Efficacy, safety and pharmacokinetic of once-daily boosted saquinavir (1500/100 mg) together with 2 nucleos(t)ide reverse transcriptase inhibitors in real life: a multicentre prospective study
© López-Cortés et al; licensee BioMed Central Ltd. 2010
Received: 5 February 2010
Accepted: 17 March 2010
Published: 17 March 2010
Ritonavir-boosted saquinavir (SQVr) is nowadays regarded as an alternative antiretroviral drug probably due to several drawbacks, such as its high pill burden, twice daily dosing and the requirement of 200 mg ritonavir when given at the current standard 1000/100 mg bid dosing. Several once-daily SQVr dosing schemes have been studied with the 200 mg SQV old formulations, trying to overcome some of these disadvantages. SQV 500 mg strength tablets became available at the end of 2005, thus facilitating a once-daily regimen with fewer pills, although there is very limited experience with this formulation yet.
Prospective, multicentre study in which efficacy, safety and pharmacokinetics of a regimen of once-daily SQVr 1500/100 mg plus 2 NRTIs were evaluated under routine clinical care conditions in either antiretroviral-naïve patients or in those with no previous history of antiretroviral treatments and/or genotypic resistance tests suggesting SQV resistance. Plasma SQV trough levels were measured by HPLV-UV.
Five hundred and fourteen caucasian patients were included (47.2% coinfected with hepatitis C and/or B virus; 7.8% with cirrhosis). Efficacy at 52 weeks (plasma RNA-HIV <50 copies/ml) was 67.7% (CI95: 63.6 - 71.7%) by intention-to-treat, and 92.2% (CI95: 89.8 - 94.6%) by on-treatment analysis. The reasons for failure were: dropout or loss to follow-up (18.4%), virological failure (7.8%), adverse events (3.1%), and other reasons (4.6%). The high rate of dropout may be explained by an enrollement and follow-up under routine clinical care condition, and a population with a significant number of drug users. The median SQV Cmin (n = 49) was 295 ng/ml (range, 53-2172). The only variable associated with virological failure in the multivariate analysis was adherence (OR: 3.36; CI95, 1.51-7.46, p = 0.003).
Our results suggests that SQVr (1500/100 mg) once-daily plus 2 NRTIs is an effective regimen, without severe clinical adverse events or hepatotoxicity, scarce lipid changes, and no interactions with methadone. All these factors and its once-daily administration suggest this regimen as an appropriate option in patients with no SQV resistance-associated mutations.
Saquinavir was the first protease inhibitor (PI) commercially available for the treatment of patients with HIV infection. Its oral bioavailability is markedly increased when concomitantly administered with low dose retainer, which allows for reduced dosing frequency and dosage. Ritonavir-boosted saquinavir (SQVr) at the standard dosing of 1000/100 mg twice daily has shown as effective as ritonavir-boosted-lopinavir, although requiring a higher pill burden when prescribed as the 200 mg hard or soft-gel capsules, which frequently leads to a bad compliance and high rates of therapy discontinuation [1, 2]. In several guidelines for the treatment of HIV-1-infected patients, SQVr has remained as an alternative antiretroviral drug, probably due to its high daily pill burden, twice daily dosing and the requirement of 200 mg per day of ritonavir when given at the currently recommended dose [3, 4]. On the other hand, several once-daily SQVr dosing schemes have been studied with these classic formulations, being 1600/100 mg/day the most frequently assessed regimen [5–8], but lower doses have also been tested, such as 1200/100 mg once-daily, with a favorable pharmacokinetic profile and clinical results [9–11].
SQV 500 mg strength tablets became available at the end of 2005. This formulation would facilitate a once-daily regimen (1500/100 mg) with fewer pills, although the experience with this dosage is still very scarce .
The aim of the present study was to assess the efficacy, safety and pharmacokinetics of once-daily SQVr 1500/100 mg plus 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in antiretroviral-naive patients or in those with no previous antiretroviral treatment history and/or genotypic resistance tests suggesting SQV resistance, under routine clinical care conditions.
