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RESEARCH LETTERS

Lopinavir/ritonavir plus saquinavir in salvage therapy; pharmacokinetics, tolerability and efficacy

la Porte, Charles JLa; Wasmuth, Jan-Christianb; Schneider, Katrinb; Rockstroh, Jürgen Kb; Burger, David Ma

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Patients receiving a lopinavir/ritonavir and saquinavir dual protease inhibitor-based antiretroviral salvage regimen were studied to evaluate the pharmacokinetics, tolerability and efficacy of the regimen. Pharmacokinetic curves were obtained for lopinavir and saquinavir. Patient records were studied for adverse events and efficacy data. The pharmacokinetics of lopinavir and saquinavir were comparable with literature data, except for the saquinavir 0–12 h area under the curve and maximum concentration. The tolerability of the regimen was good and efficacy was encouraging.

HIV-infected patients are treated with highly active antiretroviral therapy (HAART) for longer periods. Second-line and further regimens are seen more often, as patients fail their initial HAART regimen. This development underlines the need for more options in salvage therapies. Dual protease inhibitor (PI)-based HAART might lead to a powerful suppression of HIV infection and improve outcomes in salvage therapy. Accordingly, a combination of lopinavir/ritonavir and saquinavir in standard dosages could be used in the treatment of heavily pre-treated HIV-1-infected patients. Combining saquinavir with lopinavir/ritonavir has the advantage that ritonavir has a ‘double boosting’ function for both lopinavir and saquinavir. Another advantage of this combination might be the described in-vitro synergy of lopinavir and saquinavir [1]. Negative pharmacokinetic interactions, as seen for lopinavir/ritonavir plus amprenavir [2], are not expected for lopinavir/ritonavir plus saquinavir. Increasing interest in the combination of lopinavir/ritonavir and saquinavir for the treatment of HIV infection has led to several studies on this combination of drugs. However, only sparse data have so far been published. The objectives of the study were to evaluate the pharmacokinetics, tolerability and efficacy of salvage regimens containing lopinavir/ritonavir plus saquinavir.

Patients older than 18 years who had failed at least three previous antiretroviral regimens including non-nucleoside reverse transcriptase inhibitors and PI were eligible. Selected patients were treated with lopinavir/ritonavir 400/100 mg twice a day and saquinavir soft gel capsules (Fortovase) 1000 mg twice a day; backbone therapy was at the physician's discretion. All patients had been on the current treatment for at least 4 weeks before the pharmacokinetics were studied. To evaluate the pharmacokinetics of lopinavir and saquinavir, patients received a morning dose together with standard breakfast at the clinic. Blood samples were drawn immediately before and up to 12 h after dosing. All available plasma samples were measured using a modified version of a validated high-performance liquid chromatography method [3]. Non-compartmental methods were used to evaluate drug concentration versus time data. The pharmacokinetic parameters evaluated were: area under the curve (AUC)0–12 h, maximum concentration (Cmax), minimum concentration (Cmin), apparent clearance (Cl/F) and half-life (T1/2). Pharmacokinetic data were compared with literature data of lopinavir/ritonavir dosed as 400/100 mg twice a day and saquinavir plus ritonavir dosed as 1000/100 mg twice a day.

Patient characteristics including concomitant medication and data on viral loads and CD4 cell counts were obtained from patient records in the hospital. All viral loads were quantified using the Versant HIV-1 RNA 3.0 test kit (Bayer Diagnostics, Leverkusen, Germany).

Seven male patients with a mean age of 45 years (range 32–55) were included, all were in Centers for Disease Control and Prevention (CDC) class C3. Lamivudine was part of the backbone therapy for all patients; six patients also used tenofovir and five patients used T20. Three patients used stavudine. Abacavir, didanosine and zidovudine were used by one patient each.

Six out of seven patients used concomitant medication (fluconazol, pyrimethamin, sulfadiazin, folinate, loperamide, ganciclovir, alprazolam, bezafibrate and l-thyroxine). None of these medications are known to interact with either lopinavir or saquinavir.

For lopinavir the median and interquartile ranges (IQR) of pharmacokinetic parameters were: AUC0–12 h 88.0 h*mg/l (68.6–118.9 h*mg/l), Cmax 9.9 mg/l (7.9–12.5 mg/l), Cmin 4.8 mg/l (3.9–5.6 mg/l), Cl/F 5.8 l/h (4.3–6.1 l/h) and T1/2 5.0 h (4.7–9.8 h). See Fig. 1 for individual plasma concentration-time profiles of lopinavir. Lopinavir product information [4] reported similar mean AUC0–12 h 82.8 h*mg/l, Cmax 9.6 mg/l, Cmin 5.5 mg/l, Cl/F 6–7 l/h and T1/2 5–6 h. Other studies [5,6] also reported that lopinavir levels were not negatively affected by saquinavir when co-administered.

F1-18
Fig. 1.:
Lopinavir and saquinavir individual plasma concentration-time profiles. Presented are the data of seven patients: —•— Patient 1; – – ○ – – patient 2; —▾— patient 3; – – ▿ – – patient 4; —▪— patient 5; – – □ – – patient 6; – – ♦ – – patient 7.

