Clinical Science: Concise Communication
Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir
Stephan, Christopha; Hentig, Nils vb; Kourbeti, Irenea; Dauer, Brendaa; Mösch, Manfreda; Lutz, Thomasa; Klauke, Stephana; Harder, Sebastianb; Kurowski, Michaelc; Staszewski, Schlomoa
From the aDivision of Infectious Disease, and bInstitute of Clinical Pharmacology, Pharma Center, J.W. Goethe University Hospital, Frankfurt, Germany; and cHIV-LAB, c/o Auguste-Viktoria Hospital, Berlin, Germany.
Correspondence to Dr Christoph Stephan, Uniklinik Frankfurt, Med. Klinik III, Infektionsambulanz Haus 68, I.OG, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Received: 16 April 2003; revised: 11 August 2003; accepted: 14 July 2003.
Objective: To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir.
Design: Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed.
Methods: Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography–tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated.
Results: Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). Lopinavir levels were similar to historical data.
Conclusion: Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir. This boosted double PI combination could be an effective option for patients with limited RTI options.
The clinical efficacy of highly active antiretroviral therapy including protease inhibitors (PI) has been demonstrated by the decrease in morbidity and mortality in HIV-positive individuals. Most currently available PI are characterized by pharmacokinetic limitations such as modest oral bioavailability, food or fluid-dependent dosing, high protein binding and considerable first-pass metabolism, resulting in a short plasma half-life and variable drug concentrations [1,2]. The result is multiple daily doses and a high pill burden, which can lead to poor regimen adherence and the emergence of resistant HIV strains.
The administration of low-dose ritonavir as a booster agent has become the standard of care to overcome these pharmacokinetic limitations . Currently available PI are metabolized by cytochrome P450 isoenzymes, mainly by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6 . Ritonavir primarily inhibits the metabolism of drugs by CYP3A4 and to a lesser extent by CYP2D6 . For PI that are characterized by a high first-pass metabolism such as saquinavir and lopinavir the booster effect of low-dose ritonavir is principally caused by an elevation of both maximum and minimum plasma concentrations (Cmax and Cmin). For other drugs such as indinavir the predominant effect of low-dose ritonavir is a prolongation of the half-life (t½) and a Cmin increase .
The benefit of using two PI in ‘salvage’ therapy has recently been demonstrated [1,4]. However, there is limited experience with ritonavir-boosted double PI regimens. Because of both the induction and inhibition of the cytocrome P450 system, the interaction potential among three PI is hard to predict, and pharmacokinetic investigations are needed. As in-vitro studies have suggested a synergistic inhibition of HIV-1 replication by the combination of saquinavir and lopinavir , we set up a clinical study to investigate the outcome of a combination containing the boosted double PI lopinavir/ritonavir and saquinavir in a cohort of patients with limited reverse transcriptase inhibitor (RTI) treatment options. In this paper we report on the pharmacokinetic results of this regimen.
Patients and methods
This study was performed as part of a clinical investigation of boosted double PI treatment that took place in the Frankfurt HIV cohort from October 2001 to September 2002 . Patients with any CD4 cell count and limited RTI options because of resistance or toxicity gave verbal consent to be treated with lopinavir/ritonavir (400/100 mg twice a day) and saquinavir soft-gel capsule (1000 mg twice a day) without any other antiretroviral agents (LOPSAQ group). A group of predominantly antiretroviral treatment-naive individuals with advanced HIV disease served as controls (the RITSAQ group). These patients received ritonavir (100 mg twice a day) plus saquinavir soft-gel capsules (1000 mg twice a day) in combination with two or three nucleoside reverse transcriptase inhibitors (NRTI).
For both groups a pharmacokinetic assessment of the PI was performed in steady-state conditions after at least 2 weeks of stable treatment. Before this, liver function tests were performed as part of the routine treatment. The patients were instructed to document all antiretroviral drugs and all concomitant medications ingested in a diary for 3 days before the pharmacokinetic assessment day. On the day of the assessment fasting trough levels were obtained immediately before the morning dose. This was followed by a standard continental breakfast, without any citrus fruits. Plasma samples were collected at 1, 2, 4, 6, 9 and 12 h after the morning dose.