Baseline patients' characteristics
A total of 518 patients started a regimen of SQVr (1500/100 mg qd) plus 2 NRTIs at the mentioned centres during the mentioned period. One hundred and twenty patients (naïve, 14; experienced, 106) had a genotypic resistance test available just before starting SQVr. Four experienced patients had HIV protease mutations associated with SQV resistance (L90M) and were excluded from further analysis. Among the remaining cases, 33 (27.5%) had wild-type isolates, and 71 (59.1%) had resistance mutations in the reverse transcriptase (TAMs in 29 patients with a median (range) of 2 (1 -5); the K65R mutation was present in 5, the L74V in 6, and the M184I/V in 44; other mutations which confer resistance to non-nucleoside reverse transcriptase inhibitors was observed in 53 patients). Sixty eight patients had PI-related mutations, either minor mutations or polymorphism in most cases. One minor SQV-related mutation was present in 16 cases (L10I/V or I54V or I62V or A71T/V or V77I), and 3 minor resistance mutations (L10V, I62V and V77I) in 1 case. Genotypic resistance tests were not available in the rest of the patients, since amplification was not possible in cases with a VL <1000 copies/ml, or the test had not been requested in cases of treatment interruption for a long period, so that it was not expected to add relevant data.
Patients' characteristics at inclusion (n = 514).
n = 50
n = 80
n = 81
n = 303
39 (20 - 51)
41 (32 - 66)
41 (25 - 75)
41 (23 - 75)
68 (50 - 102)
64 (42 - 98.5)
65.5 (36 - 111)
65.9 (39 - 121)
Risk factor for HIV
IV drug use
Blood products transfusion
Active illegal drug use
140 (4 - 563)
227 (4 - 546)
277 (14 - 923)
475 (27 - 1196)
HIV-RNA log10 cop./ml
< 1.69 (< 1.69-2.45)
Clinical category C
152 (4 - 417)
120 (1 - 476)
120 (1 - 815)
130 (1 - 825)
Previous ART (months)
46 (1 - 164)
38 (1 -192)
71 (1 - 269)
TDF + FTC
ABV + 3TC
ddI + 3TC
Chronic viral hepatitis
HCV + HVB
Virological and immunological response
Genotypic resistance tests at failure according to treatment groups.
ABV + 3TC
TDF + FTC
TDF + FTC
L63P, M46I, F53L
ABV + 3TC
TDF + ddI
AZT + ddI
TDF + FTC
K70R, T215F, 219Q
ZDV + TDF
M41L, D67N, K70R, L210W, T215Y
E35D, M36I, F53L, D60E, L63P, A71V, I84V
ZDV + TDF
Adverse events during the follow-up.
Clinical adverse events
Nausea or vomiting and/or abdominal discomfort
Laboratory adverse events
AST or ALT increase (grade 2-4)
SCr elevation (grade 1)
Anemia and thrombocytopenia
Lipid levels throughout the follow-up.
(n = 514)
(n = 433)
(n = 388)
(n = 352)
(n = 355)
Total cholesterol, mg/dl
Individuals with ≥ 240 mg/dl
LDL cholesterol, mg/dl
Individuals with ≥ 160 mg/dl
Total triglycerides, mg/dl
Individuals with ≥ 200 mg/dl
Individuals with ≥ 400 mg/dl
Naive and ART-restarting patients (groups A and B)
(n = 130)
(n = 102)
(n = 87)
(n = 79)
(n = 69)
Total cholesterol, mg/dl
Individuals with ≥ 240 mg/dl
LDL cholesterol, mg/dl
Individuals with ≥ 160 mg/dl
Total triglycerides, mg/dl
Individuals with ≥ 200 mg/dl
Individuals with ≥ 400 mg/dl
Plasma Saquinavir levels
SQV trough levels were available in 49 patients (41 M, 8 F) weighing a median of 65.5 kg (range, 44 - 98.5). Twenty four (49%) of them were affected by viral chronic hepatitis and 9 (18.3%) by cirrhosis. The median SQV trough level was 295 ng/ml (range, 53 - 2172); four patients (8.1%) had values under 100 ng/ml, and 3 of them had a satisfactory virological response. No correlations were found between SQV levels and either weight, gender or the presence of chronic hepatitis and/or cirrhosis.
