TABLE 2.
Pharmacokinetic parameters for delamanid and the delamanid metabolite DM-6705 following oral dosing on day 10 in children with multidrug-resistant tuberculosisa,b
| Parameter | Value for group: |
||||
|---|---|---|---|---|---|
| 12–17 yrs (n = 7)c | 6–11 yrs (n = 6)c | 3–5 yrs (n = 12)d | 0–2 yrs (n = 12)e | Adults (n = 744)f | |
| Delamanid dose | 100 mg BID | 50 mg BID | 25 mg BID | 10 mg BID, 5 mg BID, or 5 mg QD | 100 mg BID |
| Delamanid PK parameter | |||||
| Cmax (ng/mL) | 557 (304–803) | 573 (485–682) | 500 (287–919) | 179 (45.2–298) | 333 (28)g |
| tmax (h) | 3.98 (0.0–24.0) | 11.98 (2.0–24.0) | 4.00 (0.0–24.0) | 13.75 (2.0–23.97) | |
| AUC0–24 h (ng × h/mL) | 9,790 (6,170–13,000) | 12,000 (9,810–13,300) | 9,290 (5,180–12,900) | 2,740 (701–4,910) | 6,863 (31)g |
| CL/F (mL/min) | 341 (257–541) | 139 (125–170) | 89.8 (64.5–161) | 87.4 (67.9–123) | 655 (625–685)h |
| t1/2, z (h) | 30.4 (19.7–54.7) | 23.7 (19.1–82.1) | 20.5 (16.8–31.3) | ND | 30–38i |
| RacAUC0–24 h | 2.68 (1.86–4.71) | 2.55 (1.72–4.11) | 2.70 (1.85–4.00) | 2.69 (1.24–4.20) | 3.0–3.3h |
| DM-6705 PK parameter | |||||
| Cmax (ng/mL) | 81.7 (52.9–93.2) | 90.0 (62.4–112) | 68.7 (33.7–95.0) | 14.2 (2.38–35.9) | |
| tmax (h) | 12.0 (10.0–14.0) | 12.0 (2.0–24.0) | 3·00 (0.0–24.0) | 10.49 (1.97–24.0) | |
| AUC0–24 h (ng × h/mL) | 1,780 (1,210–2,010) | 1,880 (1,210–2,210) | 1,370 (671–2,160) | 291 (49.6–774) | |
| t1/2, z (h) | 237.3 (217.0–350.5) | ND | 155.4 (88.8–341.8) | 128.2 (70.0–201.4) | |
| RacAUC0–24 h | 12.90 (7.87–19.95) | 11.0 (6.3–23.44) | 11.15 (6.15–19.83) | 15.19 (5.23–65.26) | |
| Ratio of delamanid/DM-6705 AUC0–24 h | 0.18 (0.155–0.198) | 0.148 (0.123–0.181) | 0.164 (0.119–0.190) | 0.12 (0.071–0.161) | |
AUC0–24 h, area under the plasma-time concentration curve from time 0 to 24 h; BID, twice-daily; Cmax, peak (maximum) concentration of drug in plasma; CL/F, oral clearance; ND, not determined; Rac, accumulation ratio; t1/2, z, terminal phase elimination half-life; tmax, time of peak concentration (Cmax).
Delamanid was administered in combination with an optimized background regimen. All values are expressed as median (range). Included for comparison are published PK data from adults with multidrug-resistant TB receiving delamanid (10).
Group 1 and group 2 received adult formulation delamanid (2× 50 mg tablet and 1× 50 mg tablet, respectively).
Group 3 received delamanid pediatric formulation (1× 25 mg dispersible tablet).
Group 4 received delamanid pediatric formulation (administered as 5 mg dispersible tablets) according to their baseline body weights, i.e., patients who were >10 kg received 10 mg BID, >8 and ≤10 kg received 5 mg BID, and ≥5.5 kg and ≤8 kg received 5 mg QD.
From Wang et al. (10).
Predicted steady-state parameters in a non-Asian male (55 kg) with serum albumin of >3.4 g/dL. Shown are means (coefficient of variation percentage [CV%]).
In a 55 kg male with serum albumin of >3.4 g/dL. For CL/F, shown are means (95% confidence interval [CI]).
From Gler et al. (11).