The individual plasma levels of saquinavir, lopinavir and ritonavir were determined by liquid chromatography–tandem mass spectrometry . The lower limit of quantification was 0.5–2 ng/ml; linearity was proved up to 20–30 μg/ml. All pharmacokinetic calculations were based on plasma concentrations that were above the lower limit of quantification. In this analysis Cmin and Cmax represent the lowest and the highest plasma drug concentrations observed over the standard 12-h dosing interval and were read directly from the plasma concentration time curves of lopinavir, saquinavir and ritonavir. The area under the curve (AUC) represents the area under the concentration time curve at steady-state conditions over the standard 12-h dosing interval according to the logarithmic trapezoidal rule. The total clearance of saquinavir and ritonavir was determined by the formula:
Equation (Uncited)Image Tools
The main objective was to compare Cmin, Cmax and AUC of the PI saquinavir and ritonavir between the LOPSAQ and the RITSAQ groups (double-boosted versus single PI), using the Mann–Whitney U-test, including the Moses confidence interval and the Hodges–Lehmann point estimator for the absolute difference between the groups. All statistical analyses were carried out using BIAS 7.06 (BIAS for Windows; epsilonVerlag, Hochheim, Darmstadt, Germany) .
Data from 45 patients in the LOPSAQ group and 32 patients in the RITSAQ group were analysed. The demographics and characteristics at the time of the pharmacokinetic assessment were comparable between the two groups. The majority of patients were male (86.7% LOPSAQ group, 84.4% RITSAQ group) Caucasians (97.8% LOPSAQ group, 87.5% RITSAQ group). The median age was 42 years in both groups and the median body mass index was 24.3 in the LOPSAQ group and 22.8 in the RITSAQ group. A minority of patients were hepatitis B or C positive (11.1% LOPSAQ group, 6.3% RITSAQ group). Patients in the RITSAQ group had lower plasma viral loads (median 1.5 log10 HIV-1-RNA copies/ml) than patients in the LOPSAQ group (median 2.7 log10 HIV-1-RNA copies/ml) but were at a more advanced Centers for Disease Control and Prevention stage of HIV disease and had a lower median CD4 cell count (168 versus 274 cells/μl). The median number of previous antiretroviral treatments received by patients in the LOPSAQ group was nine (range one to 17). In the RITSAQ group only nine patients (28%) were treatment-experienced (with between two and nine previous antiretroviral regime). The concomitant NRTI in the RITSAQ group included lamivudine (n = 31), zidovudine (n = 27), abacavir (n = 11), didanosine (n = 3) and stavudine (n = 2). With regard to other concomitant medications, the main difference was the increased use of trimethoprim–sulphamethoxazole in the RITSAQ group. Routine liver function tests could not determine any relevant hepatic insufficiency indicating a Child–Pugh class B or C cirrhosis.
Plasma levels of ritonavir, in terms of AUC, Cmin and Cmax, were significantly lower in the LOPSAQ group than in the RITSAQ group, whereas the CLtot was increased (Table 1). The median AUC for ritonavir was 2972 ng*h/ml in the LOPSAQ group versus 6435 ng*h/ml in the RITSAQ group (P < 0.002). The ranges of measured plasma concentrations showed an evident difference between the two groups at every timepoint over the 12-h time interval.
There was no statistically significant difference between the LOPSAQ and RITSAQ groups for saquinavir Cmin, Cmax, CLtot and AUC (Table 1). However, a broad interindividual range of plasma saquinavir concentrations was found for both groups. For the saquinavir AUC the upper range extended higher for the LOPSAQ group than for the RITSAQ group (Fig. 1b). The range of measured plasma saquinavir concentrations above the median was also higher at each timepoint during the 12-h assessment period (Fig. 1a).
The median Cmax for lopinavir was 7130 ng/ml (range 3680–14 700), the median Cmin was 3310 ng/ml (range 300–10 900), and the AUC was 64 940| ng*h/ml (range 19 743–164 700). These values are slightly lower than those previously published (Cmax 8490 ± 2700 ng/ml, Cmin 3700 ± 2580 ng/ml and 12 h AUC 76 500 ± 30 700 ng*h/ml) .
