Advertisement
Advertisement

TheBody.com/TheBodyPRO.com covers The 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012)

Efavirenz Interaction Studies With TB Compounds Bedaquiline and Delamanid

September/October 2012

HIV and TB co-infection is common and treatment is complicated by drug-drug interactions. 

Two poster presentations at ICAAC described potential reduced exposure of bedaquiline and a lack of interaction with delamanid when co-administered with efavirenz (EFV).

Bedaquiline, is metabolised to an N-monodesmethyl metabolite (M2) by CYP3A4. For the population pharmacokinetic (PK) study presented, data were obtained from a previously reported drug-drug interaction trial (ACTG A5267) conducted in 33 HIV negative volunteers, who received two doses of 400 mg bedaquiline, the second co-administered with EFV after two weeks of receiving this at 600 mg once daily. Samples were obtained over 14 days after each bedaquiline dose. The investigators used non-linear mixed effects modeling for this analysis.

Advertisement
They reported oral clearance of bedaquiline (CL/F) and M2 (CL/F/fm) of 3.1 L/h (relative standard error, RSE, 6.9%) and 13.2 L/h (RSE 7.1%) respectively. The impact of induction was described as an immediate change in CL/F one week after starting EFV. The estimated change in CL/F was the same for bedaquiline and M2, an increase of 104% (RSE 4.3%).

Both bedaquiline and M2 exposure was decreased by 40-50% under a range of plausible assumptions used in this model-based analysis. This is more than previously concluded from the single-dose data.

Delamanid does not inhibit or induce CYP enzymes. EFV is metabolised by CYP2B6.

Data were presented from a phase 1, open-label, randomised, multiple dose trial in 30 (15 per group) healthy volunteers, conducted to investigate the effect on drug exposure and safety of co-administered delaminid 100 mg twice daily and EFV 600 mg once daily.

In this study, EFV was given alone for 10 days (Group 1); delamanid was given alone for seven days and with EFV for a further 10 days (Group 2). Pre-dose and at trough samples were obtained before full PK sampling. For EFV PK, samples were taken on day 10/11 (Group 1) and day 17/18 (Group 2); for delamanid PK on day 7/8 (Group 1) and day 17/18 (Group 2).

The investigators calculated plasma PK parameters including geometric mean ratios for Cmax and AUCt with 90% CI. This revealed that exposure to both drugs does not appear to be affected by co-administration. One participant in each group had elevated EFV exposure associated with CYP2B6 polymorphisms.

Adverse events were reported in 93% of participants who received both drugs, 73% EFV alone and 60% delamanid alone. All were mild to moderate. One participant discontinued while on two drugs due to abnormal liver function tests.

The phase 3 trial of delaminid is now enrolling a subgroup of HIV positive people receiving ART.


References

  1. Svensson E et al. Population pharmacokinetics (PK) of TMC207 and its M2 metabolite with efavirenz (EFV) demonstrate reduced Exposure. 52nd ICAAC, San Francisco, 9-12 September 2012. Poster abstract A-1256.
  2. Petersen C et al. Delamanid, a new drug for multi-drug resistant tuberculosis (MDR-TB), and efavirenz do not show clinically relevant drug interactions in healthy subjects. 52nd ICAAC, San Francisco, 9-12 September 2012. Poster abstract A-1255.



Visit HIV i-Base's website to find out more about their activities, publications and services.
 


No comments have been made.
 

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read TheBody.com's Comment Policy.)

Your Name:


Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:


Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

Advertisement