TMC-310911Other Names: ASC-09 Drug Class: Protease Inhibitors
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(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Journal of Acquired Immune Deficiency Syndromes article3)
Mechanism of Action: Protease inhibitor (PI). TMC-310911 is a novel HIV-1 PI that is structurally similar to the FDA-approved PI darunavir (Prezista).4 PIs bind the HIV-1 protease enzyme to inhibit cleavage of viral Gag and Gag-Pol polyproteins, thereby preventing the formation of mature, infectious virus particles.5-7 TMC-310911 is characterized as having a broader in vitro resistance profile than that of currently approved PIs, including darunavir.4
Half-life (T½): In a single-dose study of oral TMC-310911 (75 to 2000 mg) given with or without ritonavir in healthy participants (under fed and fasted conditions), the terminal elimination half-life of TMC-310911 ranged from 1.25 to 3.751 hours. Following multiple oral doses of TMC310911 (various dosing regimens ranging from 150 mg twice daily to 900 mg twice daily) given with or without ritonavir in healthy participants (under fed conditions), the terminal elimination half-life of TMC-310911 ranged from 12.23 to 16.48 hours.8
Metabolism/Elimination: TMC-310911 is primarily metabolized by CYP enzymes.8
Resistance: TMC-310911 has demonstrated in vitro activity against a broad panel of recombinant HIV-1 clinical isolates, including viruses that are resistant to multiple PIs. In vitro resistance selection (IVRS) experiments performed with wild-type (WT) virus and TMC-310911 selected viruses with the R41G or R41E mutation. However, resistant viruses emerged more slowly when IVRS was conducted with WT virus and TMC-310911 than with WT virus and darunavir. In selection experiments performed with r13025 (a clinical isolate containing 7 PI resistance-associated mutations) and TMC-310911, the L10F, I47V, and L90M mutations emerged. In comparison, IVRS with r13025 and darunavir was not only faster, but also produced more PI resistance-associated mutations.4
In a 14-day, Phase IIa study (NCT00838162), 33 treatment-naive participants with HIV received TMC-310911 at one of four different dosing regimens coadministered with low-dose ritonavir. In this study, paired baseline/Day 15 genotypic testing results were available for 18 participants. An emerging PI resistance-associated mutation (A71I/T) was detected on Day 15 in one participant who was in the 75-mg twice-daily dose group and who had the A71T mutation at baseline. No emerging primary PI mutations were detected. Based on phenotypic testing, none of the 18 participants showed reduced susceptibility to currently approved PIs or to TMC-310911.3
Select Clinical Trials
Study Identifiers: NCT00838162
Sponsor: Tibotec Pharmaceuticals, Ireland
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety and antiviral activity of TMC-310911 when co-administered with low-dose ritonavir.
- Participants were treatment-naive adults who had HIV infection for at least 6 months before screening.
- Participants had HIV RNA >5,000 copies/mL and CD4 counts >200 cells/mm3.3,9
Selected Study Results:
- J Acquir Immune Defic Syndr article, 2014: Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1–infected patients
This Phase IIa study enrolled 33 treatment-naive participants with HIV. Participants were randomized to one of four groups to receive ritonavir 100 mg plus one of four dosing regimens of TMC-310911: 75 mg, 150 mg, 300 mg administered twice daily, or 300 mg administered once daily. Nineteen participants had at least one treatment-emergent adverse event (TEAE). The most common TEAEs occurring in at least 10% of participants were fatigue and nausea. TEAEs related to the gastrointestinal system (nausea, diarrhea, and frequent bowel movements) occurred in nine (27.3%) participants. No deaths or serious TEAEs were reported, and none of the TEAEs resulted in participant study discontinuation. Two participants (one in the 150-mg arm and one in the 300-mg once-daily arm) experienced Grade 4 transient increases in ALT and AST levels. The liver enzyme increases seen in the participant receiving 150-mg TMC-310911 were possibly related to treatment, while the participant receiving 300-mg once-daily TMC-310911 was diagnosed with cytomegalovirus (CMV) hepatitis. None of the changes in laboratory findings or ECG parameters were considered as clinically relevant.3
Drug interactions related to TMC-310911 are currently unknown.
- United States National Library of Medicine. ChemIDplus advanced: TMC-310911. https://chem.nlm.nih.gov/chemidplus/rn/1000287-05-7. Accessed January 2, 2019.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed January 2, 2019.
- Stellbrink H-J, Arastéh K, Schürmann D, et al. Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1–infected patients. J Acquir Immune Defic Syndr. 2014;65(3):283-289.
- Dierynck I, Van Marck H, Van Ginderen M, et al. TMC310911, a novel human immunodeficiency virus Type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors. Antimicrob Agents Chemother. 2011;55(12):5723–5731.
- Adamson C. Protease-mediated maturation of HIV: inhibitors of protease and the maturation process. Mol Biol Int Artic ID 604261. 2012;Article ID 604261. doi:10.1155/2012/604261
- Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012;2(4).
- van Maarseveen N, Boucher C. Resistance to protease inhibitors. In: Geretti AM, ed. Antiretroviral Resistance in Clinical Practice. London: Mediscript; 2006.
- Hoetelmans RMW, Dierynck I, Smyej I, et al. Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 Phase 1 studies. JAIDS. 2014;65(3):299.
- Tibotec Pharmaceuticals, Ireland. A Phase IIa, open-label, randomized trial in treatment-naive HIV-1-infected subjects to determine the antiviral activity of 14 Days of monotherapy with 4 different dose regimens of TMC310911 coadministered with ritonavir. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 5, 2009. NLM Identifier: NCT00838162. https://clinicaltrials.gov/ct2/show/NCT00838162. Accessed January 2, 2019.
Last Reviewed: January 2, 2019