The promising experimental tuberculosis (TB) drug delamanid does not interact with the widely used antiretrovirals tenofovir (Viread) and lopinavir/ritonavir (Kaletra) in ways likely to cause clinical problems, researchers reported at the XIX International AIDS Conference (AIDS 2012) last month in Washington, DC.

Tuberculosis is the leading cause of death for people with HIV worldwide. Studies have shown that starting antiretroviral therapy (ART) promptly while undergoing TB treatment leads to better outcomes, but this can be a challenge due to potential interactions between TB and HIV drugs.

In recent years concern has arisen about multidrug-resistant TB (MDR-TB), which does not respond to standard first-line medications, and extensively drug-resistant TB (XDR-TB), which is resistant to most or all available therapies.

As previously reported, the investigational nitro-dihydro-imidazooxazole derivative antibiotic delamanid (OPC-67683) has demonstrated good activity against highly-resistant TB, clearing infection in more than 40% of Phase 2b trial participants.

In preparation for trials of delamanid in people with HIV, Otsuka Pharmaceutical researchers conducted a study of drug-drug interactions between delaminid and 2 widely used antiretroviral medications: the nucleotide reverse transcriptase inhibitor tenofovir -- a component of the 4 available HIV single-tablet regimens -- and the boosted protease inhibitor lopinavir/ritonavir.

Ritonavir is a strong inhibitor of the CYP3A enzyme that processes drugs in the liver, the investigators noted as background. This makes it a challenge to use with other drugs metabolized by the same enzyme, including rifampin for TB. Delamanid, in contrast, does not inhibit or induce CYP enzymes.

In this open-label Phase 1 study, healthy adult volunteers (age 18-45 years) without HIV or TB were randomly assigned to receive multiple doses of delamanid alone or with tenofovir or lopinavir/ritonavir to assess the potential for drug-drug interaction.

After 14 days of administration to reach steady-state levels, the researchers collected blood samples and performed pharmacokinetic measurements including pre-dose, peak, and trough (lowest) drug levels.

Results

• Delamaniddid not significantly affect drug exposure levels of tenofovir, lopinavir, or ritonavir.
  
  
• Tenofovir, likewise, had no significant effect on delamanid exposure.
  
  
• Lopinavir/ritonavir was associated with about a 20% increase in delamanid exposure, which the researchers suggested may be due to CYP3A inhibition by ritonavir.
  
  
• Treatment-emergent adverse events were infrequent when using delamanid alone, and adding delamanid did not increase the frequency of side effects in people taking tenofovir or lopinavir/ritonavir.
  
  

"No clinically relevant changes in drug exposure occurred with combined administration of delamanid and tenofovir or lopinavir/ritonavir in healthy subjects," the researchers concluded. "Delamanid is a promising new agent to treat MDR-TB patients on antiretroviral therapy containing tenofovir or lopinavir/ritonavir."

By Liz Highleyman

Reference

A Paccaly, C Petersen, S Patil, et al. Absence of clinically relevant drug interaction between delamanid, a new drug for multidrug-resistant tuberculosis (MDR-TB) and tenofovir or lopinavir/ritonavir in healthy subjects. IX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Poster WEPE043.