Although the approved dosage of SQVr is 1000/100 mg twice daily, several once-daily schemes (1200/100, 1600/100 and 2000/100 mg/day) plus 2 NRTIs have demonstrated a good virological efficacy in patients with no SQV resistance mutations [5–11]. From a pharmacokinetic point of view, once-daily SQVr 1500/100 mg yielded SQV trough levels similar to those observed with a dose of 1600/100 mg daily [14–20], exceeding both the IC95 value (25 ng/ml) for wild HIV-1 isolates and the estimated trough level required to obtain the half-maximal antiviral response (EC50: 50 ng/ml) . In our study, SQV trough levels in plasma were similar between patients with and without chronic viral hepatitis or cirrhosis, as previously reported in the absence of liver function impairment . Four out of 49 sampled patients had a SQV C min below 100 ng/ml, and 3 of them had a satisfactory virological response. Although 100 ng/ml is suggested as the minimum target trough concentration for wild-type HIV-1 , this value has not been corroborated yet in clinical trials, especially in the presence of other drugs with activity against HIV. Moreover, SQV has been demonstrated to accumulate in peripheral mononuclear blood cells in vivo, resulting in a median intracellular drug accumulation ratio of 2.75-3 as compared with that in plasma, suggesting that intracellular exposure to SQV may be a better predictor of the virological response to therapy . Thus, our pharmacokinetic data support the 1500/100 mg qd dose as adequate for patients without SQV resistance mutations.
The efficacy in the ITT analysis in our series (65.7%) is similar to that observed in the MaxCmin2 trial and in the Gemini study with a 1000/100 bid SQVr dosing [1, 2], although with a higher failure rate due to dropout, loss to follow-up or other causes not related with the antiretroviral regimen itself, but mainly explained by the fact that patients were enrolled and followed up under routine clinical care conditions, without the selection criteria used in clinical trials, and with a significant number of drug users, a population known to be particularly non-adherent. Actually, many of them had previously discontinued other antiretroviral treatments. The virological failure rate observed was just 8.5%, being adherence the only variable related in the multivariate analysis. In the OT analysis, the efficacy raised to 90.4%, with similar results regardless of baseline VL and CD4 counts. The presence of more adherent patients in the "simplification" group may be the cause of the higher efficacy observed in these patients. Although the efficacy of a once daily dosing of SQV/r has mainly been shown to be effective in an Asian population whom in general have lower body weight, our results show convincing data that in Caucasians with higher body weight, the once daily dosing has also good efficacy.
Evaluation of the available genotypic tests from patients with virological failure revealed a low incidence of selection of protease inhibitors major/minor resistance mutations following treatment with SQV/r, which is consistent with previous observations made for boosted protease inhibitors, mainly in naive patients (3).
The combination of once-daily SQVr was well tolerated during the 52-week follow-up, with no clinical grade 3 or 4 adverse events recorded. Only 12 patients (3.0%) changed their regimen because of AEs. Although lypodystrophy occurred in 6 patients after switching treatment to SQVr, this may reflect long-term antiretroviral drug exposure rather than an effect caused only by this regimen, since 5 out of 6 patients belonged to the "simplification"group, and the remaining one to the ART-restart group. Particularly meaningful are the results regarding liver toxicity in a population with 58.7% of the patients presenting chronic hepatitis (VHC: 95,5%), 10,7% of them being cirrhotic. Among patients with and without chronic hepatitis and/or cirrhosis, only 1 (0.6%) and 13 cases (5.4%), respectively, developed grade 3-4 transaminase increases. Moreover, none of these cases was symptomatic, and the alterations observed were transient and improved without treatment discontinuation in every case, which may indicate that much of these elevations could be due to the natural evolution of chronic hepatitis and/or cirrhosis rather than caused by the treatment. Also, it is remarkable that patients receiving this regimen showed no changes, or just negligible increases, in the levels of total cholesterol, LDL cholesterol, and triglycerides.
