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AIDS 2006; Toronto, Canada; August 13-18, 2006

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The Body Covers: The XVI International AIDS Conference
Brecanavir Shows Favorable Pharmacokinetics When Combined With Select PIs in Double-Boosted Regimens

August 15, 2006

Brecanavir (BCV, GW640385) is a new protease inhibitor (PI) in phase 2b clinical development by GlaxoSmithKline (Glaxo). It has shown powerful antiviral activity against both wild-type and highly drug-resistant HIV. One of its main attributes is that it may be used at a relatively low dose, which could potentially translate into fewer and milder side effects.1

Much was learned about brecanavir in 2005 at the last Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) based on the results from two important studies. The first was an open-label, single-arm study in which 31 HIV-1-infected adults (naive and experienced) with CD4+ cell counts greater than 200 cells/mm3 and HIV-1 RNA levels above 1,000 copies/mL received brecanavir 300 mg twice daily + ritonavir (RTV, Norvir) 100 mg twice daily, in combination with two nucleoside reverse transcriptase inhibitors. The proportion of patients achieving HIV-1 RNA levels below 400 and 50 copies/mL were 81% and 77%, respectively, at week 24 based on an intent-to-treat, missing-or-discontinuation-equals-failure analysis.2 At that time, it was already known that brecanavir caused no unfavorable drug interactions when combined with zidovudine (AZT, Retrovir) or lamivudine (3TC, Epivir). Its interactions with tenofovir (TDF, Viread), however, were less certain.

The second ICAAC study described the pharmacokinetic interactions between brecanavir and tenofovir in healthy volunteers.3 When tenofovir 300 mg was coadministered with brecanavir 300 mg twice daily + ritonavir 100 mg twice daily, the regimen appeared to be well tolerated and increased tenofovir concentrations by 24% to 32%, brecanavir concentrations by 15% to 20%, and ritonavir concentrations by 31% to 39% for both area under the curve and maximum plasma concentrations. These increases in drug exposure are not thought to require changes in dosing, but monitoring for tenofovir-related side effects or toxicity might be warranted.

At the XVI International AIDS Conference, additional data were presented regarding drug interactions between brecanavir and other PIs. Brecanavir is a known substrate of CYP450 3A4, the most important cytochrome P450 isoenzyme involved in metabolizing PIs and non-nucleoside reverse transcriptase inhibitors. Thus, the bioavailability of brecanavir is significantly increased when boosted with ritonavir and when taken with meals. This finding has prompted the possibility of using brecanavir in combination with another PI in a double-boosted regimen.

To explore this prospect, Shelton and colleagues examined the pharmacokinetic interactions between three double-boosted brecanavir + PI combinations: brecanavir 300 mg twice daily + lopinavir/ritonavir (LPV/r, Kaletra) 400/100 mg twice daily, brecanavir 300 mg twice daily + ritonavir 100 mg twice daily + atazanavir (ATV, Reyataz) 300 mg once daily, and brecanavir 600 mg twice daily + ritonavir 200 mg twice daily + tipranavir (TPV, Aptivus) 500 mg twice daily.4 The pharmacokinetic effects of lopinavir/ritonavir and atazanavir on brecanavir are summarized in Table 1, while the pharmacokinetic effects of brecanavir on lopinavir/ritonavir and atazanavir are shown in Table 2. Both brecanavir and atazanavir increased the exposure of the other, whereas lopinavir/ritonavir only slightly increased brecanavir concentrations and brecanavir actually decreased lopinavir/ritonavir exposure. Both double-boosted PI combinations were generally well tolerated. There were increases in bilirubin levels and ocular icterus with the brecanavir + atazanavir combination, but no serious adverse events were observed.


Table 1. Pharmacokinetic Effects of LPV/r and ATV on BCV
DrugnGLS Mean Ratio (90% CI)
AUC(0-τ)
(ng x h/mL)
Cmax
(ng/mL)
Cτ
(ng/mL)
LPV/r231.02 (0.94, 1.11)1.01 (0.94, 1.08)1.08 (0.94, 1.24)
ATV161.44 (1.32, 1.58)1.21 (1.12, 1.30)2.11 (1.81, 2.45)

AUC, area under the curve; CI, confidence interval; GLS, geometric least squares.


Table 2. Pharmacokinetic Effects of BCV on LPV/r and ATV
DrugnGLS Mean Ratio (90% CI)
AUC(0-τ)
(ng x h/mL)
Cmax
(ng/mL)
Cτ
(ng/mL)
LPV/r210.84 (0.75, 0.93)0.8 (0.80, 0.98)0.86 (0.73, 1.02)
ATV/r181.38 (1.25, 1.53)1.48 (1.29, 1.71)1.44 (1.25, 1.65)

AUC, area under the curve; CI, confidence interval; GLS, geometric least squares.


Pharmacokinetic analysis of the brecanavir + tipranavir combination could not be completed since this arm was prematurely discontinued before steady-state conditions for tipranavir were reached. This decision was based on the observation of significant liver transaminase elevations associated with the use of this combination in seven of 12 individuals. As such, the brecanavir + tipranavir combination was felt to be poorly tolerated with a high probability of negative interactions.

Shelton et al concluded that brecanavir may be co-administered with lopinavir/ritonavir without dose adjustment. Since plasma exposure to both brecanavir and atazanavir increased when the two agents were co-administered, reducing the dose of atazanavir may be necessary. Brecanavir should not be co-administered with tipranavir due to reduced plasma brecanavir trough concentrations.

Based on the in vitro and in vivo data obtained for brecanavir thus far, it appears that this agent could be highly effective for treatment-experienced HIV patients. Given that dual ritonavir-boosted PIs are frequently used in this population, it is important that we understand the pharmacokinetic interactions when combining these different drugs. On the other hand, the recent approval of TMC114 (darunavir, Prezista), the availability of TMC125 (etravirine) under the Early Access Program, and progress in the development of other agents, such as maraviroc (UK-427,857; a CCR5 entry inhibitor) and the Merck & Co. 0518 integrase inhibitor, may preclude the pressing need for double-boosted PIs in the near future.

Footnotes

  1. Reddy S, Ford SL, Stein DS, et al. Single-dose safety and pharmacokinetics (PK) of GW640385X (385): an HIV-1 protease inhibitor (PI). In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Ill. Abstract A-1800.

  2. Ward D, Lalezari J, Thompson M, et al. Preliminary antiviral activity and safety of 640385/ritonavir in HIV-infected patients (Study HPR10006): an 8-week interim analysis. In: Program and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2005; Washington, DC. Abstract H-412.

  3. Ford SL, Shelton MJ, Murray SC, Anderson MT, Ng-Cashin J, Johnson MA. A study to investigate the interaction between 640385/ritonavir (640385/r) and tenofovir (TDF) in healthy subjects. In: Program and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2005; Washington, DC. Abstract A-1198.

  4. Shelton MJ, Ford S, Anderson MT, Murray S, Ng-Cashin J. Overview of drug interactions between brecanavir (BCV) and other HIV protease inhibitors (PIs). In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUAB0105.
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