Clinical Development, Merck & Co., Inc., West Point, PA, USA
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Abstract |
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Keywords: pharmacokinetics, pharmacodynamics, clinical experience, dosing, tolerability
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Introduction |
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HIV treatment that includes a ritonavir-boosted PI regimen offers advantages over traditional single PI-based regimens. Ritonavir-boosted regimens combine low-dose ritonavir with a second PI, as well as two or more nucleoside reverse transcriptase inhibitors (NRTIs), to achieve higher sustained levels of the second PI. These regimens are utilized to prevent or overcome resistance and allow less frequent dosing, potentially improving adherence. Advantages offered by these regimens are attributable to the pharmacokinetic properties of ritonavir, and its effect on the second, boosted PI. Concomitant administration with ritonavir increases the bioavailability and cellular penetration of the second PI despite reduced doses and less frequent administration.3,4 The dose of ritonavir administered in boosted PI regimens is generally considered subtherapeutic (100200 mg).5 Plasma peak and trough levels of the second PI in boosted PI regimens generally exceed levels achieved when the agent is given alone because the second PI is cleared from the body more slowly. The antiretroviral activity of the second PI is, consequently, enhanced.
Regimens that combine ritonavir with saquinavir, indinavir, lopinavir or amprenavir have demonstrated efficacy in clinical studies of newly infected, treatment-naïve patients as well as patients who have failed treatment with one or more antiretroviral regimens.47 In addition, genotype and phenotype assays can now identify patients, whether treatment naïve or previously exposed to antiretroviral therapy, infected with HIV resistant to single PI-based regimens. Thus, when PIs are prescribed, whether as first line or salvage therapy, they are commonly prescribed as a boosted regimen.
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Rationale for boosted PI regimens: pharmacokinetics and pharmacodynamics |
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The pharmacokinetics of the PIs vary, as does the effect ritonavir has on their pharmacokinetics. Saquinavir is removed by first-pass metabolism in the intestine, which limits its bioavailability (Table 1).6 Ritonavir improves saquinavirs effectiveness by inhibiting first-pass intestinal metabolism and increasing AUC, Cmin and Cmax (Table 2).5,6,8 Indinavir has relatively good bioavailability, but has a comparatively short t1/2 (Table 1). Ritonavir improves indinavirs effectiveness primarily by inhibiting hepatic metabolism and decreasing systemic clearance.5,6 This leads to larger increases in Cmin than AUC, while having less effect on Cmax (Table 2).36 Trough indinavir levels are maintained above the concentration necessary to inhibit 95% of viral growth seen in the absence of drug.9 The effect of ritonavir on nelfinavir pharmacokinetics is smaller than other PIs (Table 2), as nelfinavir is metabolized by several CYP-450 enzymes and has relatively good bioavailability.4,10 Larger increases are observed in the AUC, Cmin and Cmax of nelfinavirs M8 metabolite, but the increases are generally no larger than one-fold (Table 2). Lopinavir is only available in combination with ritonavir and, like saquinavir, benefits from ritonavirs inhibition of first-pass intestinal metabolism. Ritonavirs effect on amprenavir appears to be similar to its effect on indinavir, with inhibition of hepatic metabolism leading to larger increases in Cmin than AUC (Table 2).35,11 Atazanavir was approved for use in June 2003, and is also associated with a larger percentage increase in Cmin than AUC with ritonavir boosting (Table 2). The PI, tipranavir, is under investigation and not yet approved for use.
