Mechanism of Action
: Maturation inhibitor. MPC-4326, a betulinic acid derivative, inhibits HIV-1 proteolytic maturation and production of infectious particles by specifically blocking protease–mediated capsid-spacer peptide 1 (CA-SP1) cleavage in Gag. The MPC-4326 binding pocket is located near the CA-SP1 junction within immature virus particles.5,6
: The MPC-4326 terminal elimination half-life ranged from 56 to 70 hours in a multiple-dose study in healthy participants. In a multiple-dose study in HIV-infected participants, the mean elimination half-life was 62.7 hours.7
: MPC-4326 is metabolized primarily via hepatic glucuronidation by UGT1A3 and does not interact with cytochrome P450 (CYP) enzymes or P-glycoprotein (P-gp).7,8
Animal studies indicate that MPC-4326 is eliminated primarily by a hepatobiliary route; renal excretion is minimal.9
: Intrinsic resistance and non-response to MPC-4326 have been associated with naturally occurring HIV-1 polymorphisms located at SP1 residues 6, 7, and 8 (positions 369, 370, and 371 on Gag), also referred to as the QVT (glutamine-valine-threonine) motif. These polymorphisms have a high prevalence, especially in non-clade B HIV-1 isolates.5,6,10
In addition, in vitro
drug resistance selection experiments with MPC-4326 have indicated that certain mutations in the QVT motif can be acquired under MPC-4326 pressure. MPC-4326 may also select for several mutations occurring in the vicinity of the CA-SP1 cleavage site. Furthermore, the presence of existing HIV-1 protease inhibitor mutations may significantly impact the resistance profile of MPC-4326.5,11
Dosing in Clinical Trials
MPC-4326 is administered orally.12,13
Phase II (Study 204) (treatment-naive or treatment–experienced)
- MPC-4326 (formulated as bevirimat dimeglumine tablets) monotherapy, 200 mg versus 300 mg administered twice daily over 14 days. Participants who achieved ≥0.5 log10 viral load reduction by Day 15 had the option to continue MPC-4326 in combination with an optimized background regimen for up to 72 weeks.12,14
Phase II (Study 206) (treatment-experienced)
- MPC-4326 (formulated as bevirimat dimeglumine tablets) 200 mg twice daily; or 300 mg or 400 mg once daily over 15 days, each in combination with participant’s own antiretroviral therapy regimen.13,15
A previous phase II study investigated an orally administered liquid formulation of MPC-4326 in treatment-experienced participants.16
In Study 204, the most common adverse events that occurred over 14 days of treatment with twice-daily MPC-4326 monotherapy were headache, diarrhea, and nausea. No study discontinuations, serious adverse events, or grade III or IV events were reported.14
In Study 206, the most common adverse events that occurred over 15 days of treatment with once or twice-daily MPC-4326 in combination with antiretroviral therapy were diarrhea, abdominal cramping, headache, and nausea. No serious adverse events related to the study drug were reported.15
MPC-4326 is a substrate of UDP-glucuronosyltransferases (UGTs) and has exhibited weak to moderate inhibition of UGT enzymes 1A1, 1A3, 1A4, 1A8, 1A10 and 2B7. MPC-4326 is metabolized primarily by UGT1A3 and does not interact with the CYP enzyme system or with P-gp.7,8
Coadministration with ritonavir has been shown to decrease MPC-4326 exposures. No pharmacokinetic interactions have been noted when atazanavir is coadministered with MPC-4326.7
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. Waki K, Durell SR, Soheilian F, Nagashima K, Butler SL, Freed EO. Structural and Functional Insights into the HIV-1 Maturation Inhibitor Binding Pocket
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. McCallister S, Lalezari J, Richmond G, et al. HIV-1 Gag polymorphisms determine treatment response to bevirimat (PA-457)
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. Fun A, van Maarseveen NM, Pokorná J, et al. HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat
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. Myrexis Inc. A Phase II Multicenter, Open-label, Randomized, Parallel Group, Study of Bevirimat in HIV-1 Positive Patients to Evaluate the Safety, Efficacy, and Pharmacokinetics of MPC-4326 Administered as Monotherapy for 14 Days and as Part of an Optimized Background Regimen for up to 72 Weeks
. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 25, 2009. NLM Identifier: NCT00967187. Last accessed on February 24, 2014.
. Myrexis Inc. A Phase II Multicenter, Open-label, Randomized, Parrallel Group Study to Assess the Pharmacokinetics of Bevirimat (BVM) 100 mg Tablets Administered to HIV-1 Positive Patients for 15 Days
. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 23, 2010. NLM Identifier: NCT01097070. Last accessed on February 24, 2014.
. Bloch M, Bodsworth N, Fidler M, et al. Efficacy, Safety and Pharmacokinetics of MPC-4326 (Bevirimat Dimeglumine) 200mg bid and 300mg bid Monotherapy Administered for 14 days in Subjects with HIV-1 Infection
. Abstract presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Abstract H-1230. Last accessed on February 24, 2014.
. Lalezari J, Richmond G, Thompson M, et al. Pharmacokinetics and Safety of a Novel 100 mg Tablet Formulation of MPC-4326 in Subjects with HIV-1 Infection
. Abstract presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Abstract A1-1309. Last accessed on February 24, 2014.
. Lalezari J, McCallister S, Gigliotti M, et al. A Phase 2 Safety and Efficacy Study of Bevirimat (BVM) in Heavily Treatment Experienced HIV+ Patients Identifies the Target Phase 3 Study Profile
. Abstract presented at: 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/Infectious Diseases Society of America (IDSA) 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-891. Last accessed on February 24, 2014.
Last Reviewed: February 24, 2014
Last Updated: February 24, 2014