We are aware that the open-label characteristics of the study, the heterogeneity of the analyzed population and the lack of available genotypic resistance tests in some of the patients at baseline and after virological failure are limitations of our study, although they reflect the real-life clinical setting.
This open-label multicentre study suggests that SQVr (1500/100 mg) once-daily plus 2 NRTIs is an effective regimen, without severe clinical adverse events or hepatotoxicity, scarce lipid changes, and no interactions with methadone. All these factors and its once-daily administration make this regimen make this regimen worth to be considered as an alternative in patients with no SQV resistance-associated mutations. In addition, the 1500/100 mg qd dosage is one of the cheapest PI combinations and, given that the patent will soon expire, a more affordable generic formulation would then be available, making it possible a more extended use of this drug.
Study Population and design
From November 2005 to May 2007, HIV-1 infected patients older than 18 years attended at the HIV clinics in 17 hospitals from Andalusia, Ceuta and Extremadura (Spain), and scheduled to receive a regimen of SQVr 1500/100 mg once-daily plus 2 NRTIs, were consecutively enrolled in this observational, prospective, single-arm, open-label study. NRTIs prescribed as part of HAART were selected by the responsible physicians on the basis of previous antiretroviral treatments (ART) and/or genotypic resistance testing. Patients were enrolled and followed-up under routine clinical care conditions, and no entry restrictions were made except for pregnancy, history of previous ART and/or genotypic resistance tests suggesting resistance to SQV according to the 2005 International AIDS Society , and the concomitant use of drugs with potential adverse interactions with SQV pharmacokinetics, such as rifampin. Patients who received pegylated interferon-alpha plus ribavirin for chronic hepatitis C during their follow-up were excluded hereinafter from CD4 cell counts changes analysis since this treatment usually modifies the hematologic profiles and CD4 cell counts. Patients were initially classified according to previous ART in the following groups: A) antiretroviral-naïve patients, B) patients who restarted ART after a temporary dropping out or lost to follow-up, C) patients with virological failure to a preceding protease inhibitor (PI)- or non-nucleoside reverse transcriptase inhibitors (NNRTI)-based regimen, and D) those with an undetectable viral load who simplified a PI-based regimen to an once-daily regimen or had toxicity to a previous regimen based on PIs or NNRTIs. The study was approved by the Regional Ethics Committee for Clinical Research of the Community of Andalusia, and conducted according to the principles contained in the Declaration of Helsinki. All patients gave an informed consent. The patients' inclusion was censored in May 2007 to allow a minimum of 12 months of follow-up.
Follow-up, assessments and endpoints
Patients' assessment was performed at baseline, after the first month on treatment and every three months thereafter, including adverse effects (AEs), biochemical and hematologic profiles, flow cytometric count of CD4/μl and plasma HIV-1-RNA (VL) measured by polymerase chain reaction (lower detection limit: 50 copies/ml. Amplicor HIV-1 Monitor test version 1.0; Roche Diagnostic Systems). Adherence was evaluated by personal interview at each following visit. Efficacy at 52 weeks, analyzed by intention-to-treat (ITT), was the primary clinical endpoint. Virological failure was defined as inability to suppress plasma VL to <50 copies/ml after 24 weeks on treatment, or a confirmed viral load >200 copies/ml in patients who had previously achieved a viral suppression or had an undetectable viral load at inclusion. If confirmed, the time of the first measurement meeting the failure criteria was selected as the time of failure. Secondary outcomes included virological efficacy according to on-treatment (OT) analysis, changes in CD4 cell counts, incidence of AEs and lipid profiles. The changes in serum ALT and AST from pre-treatment levels to the highest level during treatment were categorized via a standardized toxicity grade scale, modified from that used by the AIDS Clinical Trials Group. Patients with pre-treatment serum AST and ALT levels within normal range (AST <35 IU/L and ALT <31 IU/L) were classified according to the changes observed with respect to the upper limit of normal (ULN): grade 0 (<1.25 ULN); grade 1 (1.25-2.5 × ULN); grade 2 (2.6-5 × ULN); grade 3 (5.1-10 × ULN); and grade 4 (>10 × ULN). In patients with chronic viral hepatitis or cirrhosis, toxicity was classified according to changes relative to baseline values rather than ULN: grade 0 (<1.25 × baseline); grade 1 (1.25-2.5 × baseline); grade 2 (2.6-3.5 × baseline); grade 3 (3.6-5 × baseline); and grade 4 (>5 × baseline). Genotypic resistance tests were performed in patients with virological failure whenever viral load levels allowed. Patients missing two consecutive scheduled visits were considered lost to follow-up.