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Although less well established, it has been suggested that concomitant ritonavir administration may also boost the unbound fraction (the only therapeutically active form of a PI) of the second PI in the systemic circulation.3,6 Protein binding of the individual PIs varies, with ritonavir one of the most highly protein bound at 9899%, indinavir the lowest at approximately 60%, whereas the other PIs are intermediate (8699%).3,6 Ritonavir may boost levels of the second PI through saturation of protein binding sites or through competition with the second PI for protein binding sites if present at significant levels, thus increasing levels of the unbound fraction of the second PI.3,5,6 Additional research is needed in this area to confirm that ritonavir boosting impacts the level of unbound drug and the mechanism behind this effect.19
Once a PI is available in the systemic circulation and reaches an infected CD4 cell, the quantity of the PI that enters and remains in the cell determines its ability to suppress HIV replication. There is variability between the different PIs in their level of intracellular accumulation and intracellular t1/2, which, as mentioned above, appears to correspond to the degree of P-glycoprotein and MRP channel expression present in the cell membrane.13,20,21 Limited data indicate that ritonavir inhibits these channels on CD4 cells allowing greater intracellular accumulation of the second PI, but more conclusive evidence is needed to define the role these channels play in virological failure of PI regimens and the exact benefit provided by concomitant administration of ritonavir.3,5,12,2224
In summary, ritonavirs inhibition of CYP3A4 is the most clearly defined of its mechanisms for improving the efficacy of the second PI in a boosted PI regimen. The resultant increases in AUC and Cmin of the second PI have therapeutic implications related to increased bioavailability. A potentially lower proportion of patients receive subtherapeutic dosing, thus the level of HIV suppression is increased in the clinical setting. Effects on efflux channels and protein binding require further research to more accurately define their role in PI boosting.
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Clinical experience |
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Initial studies of dual PI combinations used a 400 mg dose of ritonavir with either saquinavir 600 mg or indinavir 400 mg plus two NRTIs.6 Saquinavir/ritonavir 600/400 mg provided greater efficacy than ritonavir 600 mg as a single PI (68% versus 40% vRNA < 200 copies/mL), when both were given twice a day with two NRTIs in PI naïve patients over 48 weeks.26 Saquinavir/ritonavir 400/400 mg twice a day plus one NRTI was less efficacious than indinavir 800 mg three times daily plus two NRTIs in a 48-week study of PI-naïve patients (43% versus 63% vRNA < 400 copies/mL).27 Saquinavir/ritonavir 600/400 mg provided modest efficacy (0.2 log10 reduction in median plasma vRNA) in a study of prior indinavir-treated patients,7 but produced greater viral suppression in patients previously treated with nelfinavir.6,7 Indinavir/ritonavir 400/400 mg plus two NRTIs demonstrated efficacy in antiretroviral-naïve patients over 72 weeks with suppression of vRNA < 500 copies/mL (100% completers and 63% non-completers equal failures) and <80 copies/mL (95% completers and 60% non-completers equal failures).28 The 400 mg dose of ritonavir used in these studies may act as a fourth active agent (providing what is better considered dual PI therapy) as well as boosting the second PI but has been associated with an increased incidence of side effects.
There are a limited number of studies that compare single PI-based regimens with regimens that include lower ritonavir doses used solely to boost the second PI. Indinavir/ritonavir 800/100 mg twice a day demonstrated similar efficacy to indinavir 800 mg three times daily, both with two NRTIs, in a study of PI-naïve patients, as well as in a study of patients responsive to treatment with a conventional indinavir 800 mg three times daily regimen.4 Lopinavir/ritonavir twice a day demonstrated greater efficacy over 48 weeks than nelfinavir (vRNA < 400 copies/mL: 75% and 63%, respectively, and vRNA < 50 copies/mL: 67% and 52%, respectively), both combined with two NRTIs in antiretroviral naïve patients.29 Lopinavir/ritonavir twice a day demonstrated greater efficacy over 24 weeks than atazanavir 400 mg daily (vRNA < 400 copies/mL: 75% and 54%, respectively, and vRNA < 50 copies/mL: 50% and 34%, respectively), both combined with two NRTIs in patients who failed only one prior PI-containing regimen.30
