Efavirenz interaction studies with TB compounds bedaquiline and delamanid
Polly Clayden, HIV i-Base
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.
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.
- 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.
- 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.