Blood sampling and determination of saquinavir concentrations
Blood samples for SQV plasma levels were obtained 24 ± 0.3 hours post-dose, after at least one month on treatment, from random patients who usually took SQVr in the morning and who were included in the study at Hospitales Universitarios Virgen del Rocío. Plasma samples were stored frozen at -80°C for determination of SQV by high-performance liquid chromatographic assay according to a validated method .
Descriptive statistic was used for demographic, epidemiological and clinical data, prior ARTs, CD4 cell count, viral load and SQV trough concentrations. Kaplan-Meier plots were produced for the 'time to event' analyses and comparisons among the 3 treatment groups were made using the log-rank test. The relationships between virological failure and different variables were assessed by the chi-square test for qualitative variables and by the Spearman's rank-correlation coefficients for quantitative variables. The variables tested by univariate analysis as predictors of virological failure with a p value <0.1 were included in a multivariate analysis to identify possible independent predictors of virological failure. Statistical calculations were performed with the Statistical Product and Service Solutions for Windows (15.0 version, SPSS, Chicago, IL).
We are indebted to Ana Marin-Niebla, MD, for her assistance with the English version of the manuscript, and to Magdalena Rodriguez and Rosario Pascual for specimen processing. We also thank the patients who participated in this study. The determination of saquinavir concentrations has been supported by unrestricted research funds by Roche S.A. (Spain) without participating in the collection, analysis, or interpretation of the data.
In addition to the authors, other contributing members of the SQV1500 QD study group were as follows: Miguel A. López-Ruz, Hospital Universitario Virgen de las Nieves, Granada; Ma José Rios, Juan Gálvez and Jesús Rodríguez, Hospital Universitario Virgen Macarena, Sevilla; Leopoldo Muñoz, Rafael del Castillo, Antonia Martínez, Jorge Parra, and José Hernández-Quero, Hospital Universitario San Cecílio, Granada; José J. Hernández-Burruezo, Hospital Ciudad de Jaén, Jaén; Ignacio Suáarez, Hospital Infanta Elena, Huelva; Eugenio Pérez-Guzmán, Hospital Universitario Puerta del Mar, Cádiz; Carlos Martín, Hospital San Pedro de Alcántara, Cáceres; Manuel Leal, Hospitales Universitarios Virgen del Rocío, Sevilla; Antonio Collado, Hospital Torrecárdenas, Almeria; Juan A. Pineda, Hospital Universitario de Valme, Sevilla.