This article describes the pharmacokinetics of saquinavir (soft-gel capsules, 1000 mg twice a day) whether administered with lopinavir/ritonavir (400/100 mg twice a day), 45 patients (LOPSAQ group), or with ritonavir (100 mg twice a day) and NRTI, 32 patients (RITSAQ group). The main finding was that the pharmacokinetic parameters of saquinavir were no different in the two groups and within the recommended plasma level ranges for effective treatment , regardless of whether the ritonavir was administered separately or in a fixed combination with lopinavir.
In contrast, the ritonavir levels were significantly lower in the LOPSAQ than in the RITSAQ patients, even though the same dose of ritonavir was administered for both groups. Low plasma concentrations of ritonavir during treatment with lopinavir/ritonavir have also been seen by other investigators [11,12]. However, the lower ritonavir levels achieved with the fixed-dose combination were no less effective as a boosting agent. The saquinavir plasma exposure was not impaired. Moreover, the upper quartile of saquinavir plasma concentrations tended to extend higher in the LOPSAQ group than in the RITSAQ group. A possible explanation for this finding could be a so far unknown pharmaco-enhancing effect of lopinavir on saquinavir.
Although the lopinavir plasma levels were not a primary endpoint, they are of importance in the patient's treatment. The results in our study were found to be comparable with previously published data . There is no evidence of any relevant negative pharmaco-interaction with saquinavir. Two previous studies have confirmed this finding [12,13]. An analysis of the virological responses in patients in the LOPSAQ group (to be published in full elsewhere) showed a median viral load decrease at 24 weeks of 3.5 log10 copies/ml . Studies investigating the use of this double-boosted PI combination with an NRTI or non-nucleoside reverse transcriptase inhibitor backbone have also demonstrated a favourable response. In two separate studies [11,12] 42 and 36% of the patients were below the detection limit (< 50 and < 80 copies/ml, respectively) after 24 weeks [11,12]. Zala et al.  showed that the virological response after 48 weeks (< 50 copies/ml) was durable with nine out of 23 salvage patients (40%) having a viral load of less than 500 copies/ml. Another study demonstrated an initial response of −0.8 log in 61% of patients after 4 weeks .
In a boosted double PI regimen, the three-way pharmacological interactions between the PI components are hard to predict. The co-administration of nelfinavir with lopinavir/ritonavir has been shown to reduce the bioavailability of both lopinavir and ritonavir . Amprenavir appears to have an unfavourable effect on both saquinavir and ritonavir plasma levels . Amprenavir levels are significantly reduced in the presence of lopinavir/ritonavir at the standard dosage [18–20]. This could not be balanced by a dose escalation of amprenavir [21,22]. The effect of a dose escalation of ritonavir is not yet clear. Two different studies that investigated the question of whether an additional ‘surboost’ of ritonavir can balance the decreased lopinavir levels in a boosted double PI regimen came to contradictory results [23,24]. It is important to understand these pharmacological interactions because sub-inhibitory plasma levels of any one component of the combination will increase the risk of virological failure and the emergence of resistance mutations.
Another important finding of this study was the wide inter-patient variability in the plasma levels of both lopinavir and saquinavir, underscoring the importance of therapeutic drug monitoring in the individual patient. Although this pharmacokinetic assessment followed a standardized schedule, the day-to-day variability of the results obtained cannot be excluded as a bias. Other concomitant medication, including the different use of the NRTI and trimethoprim–sulphamethoxazole within the groups, was generally not considered as a relevant bias in this pharmacokinetic model; however, it is not known. A comparison of drug interactions in two groups of patients is not a standard design to study drug–drug interactions. However, such phase IV studies are difficult to perform in HIV-infected patients. This pilot study may represent a viable pharmacokinetic assessment under ‘real-life’ conditions.
The findings of this study suggest that saquinavir can be combined with lopinavir/ritonavir without dose adjustments. The clinical implications of this regimen have to be evaluated.
1. van Heeswijk RPG, Veldkamp AL, Mulder JW, Meenhorst PL, Lange JMA, Beijnen JH, et al. Combination of protease inhibitors for the treatment of HIV-1 infected patients: a review of pharmacokinetics and clinical experience. Antivir Ther 2002, 6:201–229.
