV/r 1600/100 mg OD dosing, subjects in this study have shown viral suppression for up to 48 weeks. If the 2000/100 mg OD dosing achieves similar tolerability to the 1600/100 mg BID dose, then both the 1000/100 mg BID and 2000/100 mg BID dosing would be expected to perform clinically as well as or better than 1600/100 mg BID. SQV/r when dosed 2000/100 mg OD or 1000/100 mg BID achieves higher SQV plasma levels compared with 1600/100 mg OD dosing.
The second study was an open-label, single arm, pilot PK study performed at a single site that enrolled 18 HIV-positive subjects receiving SQV/r 1000/100 mg BID. Three days before baseline (day 1), all subjects on other formulations of SQV were switched to SQV hard-gel (200 mg capsule)/r 1000/100 mg BID, and this SQV formulation was used throughout the study period. The drug concentration for SQV is targeted to be maintained above the minimum effective concentration (MEC; SQV MEC = 50 ng/mL), in order to maximize ARV activity and minimize the selection of drug-resistant viruses.
Subjects were given SQV/r 1000/100 mg BID with a 40 g-fat meal on day 1 and were subsequently switched to SQV/r 1600/100 mg OD on day 2 and to SQV/r 2000/100 mg OD on day 12. PIs were administered as part of a combination antiretroviral regimen containing two nucleoside/nucleotide reverse transcriptase inhibitors (RTIs). Concomitant administration of non-nucleoside RTIs was not permitted during the study period. There were 15 men. Age: 41 yrs. Average CD4 count was 362. 8 patients had <50 copies/ml HIV-RNA. For those with detectable viral load, average HIV-RNA was 646 copies/ml. plasma HIV replication. Central to this approach is the need to maintain PI trough concentrations above the minimum effective concentration (MEC; SQV MEC = 50 ng/mL), in order to maximize ARV activity and minimize the selection of drug-resistant viruses.
SQV median Ctrough
1000/100 mg bid 569 ng/mL (250-1178)
1600/100 mg QD 95 ng/mL (57-192)
2000/100 mg QD 209 ng/mL (100-529)
SQV median AUV-0-24
1000/100 mg bid 28,733 ng.h/mL (14,083-46,076)
1600/100 mg QD 17,877 ng.h/mL (12,095-34,166)
2000/100 mg QD 31,418 ng.h/mL (22,705-55,292)
Reported adverse events that were potentially dose related were mild constipation after switching to SQV/r 1600/100 mg OD (n = 1), mild abdominal pain and mild diarrhea after switching to 2000/100 mg OD (n = 2) and moderate abdominal pain and moderate diarrhea after switching to 2000/100 mg OD (n = 1). No significant changes in ALT, AST, glucose, total cholesterol or triglycerides were observed during the study period.
A once-daily dosing regimen of SQV/r 2000/100 mg OD achieved a 30% higher SQV AUC, a 136% higher SQV Cmax, but a 59% lower Ctrough than the standard 1000/100 mg BID dosage (excluding one outlying subject). One subject experienced a Ctrough value below the SQV MEC of 50 ng/mL while on this regimen. The authors said that the PKs of SQV/r 2000/100 mg OD showed that a higher drug exposure was due to increased drug absorption.
500 mg Pill of Invirase: bioequivalence study
Saquinavir (SQV), an HIV protease inhibitor, is widely used for the treatment of HIV infection. Two 200 mg formulations are currently marketed for oral administration: Invirase, a hard gelatin capsule (saquinavir mesylate); and Fortovase, a soft gelatin capsule (saquinavir base).
These formulations have shown good efficacy and safety when boosted with ritonavir (r) at a SQV/r dosage regimen of 1000/100 mg bid. Saquinavir is approved in the EU for administration as SQV/r, 1000/100 mg bid, as either the Invirase or Fortovase formulations. Ritonavir enhances the oral bioavailability of SQV by inhibiting CYP3A4-and P-gp-mediated metabolism and transport of SQV. Ritonavir also increases the activity of CYP3A4 through an inhibition- associated induction mechanism that requires repeated administration of ritonavir for 1–2 weeks to obtain a stable effect on CYP3A4 activity.