- Dragsted UB, Gerstoft J, Youle M, Fox Z, Losso M, Benetucci J, Jayaweera DT, Rieger A, Bruun JN, Castagna A, Gazzard B, Walmsley S, Hill A, Lundgren JD, MaxCmin2 Trial Group: A randomized trial to evaluate lopinavir/ritonavir versus saquinavir/ritonavir in HIV-1-infected patients: the MaxCmin2 trial. Antivir Ther. 2005, 10: 735-743.PubMedGoogle Scholar
- Walmsley S, Avihingsanon A, Slim J, Ward DJ, Ruxrungtham K, Brunetta J, Bredeek UF, Jayaweera D, Guittari CJ, Larson P, Schutz M, Raffi F: Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir Immune Defic Syndr. 2009, 50: 367-374. 10.1097/QAI.0b013e318198a815View ArticlePubMedGoogle Scholar
- Roche Pharmaceuticals Invirase Prescribing Information, July. Accessed: 20 Jan 2010.http://www.rocheusa.com/products/invirase/pi.pdf
- Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2009, 1-161. Accessed: 15 Jan 2010.http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdfGoogle Scholar
- Lamotte C, Landman R, Peytavin G, Mentre F, Gerbe J, Brun-Vezinet F, Boue F, Spiridon G, Valantin MA, Michelet C, Farinotti R, Yeni P: Once-daily dosing of saquinavir soft-gel capsules and ritonavir combination in HIV-1-infected patients (IMEA015 study). Antivir Ther. 2004, 9: 247-256.PubMedGoogle Scholar
- Cardiello P, Srasuebkul P, Hassink E, Mahanontharit A, Samor T, Ruxrungtham K, Lange J, Cooper D, Phanuphak P: The 48-week efficacy of once-daily saquinavir/ritonavir in patients with undetectable viral load after 3 years of antiretroviral therapy. HIV Med. 2005, 6: 122-128. 10.1111/j.1468-1293.2005.00274.xView ArticlePubMedGoogle Scholar
- Ananworanich J, Gayet-Ageron A, Ruxrungtham K, Chetchotisakd P, Prasithsirikul W, Kiertiburanakul S, Munsakul W, Raksakulkarn P, Tansuphasawadikul S, LeBraz M, Jupimai T, Ubolyam S, Schutz M, Hirschel B, Staccato Thailand Study Group: Long-term efficacy and safety of first-line therapy with once-daily saquinavir/ritonavir. Antivir Ther. 2008, 13: 375-380.PubMedGoogle Scholar
- Montaner JS, Schutz M, Schwartz R, Jayaweera DT, Burnside AF, Walmsley S, Saag MS: Efficacy, safety and pharmacokinetics of once-daily saquinavir soft-gelatin capsule/ritonavir in antiretroviral-naive, HIV-infected patients. MedGenMed. 2006, 8: 36-PubMed CentralPubMedGoogle Scholar
- López-Cortés LF, Ruiz-Valderas R, Viciana P, Mata R, Gómez-Vera J, Alarcón A, Pachón J: Once-daily saquinavir-sgc plus low-dose ritonavir (1200/100 mg) in combination with efavirenz: pharmacokinetics and efficacy in HIV-infected patients with prior antiretroviral therapy. J Acquir Immune Defic Syndr. 2003, 32: 240-2.View ArticlePubMedGoogle Scholar
- Marin-Niebla A, Lopez-Cortes LF, Ruiz-Valderas R, Viciana P, Mata R, Gutierrez A, Pascual R, Rodriguez M: Clinical and pharmacokinetic data support once-daily low-dose boosted saquinavir (1200 milligrams saquinavir with 100 milligrams ritonavir) in treatment-naive or limited protease inhibitor-experienced human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2007, 51: 2035-2042. 10.1128/AAC.01136-06PubMed CentralView ArticlePubMedGoogle Scholar
- Lopez-Cortes LF, Ruiz-Valderas R, Rivero A, Camacho A, Marquez-Solero M, Santos J, García-Lazaro M, Viciana P, Rodriguez-Baños J, Ocampo A: Efficacy of low-dose boosted saquinavir once daily plus nucleoside reverse transcriptase inhibitors in pregnant HIV-1-infected women with a therapeutic drug monitoring strategy. Ther Drug Monit. 2007, 29: 171-176. 10.1097/FTD.0b013e31803bb54eView ArticlePubMedGoogle Scholar
- Knechten H, Stephan C, Lutz T, Stoehr A, Carganico A, Knecht G, Schewe K, Jaeger H, Mayr C, Mosthaf FA, Wolf E, Wellmann E, Tappe A: The Rainbow Cohort: saquinavir/r is effective and well tolerated in antiretroviral therapy (ART)-naïve patients - 48-week results from Germany. J Int AIDS Soc. 2008, 11 (Suppl 1): P13-10.1186/1758-2652-11-S1-P13.View ArticleGoogle Scholar