2. Moyle GJ, Back D. Principles and practice of HIV-protease inhibitor pharmacoenhancement. HIV Med 2001, 2:105–113.
3. Hsu A, Granneman RG, Bertz RJ. Ritonavir. clinical pharmacokinetics and interactions with other HIV agents. Clin Pharmacokinet 1998, 35:275–291.
4. Hammer SM, Vaida F, Bennett KK, Holothan MK, Sheiner L, Eron JJ, et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure; ACTG 398 study team. JAMA 2002, 288:169–180.
5. Molla A, Mo H, Vasavanonda S, Han L, Lin CT, Hsu A, Kempf DJ. In vitro interaction of lopinavir with other protease inhibitors. Antimicrob Agents Chemother 2002, 46:2249–2253.
6. Staszewski S, Dauer B, Stephan C, Kurowski M, Stürmer M, von Hentig N, et al. A new strategy: boosted double protease inhibitor regimen lopinavir/r plus saquinavir without reverse transcriptase inhibitors. In: 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego, USA, September 2002 [Abstract H-176].
7. Kurowski M, Müller M, Arasteh K, Moecklinghoff C. Simultaneous monitoring of five protease-inhibitors in HIV-infected patients by LC-tandem mass spectrometry. In: 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA, September 1999 [Abstract 320]
8. Ackermann H. BIAS für Windows 95/98/ME/NT/2000/XP (version 7.06). Hochheim, Darmstadt: epsilon Verlag; 2002.
9. Corbett AH, Lim ML, Kashuba AD. Kaletra (lopinavir/ritonavir). Ann Pharmacother 2002, 36:1193–1203.
10. Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, Del Giudice P, et al. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study. AIDS 2000, 14:1333–1339.
11. Hellinger J, Cohen CJ, Morris AB, Piscitelli S, Gordon D, Foy K, et al. Pilot study of the safety and antiviral activity of saquinavir 1000 mg twice daily and lopinavir/ritonavir (Kaletra) combination therapy in HIV positive individuals. In: 9th Conference on Retroviruses and Opportunistic Infections. Seattle, USA, February 2002 [Abstract 451-W].
12. Ruiz L, Ribera E, Bonjoch A, Martinez-Picado J, Díaz M, Romeu J, et al. Virological and immunological benefit of a salvage therapy that includes Kaletra plus Fortovase preceded or not by antiretroviral therapy interruption (TI) in advanced HIV-infected patients (6-month-follow-up). In: 9th Conference on Retroviruses and Opportunistic Infections. Seattle, USA, February 2002 [Abstract 421-W].
13. Bertz RJ, Foit C, Ashbrenner E, Burt D, Williams LA, Chira T, et al. Assessment of the steady state pharmacokinetic interaction of lopinavir/ritonavir with either indinavir or saquinavir in healthy subjects. In: 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego, USA, September 2002 [Abstract A-1822].
14. Zala C, Patterson P, Coll P, Bouzas MB, Kaufman S, Gun A, et al. Virological response and safety of double boosted protease inhibitors with lopinavir/r plus either saquinavir or amprenavir in heavily pretreated HIV infected patients. In: XIVth International AIDS Conference. Barcelona, Spain, July 2002 [Abstract TuPeB4492].
15. Smith GHR, Klein MB, Murphy T, Gilmore N, Leblanc RP, Macleod J, et al. Double, boosted salvage therapy with lopinavir/ritonavir and saquinavir-sgc in HIV-1 infected patients having failed 3 classes of antiretrovirals. In: XIVth International AIDS Conference. Barcelona, Spain, July 2002 [Abstract TuPeB4547].
16. Klein C, Bertz R, Ashbrenner E, Chira T, Williams L, Hsu A, et al. Assessment of the multiple-dose pharmacokinetic interaction of lopinavir/ritonavir with nelfinavir. In: 10th Conference on Retroviruses and Opportunistic Infections. Boston, USA, February 2003 [Abstract 536].
17. Corbett A, Eron J, Rezk N, Diebold M, Kashuba A. A triple protease inhibitor salvage regimen of amprenavir + saquinavir + ritonavir: steady state pharmacokinetics and initial RNA and CD4 response. In: XIVth International AIDS Conference. Barcelona, Spain, July 2002 [Abstract TuPeB4464].