The pill count for a SQV/r regimen (1000/100 mg bid), using the current 200 mg formulation, is 12 pills per day (5 SQV capsules + 1 ritonavir capsule, bid). Roche is developing a 500 mg saquinavir mesylate tablet, using aqueous granulation technology and standard excipients, that is smaller than the existing 200 mg formulation and will allow the use of only two SQV tablets twice daily in combination with ritonavir. The lower pill count and improved convenience may improve adherence to SQV/r regimens.
A study was conducted in healthy volunteers to determine the bioavailability of the new SQV 500 mg tablet formulation (SQVtablet) relative to Invirase capsules, When both are taken with ritonavir: twenty healthy, male, non-smoking volunteers of mean age 30 years (range:19–56 years) and mean body mass index of 24 kg/m2 (range:19–29 kg/m2).
Four subjects discontinued at different time points. One due to a gastrointestinal adverse event prior to the first saquinavir administration, the others for either protocol violation or withdrawal of consent.
The study authors concluded the new formulation exhibits similar bioavailability to Invirase. The mean exposure ratio was 1.05 (90% CI, 0.94–1.17) for AUC 0–-- and 1.13 (1.00–1.26) for Cmax. Large inter-subject variability was observed in AUC 0–-- and Cmax, which is well known for saquinavir and related to the effect of CYP3A4 and P-gp on its absorption. Contrary to previous observations, however, intra-subject variability was moderate with an estimated CV of about 25%.
Based on the promising results of this pilot study, a pivotal bioequivalence study will be performed comparing Invirase/r with SQV tablet/r. The effectiveness of antiretroviral therapy is closely related to adherence, which is driven by the convenience and tolerability of the regimen.
The smaller size and reduced pill count for the new 500 mg tablet - 6 pills daily in total for bid dosing of 1000 mg with 100 mg ritonavir, versus 12 for the 200 mg formulations, could improve treatment success through encouraging better adherence.
The new saquinavir 500 mg tablet could replace both the existing Invirase and Fortovase 200 mg capsules.
Roche is developing a new saquinavir 500 mg tablet formulation which shows similar bioavailability to the Invirase 200 mg capsule formulation when dosed at 1000/100 mg in combination with ritonavir.
References 9th EACS, Oct 2003, Warsaw, Poland. Poster. SAQUINAVIR 500 MG TABLET, A NEW FORMULATION, HAS SIMILAR BIOAVAILABILITY TO INVIRASE 200 MG CAPSULE FOR HEALTHY VOLUNTEERS AT 1000/100 MG BID DOSING WITH RITONAVIR. Y.Hijazi1,M.Riek1,E.Gaudeul-Ehrhart2 and S.Grange. 1 Roche, Basel, Switzerland; 2 Clinical Pharmacology Unit of Roche, Strasbourg, France Youssef.
9th EACS, October 2003, Warsaw, Poland. Oral Abstract. SAQUINAVIR/RITONAVIR (SQV/r) PHARMACOKINETICS (PKs) IN HIV+ SUBJECTS: 1000/100 MG BID VS 1600/100 AND 2000/100 MG ONCE DAILY (OD). Marta Boffito1, Laura Dickinson2, Andrew Hill3, Chris Higgs1, Carl Fletcher1, Cameron Johnson1, Sundhiya Mandalia1, David Back2, Brian Gazzard1 and Anton Pozniak1. 1 Chelsea and Westminster Hospital, London, UK;2 University of Liverpool, Liverpool, UK; 3 Roche, Welwyn, UK
9th EACS, October 2003, Warsaw, Poland. Poster. Pharmacokinetics (PK) Study of Saquinavir Hard Gel Caps/Ritonavir (SQV-HGC/RTV) in HIV-1 Infected Patients: 1600/100 mg OD Compared To 2000/100 Mg OD and 1000/100 Mg BID. Autar RS, Ananworanich J, Apasteerapong W, Sankote J, Hill A, Hirschel B, Cooper D, Lange J, Phanuphak P, Ruxrungtham K, Burger D. The HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration; The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; International Antiviral Therapy Evaluation Center, Amsterdam, The Netherlands; Roche, London, UK; Geneva University Hospital, Geneva, Switzerland; National Center in HIV Epidemiology and Clinical Research, University ofNew South Wales, Sydney, Australia; University Medical Center, Nijmegan, the Netherlands.
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