- Johnson VA, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, Pillay D, Schapiro JM, Telenti A, Richman DD: Update of the drug resistance mutations in HIV-1: Fall 2005. Top HIV Med. 2005, 13: 125-131.PubMedGoogle Scholar
- Kurowski M, Müller M, Donath F, Mrozikiewicz M, Möcklinghoff C: Single daily doses of saquinavir achieve HIV-inhibitory concentrations when combined with baby-dose ritonavir. Eur J Med Res. 1999, 4: 101-104.PubMedGoogle Scholar
- van Heeswijk RP, Veldkamp AI, Mulder JW, Meenhorst PL, Lange JM, Beijnen JH, Hoetelmans RM: Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study. AIDS. 2000, 14: F103-110. 10.1097/00002030-200006160-00003View ArticlePubMedGoogle Scholar
- Kilby JM, Sfakianos G, Gizzi N, Siemon-Hryczyk P, Ehrensing E, Oo C, Buss N, Saag MS: Safety and pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus minidose ritonavir in human immunodeficiency virus-negative adults. Antimicrob Agents Chemother. 2000, 44: 2672-2678. 10.1128/AAC.44.10.2672-2678.2000PubMed CentralView ArticlePubMedGoogle Scholar
- Cardiello PG, Monhaphol T, Mahanontharit A, van Heeswijk RP, Burger D, Hill A, Ruxrungtham K, Lange JM, Cooper DA, Phanuphak P: Pharmacokinetics of once-daily saquinavir hard-gelatin capsules and saquinavir soft-gelatin capsules boosted with ritonavir in HIV-1-infected subjects. J Acquir Immune Defic Syndr. 2003, 32: 375-379. 10.1097/00126334-200304010-00005View ArticlePubMedGoogle Scholar
- Boffito M, Dickinson L, Hill A, Back D, Moyle G, Nelson M, Higgs C, Fletcher C, Gazzard B, Pozniak A: Pharmacokinetics of once-daily saquinavir/ritonavir in HIV-infected subjects: comparison with the standard twice-daily regimen. Antivir Ther. 2004, 9: 423-429.PubMedGoogle Scholar
- Autar RS, Ananworanich J, Apateerapong W, Sankote J, Hill A, Hirschel B, Cooper D, Lange J, Phanuphak P, Ruxrungtham K, Burger D: Pharmacokinetic study of saquinavir hard gel caps/ritonavir in HIV-1-infected patients: 1600/100 mg once-daily compared with 2000/100 mg once-daily and 1000/100 mg twice-daily. J Antimicrob Chemother. 2004, 54: 785-790. 10.1093/jac/dkh415View ArticlePubMedGoogle Scholar
- Ford J, Boffito M, Wildfire A, Hill A, Back D, Khoo S, Nelson M, Moyle G, Gazzard B, Pozniak A: Intracellular and plasma pharmacokinetics of saquinavir-ritonavir, administered at 1600/100 milligrams once daily in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2004, 48: 2388-2393. 10.1128/AAC.48.7.2388-2393.2004PubMed CentralView ArticlePubMedGoogle Scholar
- Gieschke R, Fotteler B, Buss N, Steimer JL: Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients. Clin Pharmacokinet. 1999, 37: 75-86. 10.2165/00003088-199937010-00005View ArticlePubMedGoogle Scholar
- Moltó J, Llibre JM, Ribera E, Mínguez C, del Río JS, Pedrol E, Vallecillo G, Cedeño S, Valle M, Miranda C, Negredo E, Clotet B, SQV-HEP Study Group: Saquinavir exposure in HIV-infected patients with chronic viral hepatitis. Antimicrob Chemother. 2009, 63: 992-7. 10.1093/jac/dkp070.View ArticleGoogle Scholar
- Shelton MJ, Cloen D, DiFrancesco R, Berenson CS, Esch A, de Caprariis PJ, Palic B, Schur JL, Buggé CJ, Ljungqvist A, Espinosa O, Hewitt RG: The effects of once-daily saquinavir/minidose ritonavir on the pharmacokinetics of methadone. J Clin Pharmacol. 2004, 44: 293-304. 10.1177/0091270003262956View ArticlePubMedGoogle Scholar
- Jamois C, Smith P, Morrison R, Riek M, Patel A, Schmitt C, Morcos PN, Zhang X: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. Addict Biol. 2009, 14: 321-7. 10.1111/j.1369-1600.2009.00158.xView ArticlePubMedGoogle Scholar
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