18. Mauss S, Schmutz G, Kuschak D. Unfavourable interaction of amprenavir and lopinavir in combination with ritonavir? AIDS 2002, 16:296–297.
19. Reynolds HE, Gibbons SE, Tija JF, Khoo SH, Back DJ. The pharmacokinetic interaction of lopinavir/ritonavir and amprenavir in clinical practice. In: XIVth International AIDS Conference. Barcelona, Spain, July 2002 [Abstract TuPeB4560].
20. Khanlou H, Graham E, Brill M, Farthing C. Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy. AIDS 2002, 16:797–798.
21. Harris M, McNabb K, Harrigan R, Alexander C, Press N, O'Shaughnessy M, et al. Dual boosted protease inhibitor regimens: preliminary results in rescue therapy. In: 1st IAS Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina, July 2001 [Abstract 685].
22. Sadler BM, Piliero PJ, Preston SL, Lloyd PP, Lou Y, Stein DS. Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers. AIDS 2001, 15:1009–1118.
23. Mauss S, Scholten S, Wolf E, Berger F, Schmutz G, Jaeger H, et al. Does ritonavir 200 mg bid inhibit the interference of lopinavir with amprenavir plasma concentration in HIV-positive patients? In: 6th International Congress on Drug Therapy in HIV Infection. Glasgow, UK, November 2002 [Abstract 167].
24. Raguin G, Taburet AM, Chene G, Morand-Joubert L, Droz C, LeTiec C, et al. Pharmacokinetic parameters and virological response to the combination of lopinavir/ritonavir (LPV/r) and amprenavir (APV) in HIV-infected patients with multiple treatment failures: week-6 results of Puzzle 1-ANRS study. In: 9th Conference on Retroviruses and Opportunistic Infections. Seattle, USA, February 2002 [Abstract 420-W].
This article has been cited 44 time(s).
Medical Microbiology and ImmunologyImpact of HIV-1 replication on immunological evolution during long-term dual-boosted protease inhibitor therapyMedical Microbiology and Immunology
European Journal of Medical Research
German-Austrian recommendations for the antiretroviral therapy of HIV-infection (Status May 2004)
European Journal of Medical Research, 9():
British Journal of Clinical PharmacologyPopulation pharmacokinetics of lopinavir in combination with ritonavir in HIV-1-infected patientsBritish Journal of Clinical Pharmacology
Ritonavir-boosted atazanavir-lopinavir combination: a pharmacokinetic interaction study of total, unbound plasma and cellular exposures
Antiviral Therapy, 11(1):
Journal of Antimicrobial ChemotherapyExploratory study comparing the metabolic toxicities of a lopinavir/ritonavir plus saquinavir dual protease inhibitor regimen versus a lopinavir/ritonavir plus zidovudine/lamivudine nucleoside regimenJournal of Antimicrobial Chemotherapy
Expert Opinion on Drug Metabolism & ToxicologySaquinavir, the pioneer antiretroviral protease inhibitorExpert Opinion on Drug Metabolism & Toxicology
Saquinavir 500 mg film-coated tablets demonstrate bioequivalence to saquinavir 200 mg hard capsules when boosted with twice-daily ritonavir in healthy volunteers
Antiviral Therapy, 10(7):
Pharmacokinetics, safety and efficacy of saquinavir/ritonavir 1,000/100 mg twice daily as HIV type-1 therapy and transmission prophylaxis in pregnancy
Antiviral Therapy, 13(8):
Hiv Clinical Trials
Pilot study of saquinavir and lopinavir/ritonavir twice daily in protease inhibitor-naive HIV-positive patients
Hiv Clinical Trials, 6(2):
Journal of Medical VirologyVirological and pharmacological factors associated with virological response to salvage therapy after an 8-week of treatment interruption in a context of very advanced HIV disease (GIGHAART ANRS 097)Journal of Medical Virology
Predictors of virologic response to ritonavir-boosted protease inhibitors
AIDS Reviews, 7(4):
AIDS Research and Human Retroviruses
Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV type 1-infected individuals administered different atazanavir doses
AIDS Research and Human Retroviruses, 22(8):
Pathologie BiologieRecent and future therapeutic advances in the management of HIV infectionPathologie Biologie
Expert Review of Anti-Infective TherapyLopinavir plus ritonavir: a novel protease inhibitor combination for HIV infectionsExpert Review of Anti-Infective Therapy
