From Concept to Care: Pharmacokinetic Boosting of Protease Inhibitors
Marta Boffito, MD, PhD
Associate Director, PK Research, Ltd
Chelsea and Westminster Hospital,
London, United Kingdom
Summary by Tim Horn
Published online at www.prn.org: The PRN Notebook, Volume - 9, December 2004 | Published by the Physicians’ Research Network, Inc.®, New York City. All rights reserved. © December 2004.
Protease inhibitors have played an instrumental role in decreasing mortality and morbidity among people with HIV infection. At the same time, this class of antiretrovirals has been associated with a number of disadvantages. First, protease inhibitor therapy often comes with a high pill burden, complex dosing schedules, and careful dietary considerations. Second, they are associated with a growing number of short- and long-term side effects, including a variety of metabolic complications. Third, cross-resistance remains a central concern; a simple switch from one protease inhibitor to another—if protease mutations are documented—often yields lackluster results.
Fortunately, extensive data generated over the past several years have shed more encouraging light on the utility of protease inhibitors in the treatment of HIV infection. Pharmacokinetic “boosting”—primarily the use of ritonavir (Norvir) to boost concentrations of other protease inhibitors—has, in effect, rendered many of these drugs easier to take and more effective. Research is also emerging with respect to the use of two protease inhibitors—both boosted using low-dose ritonavir—as a therapeutic option. These double-boosted protease inhibitor combinations appear to hold a great deal of promise, particularly for patients who have tried and failed protease inhibitor therapy in the past.
The need to improve both the convenience and effectiveness of protease inhibitors has led to research focusing on pharmacologic enhancement. Ritonavir is an ideal pharmacologic enhancer because it inhibits two key stages of metabolism. First, it inhibits what is known as first-pass metabolism, which occurs during absorption. Enterocytes that line the intestine contain both CYP3A4, one of the key cytochrome P450 isoenzymes associated with drug metabolism, and P-glycoprotein, an efflux transporter that can effectively pump drugs out of the gut wall and back into the intestinal lumen. Ritonavir appears to inhibit both of these proteins and, consequently, may increase a coadministered drug’s Cmax. Second, ritonavir inhibits CYP3A4 in the liver, thereby maintaining a drug’s plasma half-life. It is also possible that ritonavir inhibits P-glycoprotein found in CD4+ cells. As a result, less drug is transported back out of the cell, thereby increasing the drug’s intracellular half-life.
Ritonavir’s interactions with other drugs are complex and involve an understanding of pharmacology that extends beyond the cytochrome P450 system. This is reviewed in detail in “XEN and the Art of Pharmacology: New Learning from an Old Science,” beginning on page 10, and was also touched upon by Dr. Boffito. In one series of studies reviewed by Dr. Boffito, researchers at Vanderbilt University School of Medicine evaluated the activation of orphan nuclear receptors—proteins responsible for increased transcription of the CYP3A4 gene, including pregnane X receptor (PXR)—by different protease inhibitors (Marzolini, 2004). At the 11th Conference on Retroviruses and Opportunistic Infections (CROI), it was demonstrated that the protease inhibitors, used alone or in combination, had varied effects on these proteins. The protease inhibitors (fos)amprenavir (Agenerase; Lexiva), nelfinavir (Viracept), lopinavir (without ritonavir), and ritonavir (Norvir) are PXR substrates. When these protease inhibitors were combined with rifampicin, another PXR substrate and a well-known inducer, the extent of the maximal CYP3A4 transcriptional activity (CYP3A4 synthesis) was less than in the presence of rifampicin alone. Similar findings were observed when ritonavir was combined with lopinavir, suggesting that the protease inhibitors tested are partial agonists of PXR. “Interestingly,” Dr. Boffito commented, “the three-protease inhibitor combination of lopinavir, ritonavir, and amprenavir appeared to have a synergistic effect on PXR. This may explain the low plasma concentrations of lopinavir and amprenavir seen in clinical trials evaluating this combination.”
In discussing various boosting strategies, Dr. Boffito pointed out that the pharmacologic enhancement achieved using ritonavir depends on the coadministered protease inhibitor being used. With saquinavir (Invirase; Fortovase) and lopinavir, for example, ritonavir’s most notable effect is a boost to the Cmax. “This suggests that the effect of ritonavir on saquinavir is exerted at the absorption level and during first-pass metabolism,” Dr. Boffito explained. With indinavir (Crixivan) and (fos)amprenavir, ritonavir coadministration allows for prolongation of their half-lives. “With these drugs, ritonavir exerts its effects mainly on CYP3A4 clearance at the liver level,” she added. “We see a limited increase in the indinavir or amprenavir Cmax when using ritonavir to boost these drugs. What changes is the elimination half-life and, therefore, an increase in the Ctrough.”
| Double-Boosting at Chelsea and Westminster Hospital | Top of page |
Dr. Boffito discussed some of her own double-boosting pharmacokinetics work at Chelsea and Westminster Hospital, focusing on a pair of studies that were both initially reported at the 11th CROI in February in San Francisco.
In the first study, steady-state pharmacokinetics of 300 mg atazanavir (Reyataz), 1,600 mg saquinavir (Invirase), and 100 mg ritonavir—all administered once a day—were evaluated (Boffito, 2004). The addition of atazanavir to saquinavir/ritonavir resulted in a significant increase in the saquinavir Ctrough, Cmax, and AUC (by 112%, 42%, and 60% respectively), with a slight increase in the saquinavir half-life (17%). The ritonavir Cmax and AUC increased significantly with atazanavir administration (by 34% and 41%, respectively). As for atazanavir levels, these were comparable to those documented previously in patients receiving atazanavir/ritonavir without saquinavir. Based on these data, Dr. Boffito’s group recommended that once-daily administration of atazanavir, saquinavir, and ritonavir—using the doses specified above—should be evaluated further in clinical trials.
In the second study, the steady-state pharmacokinetics of 1,000 mg saquinavir, 700 mg fosamprenavir, and either 100 mg or 200 mg ritonavir—all administered twice a day—were evaluated in 18 HIV-infected patients (Boffito, 2004a). Accordingly, the coadministration of fosamprenavir dosed at 700 mg BID with saquinavir and ritonavir (100 mg BID) resulted in a statistically nonsignificant decrease in the saquinavir AUC, Ctrough, and Cmax (–14%, –24%, and –9%, respectively), but this was compensated for by the 200 mg BID ritonavir dose, which resulted in statistically insignificant increases in the saquinavir AUC, Ctrough, and Cmax (12%, 3%, and 20%, respectively). Fosamprenavir levels did not appear to be significantly influenced by saquinavir coadministration. A 54% decrease from baseline in the ritonavir Ctrough was observed with addition of fosamprenavir to saquinavir/ritonavir. “Here, with the use of 200 mg of ritonavir, we appeared to have enough of a boost to achieve sufficient saquinavir and fosamprenavir concentrations.”
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