For saquinavir the median and IQR of pharmacokinetic parameters were: AUC0–12 h 9.8 h*mg/l (8.3–24.5 h*mg/l), Cmax 1.6 mg/l (1.4–3.9 mg/l), Cmin 0.40 mg/l (0.22–0.93 mg/l), Cl/F 105.8 l/h (67.7–121.8 L/h) and T1/2 3.6 h (2.9–4.1 h). Fig. 1 gives an overview of individual saquinavir plasma concentration-time profiles. Veldkamp et al. [7] reported a higher median AUC0–12 h and Cmax of: 18.8 h*mg/l and 3.7 mg/l, a similar median Cmin and T1/2: 0.40 mg/l and 3.0 h. The median Cl/F was lower at 54.4 l/h. Ribera et al. [6] reported higher values, Kurowski et al. [8] reported higher AUC0–12 h but similar Cmin. Stephan et al. [5] reported that lopinavir/ritonavir was able to boost saquinavir levels as effectively as ritonavir alone.

Adverse events reported by five out of seven patients were mainly gastrointestinal and mild in nature (vomiting, two; nausea, one; diarrhea, one; heartburn, one; herpes labialis, one; exanthema, one; cutaneous herpes zoster, one). It has to be taken into account that the patients studied were experienced with regard to antiretroviral therapy. Good tolerability of this combination was also reported in other studies [9,10].

The median and IQR of the viral load in log10 copies/ml at baseline, week 12 and week 24 were 5.2 (4.9–5.5), 4.5 (2.9–5.0) and 3.9 (2.7–4.9). Two patients reached an undetectable viral load (< 400 copies/ml), one at week 12 the other at week 24. Five out of seven patients showed a decreased viral load (> 0.5 log) during 24 weeks of treatment.

The median and IQR of the CD4 cell counts × 106/l at baseline, week 12 and week 24 were 72 (31–109), 194 (59–242) and 134 (44–238). All patients showed an increased CD4 cell count during the first 12 weeks of treatment.

The chosen dosages for lopinavir/ritonavir and saquinavir may be used for the combination of these agents in a dual PI-based antiretroviral regimen. The pharmacokinetic data of seven patients obtained from this study corresponded with literature data for lopinavir [4,5] and saquinavir [5,7,8] when used separately, with the exception of saquinavir AUC0–12 h and Cmax, which appeared to be somewhat lower in this study. Therapeutic drug monitoring remains an important tool in regimens like this, with or without concomitant medications. The tolerability of the studied treatment was good. The efficacy of this regimen measured as a decline in viral load and an increase in CD4 cell count was encouraging, as also reported by others [9–11].

References

1. Molla A, Mo H, Vasavanonda S, Han L, Lin CT, Hsu A, et al. In vitro antiviral interaeraction of lopinavir with other protease inhibitors.Antimicrob Agents Chemother 2002, 46:2249–2253.
2. Bertz RJ, Foit C, Ashbrenner E, Burt D, Williams LA, Chira T, et al. Effect of amprenavir on the steady-state pharmacokinetics of lopinavir/ritonavir in HIV+ and healthy subjects. In: 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego, CA, USA, 27–30 September 2002 [Abstract A-1823].
3. Hugen PWH, Verwey-van Wissen CPWGM, Burger DM, Wuis EW, Koopmans PP, Hekster YA. Simultaneous determination of the HIV-protease inhibitors indinavir, nelfinavir, saquinavir and ritonavir in human plasma by reversed-phase high-performance liquid chromatography.J Chromatogr B Biomed Sci Appl 1999, 727:139–149.
4. Product information. Kaletra®. Chicago, IL, USA: Abbott; 2000.
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6. Ribera E, Diaz M, Pou L, Ruiz L, Ruiz I, Ocana I, et al. Steady-state pharmacokinetics of double boosting regimen of lopinavir, plus minidose ritonavir, plus saquinavir soft-gel in HIV-infected adults. In: XIVth International AIDS Conference. Barcelona, Spain, 2002 [Abstract TuPeB4545].
7. Veldkamp AI, van Heeswijk RP, Mulder JW, Meenhorst PL, Schreij G, van der GS, et al. Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-1-infected individuals.J Acquired Immune Defic Syndr 2001, 27:344–349.
8. Kurowski M, Arslan A, Arasteh K, Moecklinghoff C, Hill A. Comparative pharmacokinetics of twice daily Fortovase/ritonavir and Invirase/ritonavir. In: 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Noordwijk, the Netherlands, 2–4 April 2001 [Abstract 3.2].
9. Smith GHR, Klien MB, Murphy T, Macleod JD, Routy JP, LeBlanc RP, et al. Double, boosted salvage therapy with lopinavir (LOP)/ritonavir (RIT) and saquinavir-sgc (SQR) in HIV-1 infected patients having failed 3 antiretroviral classes. In: XIVth International AIDS Conference. Barcelona, Spain, 2002 [Abstract TuPeB4547].
10. Zala C, Patterson P, Coll P, Bouzas MB, Kaufman S, Gun A, et al. Virological response and safety at 48 weeks 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, 2002 [Abstract TuPeB4492].
11. Staszewski S, Dauer B, Stephan C, Gute P, Klauke S, Sturmer M. Switch to a simple boosted double protease inhibitor regimen of lopinavir/r and saquinavir without reverse transcriptase inhibitors after multiple therapy failures. In: XIVth International AIDS Conference. Barcelona, Spain, 2002 [Abstract TuPeB4474].
© 2003 Lippincott Williams & Wilkins, Inc.