Multiple-Dose Pharmacokinetics and??Safety of Bevirimat, a??Novel??Inhibitor??of??HIV Maturation,??in??Healthy??Volunteers

Martin, David E.; Blum, Robert A.; Doto, Judy; Galbraith, Hal; Ballow, Charles H.

doi:10.2165/00003088-200746070-00004

Cited by 45 publications

(49 citation statements)

References 10 publications

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“…Multiple-dose pharmacokinetics appear consistent with those seen after single doses [33,35]. Similarly, values for pharmacokinetic variables in HIV-positive patients appear comparable with those of bevirimat reported in healthy volunteers [34].…”

Section: Clinical Pharmacokineticssupporting

confidence: 73%

“…Bevirimat has also shown a consistent pharmacokinetic profile in studies in healthy human volunteers [32,33] and HIV-infected patients [34].…”

Section: Clinical Pharmacokineticsmentioning

confidence: 73%

“…Although atazanavir can cause hyperbilirubinaemia resulting from inhibition of bilirubin glucuronidation by UGT1A1, bevirimat does not increase bilirubin levels [37]. Of particular note, bevirimat does not significantly induce cytochrome P450 3A4, which is commonly involved in the metabolism of PIs and non-nucleoside reverse transcriptase inhibitors [33].…”

Section: Intracellular Pharmacokineticsmentioning

confidence: 99%

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Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection

Martin

Salzwedel

Allaway

2008

Antivir Chem Chemother

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Existing antiretroviral treatments for HIV type-1 (HIV-1) disease are limited by problems of resistance and drug-drug interactions. Bevirimat is a novel HIV-1 maturation inhibitor with a mechanism of action that is distinct from other antiretroviral agents. Specific inhibition of the final rate-limiting step in Gag processing by bevirimat prevents release of mature capsid protein from its precursor (CA-SP1), resulting in the production of immature, non-infectious virus particles. Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients, with peak plasma concentrations attained approximately 1-3 h after dosing. Plasma concentrations decrease in a log-linear manner with a mean plasma elimination halflife of 58-80 h, supporting once-daily dosing. Animal studies suggest that elimination of bevirimat is primarily by hepatic glucuronidation and hepatobiliary excretion. There is minimal renal elimination, with < 1% of the administered dose appearing in the urine. In responsive patients, bevirimat has demonstrated a robust dosedependent reduction in viral load (> 1.5 log10 copies/ml). Short-term administration (< or = 14 days) of bevirimat is well tolerated, even when used in combination with other antiretroviral agents. Further studies to evaluate the long-term efficacy and tolerability of bevirimat are currently underway.

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Section: Clinical Pharmacokineticssupporting

confidence: 73%

“…Bevirimat has also shown a consistent pharmacokinetic profile in studies in healthy human volunteers [32,33] and HIV-infected patients [34].…”

Section: Clinical Pharmacokineticsmentioning

confidence: 73%

Section: Intracellular Pharmacokineticsmentioning

confidence: 99%

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Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection

Martin

Salzwedel

Allaway

2008

Antivir Chem Chemother

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“…BVM targets the HIV-1 Gag CA-SP1 boundary region by blocking viral protease cleavage of SP1 from the CA-SP1 precursor and inhibiting release of the mature CA protein, which is the final step required for virion maturation. Despite the novel mechanism of action and initial progress made in small-scale clinical trials (11)(12)(13)17), further development of BVM has encountered unexpected challenges in the clinical setting, because patients whose viruses contain genetic polymorphisms in the Gag SP1 (positions 6 to 8) protein do not respond well to BVM treatment (3,10,14,16). These three residues (glutamine-valine-threonine [QVT]) are referred to as the SP1 polymorphism motif.…”

Section: -O-(3ј3ј-dimethylsuccinyl) Betulinic Acid (Dsb) Also Knowmentioning

confidence: 99%

A Single Polymorphism in HIV-1 Subtype C SP1 Is Sufficient To Confer Natural Resistance to the Maturation Inhibitor Bevirimat

Salzwedel²,

Wang

et al. 2011

Antimicrob Agents Chemother

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3-O-(3,3-Dimethylsuccinyl) betulinic acid (DSB), also known as PA-457, bevirimat (BVM), or MPC-4326, is a novel HIV-1 maturation inhibitor. Unlike protease inhibitors, BVM blocks the cleavage of the Gag capsid precursor (CA-SP1) to mature capsid (CA) protein, resulting in the release of immature, noninfectious viral particles. Despite the novel mechanism of action and initial progress made in small-scale clinical trials, further development of bevirimat has encountered unexpected challenges, because patients whose viruses contain genetic polymorphisms in the Gag SP1 (positions 6 to 8) protein do not generally respond well to BVM treatment. To better define the role of amino acid residues in the HIV-1 Gag SP1 protein that are involved in natural polymorphisms to confer resistance to the HIV-1 maturation inhibitor BVM, a series of Gag SP1 chimeras involving BVM-sensitive (subtype B) and BVM-resistant (subtype C) viruses was generated and characterized for sensitivity to BVM. We show that SP1 residue 7 of the Gag protein is a primary determinant of SP1 polymorphism-associated drug resistance to BVM.3-O-(3Ј,3Ј-Dimethylsuccinyl) betulinic acid (DSB), also known as bevirimat (BVM), is a potent inhibitor of HIV-1 maturation (7,8,20,21). BVM targets the HIV-1 Gag CA-SP1 boundary region by blocking viral protease cleavage of SP1 from the CA-SP1 precursor and inhibiting release of the mature CA protein, which is the final step required for virion maturation. Despite the novel mechanism of action and initial progress made in small-scale clinical trials (11-13, 17), further development of BVM has encountered unexpected challenges in the clinical setting, because patients whose viruses contain genetic polymorphisms in the Gag SP1 (positions 6 to 8) protein do not respond well to BVM treatment (3,10,14,16). These three residues (glutamine-valine-threonine [QVT]) are referred to as the SP1 polymorphism motif. Interestingly, these naturally occurring mutations that confer intrinsic resistance to BVM were not identified by in vitro drug resistance selection experiments and are not located in the region immediately flanking the CA-SP1 cleavage site (2,7,8). Extensive in vitro drug selection experiments identified six amino acid changes (proximal to the CA-SP1 cleavage site) that independently confer BVM resistance (2). Three substitutions were located at the 1st and 3rd residues of SP1 (A1V, A3V, and A3T), and three substitutions were identified at the extreme C terminus of CA (H226Y, L231M, and L231F).There are extensive data on HIV-1 subtype B viruses and their representative molecular clone pNL4-3 concerning BVM's mechanism of action and antiviral activity (2,4,7,8,20,21). In contrast, HIV-1 non-B subtypes and derived molecular clones have received less attention, despite knowledge that these non-B subtypes are responsible for nearly 90% of the current worldwide HIV-1 pandemic (6,19). Additionally, we noted that non-B subtypes exhibit more frequent changes in the identified SP1 polymorphism motif than B subtype viruses do. The...

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“…Phase I healthy volunteer studies have characterized the single-and multiple-dose pharmacokinetics of bevirimat when administered orally (9,10). Following oral administration, bevirimat is well absorbed, well tolerated, and has a long half-life of approximately 55 h in healthy volunteers.…”

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confidence: 99%