December 16, 2005
A key dilemma for both patients and doctors is when to use new drugs and new drug classes. A thorough understanding of the characteristics of new drugs helps in choosing what to use and what potential combinations would be appropriate, or when to wait for the next set of options.
New drugs and new drug targets offer a promise both for improved tolerance and more potent treatment strategies. Among these, the newest inhibitors of HIV protease -- tipranavir (TPV, Aptivus), TMC114 and brecanavir (BCV, GSK 640385) -- represent a distinct chemical class, called non-peptidic protease inhibitors (PIs).
Non-peptidic PIs are potentially extremely potent and bind very tightly to HIV protease, even in highly drug-resistant viruses. In previous studies, brecanavir (currently in development) was shown to have an inhibitory concentration (IC50) in the femtomolar range -- perhaps hundreds of times more potent than conventional PIs. This potency translates to possible effectiveness in the treatment of HIV in patients from across the treatment spectrum -- from wild type (drug susceptible) to highly drug resistant.
The current oral presentation by Doug Ward from Dupont Circle Physicians Group in Washington, D.C., reviewed 24-week results of a descriptive initial study of brecanavir in HIV-infected patients.
In this study, 31 patients (25 men, 6 women; 65% Caucasian, 26% African American) received brecanavir in combination therapy. Brecanavir was dosed 300 mg with 100 mg ritonavir (RTV, Norvir), twice daily with two nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir (TDF, Viread), a nucleotide reverse transcriptase inhibitor (NtRTI), was not permitted in this study because of a lack of pharmacokinetic interaction data.
Six of the patients were treatment experienced; the others were treatment naive. Overall, 81% of the patients achieved viral loads less than 400 copies/ L; 77% achieved less than 50 copies (ITT, MD=F). CD4+ cell counts increased a median of 84 cells/mm3.
While readers should be cautious about generalizing from single case anecdotes, Dr. Ward highlighted the response of a highly PI-resistant patient to brecanavir-containing treatment, consistent with the preservation of baseline brecanavir phenotypic susceptibility (despite high-level resistance to other PIs).
In this study, brecanavir appears to be well tolerated; fatigue, nausea and upset stomach (dyspepsia) were seen in 10% to 13% of the study patients. No grade 2-4 diarrhea or rash were reported. Small increases in lipids were observed. Four patients discontinued treatment: 2 for side effects (1 for nausea/vomiting and 1 for liver toxicity).
An important concern about new HIV drugs, especially PIs, is the potential for drug-drug interactions, particularly with widely prescribed initial and subsequent treatment options. Among important potential interactions are those with tenofovir. Tenofovir has known interactions (of varying degrees of significance) with other PIs, such as atazanavir (ATV, Reyataz) and lopinavir/ritonavir (LPV/r, Kaletra) -- hence knowledge of the pharmacokinetic interactions between tenofovir and brecanavir are important to clarify early in brecanavir's development.
SL Ford from GlaxoSmithKline presented data on how tenofovir (300 mg once daily) interacted with brecanavir (300 mg twice daily) and ritonavir (100 mg twice daily) in healthy HIV-uninfected persons. When coadministered, the regimen appeared well tolerated and resulted in 24%-32% (AUC, Cmax) increases in tenofovir, 15%-20% increases in brecanavir and 31%-39% increases in ritonavir. Such differences in drug exposure are thought not to require changes in dosing, although monitoring for the potential for tenofovir side effects or toxicity might be required.
Non-peptidic PIs, like tipranavir, have already shown desperately needed potency in treating patients with highly resistant virus. In our clinic, patients who have never had undetectable viral loads are suppressed for the first time using a non-peptidic PI (i.e., tipranavir). Further improvements in the class may be proffered by TMC114 and brecanavir -- better tolerability and fewer drug interactions appear to be attributes of these drugs.
Brecanavir has moved into phase IIb/III clinical trials. These studies should provide additional clarity on the effectiveness and safety of the product.
Disclosure: Dr. Young is an investigator on a GlaxoSmithKline-sponsored BCV study and consultant to GlaxoSmithKline.
Abstract: A study to investigate the interaction between 640385/ritonavir (640385/r) and tenofovir (TDF) in healthy subjects (Poster A-1198)
Authored by: SL Ford, MJ Shelton, SC Murray, MT Anderson, J Ng-Cashin, MA Johnson
Affiliations: GlaxoSmithKline, Research Triangle Park, NC
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