Background
Optimal linezolid (LZD) dosing for treatment of drug-resistant pulmonary tuberculosis (DR-TB) is not established. A5356 was a phase 2, randomized clinical trial comparing two LZD dosing strategies plus delamanid (DLM), bedaquiline, and clofazimine for DR-TB. Additional objectives were to describe DLM and LZD PK and their relationship to outcomes.
Methods
Participants (pts) were randomized to LZD 600mg/d for 26 wks (Arm A) vs 1200mg/d wks 1-4, then 1200mg thrice weekly (TIW) wks 5-26 (Arm B). Both arms received DLM 300mg/d. Intensive PK was performed in 20 pts per Arm at wk 4, before dose reduction in Arm B. Blood samples were collected pre-dose and 1, 2, 4, 8, and 24 hrs after observed dose. DLM, DLM-6705 (active DLM metabolite), and LZD plasma concentrations (conc) were measured by LC-MS/MS. Maximum (Cmax), minimum (Cmin) and time to maximum conc (Tmax) were observed. Area under the curve over 24 hours (AUC), apparent oral clearance (CL/F), and volume of distribution (Vd/F) were calculated by noncompartmental methods. Proportion of pts above proposed pharmacodynamic (PD) target (AUC/MIC ratio) were calculated. Data shown are median (IQR) and compared between LZD dosing groups by geometric mean ratio (GMR; Arm B:Arm A) with 90% CI or Wilcoxon rank sum.
Results
Intensive PK pts (n=40) were 34 yrs (26, 45), 68% male, and BMI 19 kg/m2 (17, 22). Conc-time profiles are in the Figure. DLM and DLM-6705 AUCs were 6938 h*ng/mL (5247, 7883) and 2654 h*ng/mL (1925, 3217), respectively, and not different by LZD dose (GMR [90%CI]: DLM: 0.8 [0.7, 1], DLM-6705: 0.9 [0.7, 1.1]). DLM and DLM-6705 Tmax and CL/F were 4 h (4, 7.7) and 43 L/h (38, 57), respectively, and 4.2 h (3, 8) and 113 L/h (93, 156), respectively. DLM AUC/MIC PD target >252 (MIC=0.015 mcg/mL) was achieved in 97.5% of Arm B pts and 87.5% of Arm A pts at wk 4. Median LZD AUC was 371 h*mcg/mL (292, 460) for Arm B and 167 h*mcg/mL (128, 187) for Arm A (GMR [90% CI]: 2.5 [2, 3.2]). Cmax and Cmin were higher in Arm B (both p<0.01); there was no difference in Tmax (p=0.091), CL/F (p=0.12), or Vd/F (p=0.92). LZD AUC/MIC PD target >125 (MIC=1 mcg/mL) were achieved in 100% of pts in Arm B and 80% in Arm A.
Conclusions
These are the first intensive PK data reported for DLM 300mg/d and LZD 1200mg/d in pts with DR-TB. A high proportion of pts achieved LZD and DLM AUC/MIC PD targets with daily dosing at wk 4. Future analyses in A5356 will assess target attainment after LZD dose reduction to 1200mg TIW in Arm B to explore exposure-response outcomes.
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