IntervirologyPharmacokinetic Interaction between Indinavir and Darunavir with Low-Dose Ritonavir in Healthy VolunteersIntervirology
Internist"State of the HAART" - Current strategies for antiretroviral therapyInternist
Journal of Antimicrobial ChemotherapyBoosted saquinavir hard gel formulation exposure in HIV-infected subjects: ritonavir 100 mg once daily versus twice dailyJournal of Antimicrobial Chemotherapy
Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs
Antiviral Therapy, 10(4):
Journal of Korean Medical ScienceTwo cases of multidrug-resistant human immunodeficiency virus infection treated with atazanavir and lopinavir/ritonavir combination therapyJournal of Korean Medical Science
Hiv Clinical Trials
Virologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients
Hiv Clinical Trials, 6(2):
Antimicrobial Agents and ChemotherapyPharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitorsAntimicrobial Agents and Chemotherapy
Predictive factors for response to a boosted dual HIV-protease inhibitor therapy with saquinavir and lopinavir in extensively pre-treated patients
Antiviral Therapy, 12(8):
Journal of Antimicrobial ChemotherapyPharmacokinetics and short-term efficacy of a double-boosted protease inhibitor regimen in treatment-naive HIV-1-infected adultsJournal of Antimicrobial Chemotherapy
Pharmacokinetics and pharmacodynamics of drug interactions involving HIV-1 protease inhibitors
AIDS Reviews, 6(4):
Antimicrobial Agents and ChemotherapyDecrease of atazanavir and lopinavir plasma concentrations in a boosted double human immunodeficiency virus protease inhibitor salvage regimenAntimicrobial Agents and Chemotherapy
European Journal of Clinical PharmacologyAtazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy settingEuropean Journal of Clinical Pharmacology
Drugs of TodayLopinavir/ritonavir: Appraisal of its use in HIV therapyDrugs of Today
Indinavir/ritonavir 800/100mg bid and efavirenz 600mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009
Hiv Medicine, 6(6):
Nucleoside analogue-sparing strategy for the treatment of chronic HIV infection: potential interest and clinical experience
Antiviral Therapy, 10(1):
Journal of Antimicrobial ChemotherapyThe LOPSAQ study: 48 week analysis of a boosted double protease inhibitor regimen containing lopinavir/ritonavir plus saquinavir without additional antiretroviral therapyJournal of Antimicrobial Chemotherapy
Antimicrobial Agents and ChemotherapyPharmacokinetics of saquinavir, atazanavir, and ritonavir in a twice-daily boosted double-protease inhibitor regimenAntimicrobial Agents and Chemotherapy
Hiv MedicineAtazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposureHiv Medicine
Double-Boosted Protease Inhibitor Antiretroviral Regimens What Role?
Antimicrobial Agents and ChemotherapySteady-state pharmacokinetics of a double-boosting regimen of saquinavir soft gel plus lopinavir plus minidose ritonavir in human immunodeficiency virus-infected adultsAntimicrobial Agents and Chemotherapy
European Journal of Medical Research
Pharmacokinetics and tolerability of a combination of indinavir, lopinavir and ritonavir in multiply pretreated HIV-1 infected adults
European Journal of Medical Research, 11(6):
International Journal of Std & AIDS
Dose reduction effective in alleviating symptoms of saquinavir toxicity
International Journal of Std & AIDS, 18(2):
Synergistic inhibition of protease-inhibitor-resistant HIV type 1 by saquinavir in combination with atazanavir or lopinavir
Antiviral Therapy, 12(3):
Pediatric Infectious Disease JournalPharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated childrenPediatric Infectious Disease Journal
Current Opinion in Infectious DiseasesThe pharmacokinetics of HIV protease inhibitor combinationsCurrent Opinion in Infectious Diseases
Therapeutic Drug MonitoringPharmacokinetic Interaction Between Darunavir and Saquinavir in HIV-negative VolunteersTherapeutic Drug Monitoring
Double-boosted protease inhibitor; lopinavir; pharmacokinetics; ritonavir; saquinavir
© 2004 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.