The lower doses of ritonavir used for boosting were also evaluated in combination with indinavir or lopinavir in open-label studies of antiretroviral naïve patients. A study of indinavir/ritonavir 800/100 mg plus two NRTIs produced viral suppression over 48 weeks (vRNA < 400 copies/mL: 95% completers, 45% non-completers equal failures and <50 copies/mL: 88% completers, 42% non-completers equal failures).31 Likewise, lopinavir/ritonavir 200400/100200 mg achieved viral suppression over 48 weeks (85% vRNA < 400 copies/mL and 78% <50 copies/mL, both non-completers equal failures).32
More extensive clinical experience is available with the boosted PI regimens in salvage therapy use. An indinavir/ritonavir 800/200 mg plus two NRTIs study reported vRNA reductions over 24 weeks (vRNA < 400 copies/mL: 76% completers, 56% non-completers equal failures and <50 copies/mL: 50% completers, 37% non-completers equal failures) in patients who previously failed a saquinavir, indinavir, or nelfinavir-based regimen.33 Lopinavir/ritonavir has also demonstrated efficacy following 12 months of prior PI therapy (48% vRNA < 500 copies/mL and 39% <50 copies/mL, non-completers equal failures).34 One small, 24-week amprenavir salvage therapy study reported reductions in vRNA < 200 copies/mL among 9/17 (53%) patients.35
Three direct comparator studies of boosted PI regimens have been reported in the literature.3638 MaxCmin 1 included primarily patients (approximately 75%) who had previously received antiretroviral therapy.36 This 48-week, 306 patient study compared saquinavir/ritonavir 1000/100 mg to indinavir/ritonavir 800/100 mg twice a day plus two or more NRTIs/NNRTIs and found that 94% versus 90% of patients (P = NS), respectively, in the completers analysis and 68% versus 53% (P = 0.014) of patients, respectively, in the non-completers as failures analysis achieved vRNA < 400 copies/mL. The difference in the non-completers analysis appeared to be primarily the result of a higher percentage of indinavir patients switching therapy. Results of the 48-week MaxCmin 2 study of 326 patients (50% PI naïve) treated with saquinavir/ritonavir 1000/100 mg or lopinavir/ritonavir 400/100 mg twice a day plus two or more NRTIs/NNRTIs found that 75% versus 70% (P = NS) of patients, respectively, in the completers analysis and 52% versus 60% (P = NS) of patients, respectively, in the non-completers as failures analysis achieved vRNA < 50 copies/mL.37 More saquinavir (29%) than lopinavir (13%) (P = 0.001) patients switched therapy. The third study compared treatment with atazanavir/ritonavir 300/100 mg once daily, atazanavir/saquinavir 400/1200 mg once daily, or lopinavir/ritonavir 400/100 mg twice daily, each administered with tenofivir and one NRTI in patients who failed multiple antiretroviral regimens.38 Preliminary results from this 16-week, 358 patient trial demonstrated that similar percentages of patients in the atazanavir/ritonavir (64%) and lopinavir/ritonavir (65%) groups, but a lower percentage of patients in the atazanavir/saquinavir (48%) group achieved vRNA < 400 copies/mL (P value not provided).
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Dosing and tolerability |
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The type of side effects encountered with boosted PI regimens are generally similar to those associated with PI regimens that include just the second PI. The addition of ritonavir has the potential to increase the incidence of side effects, in a dose-dependent manner.5 Side effects associated with the entire PI class include nausea, vomiting, glucose intolerance, elevated lipids, and fat redistribution, while additional side effects are associated with individual PIs. Lipodystrophy is a class effect that requires monitoring and possible treatment. Among the PIs, ritonavir has the greatest association with lipodystrophy, particularly hypertriglyceridaemia.4244 Diarrhoea is associated with the use of the PIs, although less commonly with indinavir.5 Fluid requirements should be adhered to with indinavir to help prevent nephrolithiasis.4,5
Clinical studies have demonstrated effective HIV suppression with twice a day ritonavir-boosted PI regimens in both treatment naïve patients and in patients who have failed prior antiretroviral therapy including single PI regimens. In addition, these regimens improve dosing convenience relative to frequency and timing of dosing around meals. Tolerability remains a limiting factor in treatment adherence that appears related to the dose of ritonavir. Lower doses of twice a day regimens and once-daily dosing regimens are being studied and appear to be the next step in expanding patient treatment options. It is yet to be seen if these regimens will provide comparable or greater HIV suppression than the presently used twice daily regimens.
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Conclusion |
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Acknowledgements |
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Footnotes |
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References |
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