Pharmacokinetics and tolerability of MB12066, a beta-lapachone derivative targeting NAD(P)H: quinone oxidoreductase 1: two independent, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials

Figures & data

Table 1 Overview of the study design

	Single ascending dose	Multiple ascending dose
Study 001 (Single ascending-dose study, ClinicalTrials.gov identifier: NCT01285388)	10, 30, 100, 150 and 200 mg
Study 002 (Single and multiple ascending-dose study, ClinicalTrials.gov identifier: NCT01444677)	300 and 400 mg	100 and 200 mg

Table 2 Summary of the PK parameters after the oral administration of a single MB12066 dose

PK parameters	Treatment
	10 mg (n=8)	30 mg (n=8)	100 mg (n=8)	150 mg (n=8)	200 mg (n=8)	300 mg (n=8)	400 mg (n=8)
Tmax (hour)a	3.5 (1.0–4.0)	2.5 (1.0–6.0)	5.0 (1.0–10.0)	4.0 (3.0–10.0)	4.0 (2.0–10.0)	4.0 (2.0–10.0)	3.0 (3.0–8.0)
Cmax (μg/L)	0.88±0.59	1.73±1.72	1.56±0.50	2.33±1.11	8.90±7.85	5.70±4.58	9.54±6.64
AUClast (μg·hour/L)	5.15±5.51	5.49±3.37	19.74±11.92	31.52±9.52	60.81±25.87	44.80±35.41	53.39±32.25
AUCinf (μg·hour/L)	10.62±11.70b	12.04±13.35c	26.98±16.92	43.22±16.06	72.97±30.55	64.27±38.52b	74.07±23.57b
T1/2 (hour)	10.4±9.8b	18.7±36.3c	16.4±12.6	24.6±16.3	22.7±10.5	19.2±15.5b	13.4±4.3b
Vd/F (L)	15,560.9±8,862.3b	44,004.4±33,321.9c	84,798.5±20,192.7	122,603.6±56,617.4	97,757.1±38,356.8	147,885.8±100,396.5	114,983.3±56,232.9b
CL/F (L/hour)	1,959.9±1,549.5b	5,225.7±4,455.0c	7,736.5±10,096.4	3,893.2±1,400.7	4,280.1±4,859.2	6,507.8±3,821.1	5,754.6±1,343.9
Ae (μg)	73.8±22.0	116.9±69.9	285.1±137.0	541.8±163.7d	769.9±399.9d	425.4±336.9	992.5±637.5
fe	0.007±0.002	0.004±0.002	0.003±0.001	0.004±0.001d	0.004±0.002d	0.001±0.001	0.004±0.002
CLR (L/hour)	13.74±9.49b	18.10±15.58c	15.79±11.32	15.00±6.02d	12.47±5.05d	8.72±6.57b	16.45±10.30b

Notes: Values are presented as means ± SD.

a Values are presented as medians (minimum–maximum).

b N=7,

c n=6 from unestimated terminal elimination constants.

d N=7 from urine loss.

Abbreviations: A_e, cumulative amount of unchanged drug excreted into the urine; AUC_inf, area under the plasma concentration curve extrapolated to infinity; AUC_last, area under the plasma concentration curve from time 0 to the last detectable time point; C_max, maximum plasma concentration; CL/F, apparent clearance; CL_R, renal clearance; f_e, fraction of drug excreted unchanged; PK, pharmacokinetics; T_1/2, elimination half-life; T_max, time to reach the maximum plasma concentration; Vd/F, apparent volume of distribution.

Figure 1 Mean plasma concentration–time profiles after the oral administration of a single dose of MB12066 from predose to 72 hours postdose (left panel: log-linear scale; right panel: linear scale).

Figure 2 Relationship between individual (A) C_max or (B) AUC_last and doses after a single administration of MB12066.

Abbreviations: AUC_last, area under the plasma concentration curve from time 0 to the last detectable time point; C_max, maximum plasma concentration.

Table 3 Summary of the PK parameters after multiple oral administrations of MB12066 (days 1 and 7 [steady state])

PK parameters	Treatment
	100 mg (n=8)	200 mg (n=8)
Day 1
Tmax (hour)a	3.5 (2.0–6.0)	4.0 (2.0–8.0)
Cmax (μg/L)	3.83±4.04	3.70±1.91
AUCτ (μg·hour/L)	17.71±13.03	26.59±17.95
Day 7
Tmax,ss (hour)a	3.5 (3.0–6.0)	3.99 (2.0–4.0)
Cmax,ss (μg/L)	3.87±2.76	3.82±2.29
Ctrough,ss (μg/L)	0.95±0.61	1.13±0.59
AUCτ,ss (μg·hour/L)	29.92±19.10	33.13±15.40
T1/2,ss (hour)	17.35±16.91	13.74±11.40
Accumulation index	1.67±0.96	1.48±0.61
Ae,ss (μg)	283.3±151.7	510.6±401.8
fe,ss	0.003±0.002	0.003±0.002
CLR,ss (L/hour)	11.31±8.60	15.23±10.00

Notes: Values are presented as means ± SD.

a Values are presented as medians (min−max).

Abbreviations: A_e, cumulative amount of unchanged drug excreted into the urine during the steady state; AUC_inf,ss, area under the plasma concentration curve extrapolated to infinity at a steady state; AUC_last,ss, area under the plasma concentration curve from time 0 to the last detectable time point at a steady state; AUC_τ, area under the plasma concentration curve during a dosage interval; CL_R,ss, steady-state renal clearance; C_max, maximum plasma concentration; C_max,ss, maximum steady-state plasma concentration; f_e,ss, steady-state fraction of drug excreted unchanged; PK, pharmacokinetics; T_1/2,ss, steady-state elimination half-life; T_max, time to reach the maximum plasma concentration; T_max,ss, time to reach the maximum steady-state plasma concentration.

Figure 3 Mean plasma concentration–time profiles after the oral administration of multiple doses of MB12066 from predose to 96 hours after the last dose (left panel: log-linear scale; right panel: linear scale).

Table 4 Summary of dose-normalized PK parameters stratified by NQO1 genotype

Single-dose study	*1/*1 (n=21)	*1/*2 (n=28)	*2/*2 (n=7)	P-valuea
Cmax/dose (μg/L/mg)	0.035±0.036	0.044±0.051	0.023±0.006	0.659
AUClast/dose (μg*hour/L/mg)	0.297±0.369	0.202±0.146	0.217±0.090	0.781
Multiple-dose study	*1/*1 (n=5)	*1/*2 (n=9)	*2/*2 (n=1)	P-valueb
Cmax,ss/dose (μg/L/mg)	0.047±0.033	0.033±0.031	0.056	0.036
AUCτ,ss/dose (μg*hour/L/mg)	0.220±0.111	0.119±0.094	0.265	0.012

Note:

a ANOVA,

b Kruskal–Wallis test.

Abbreviations: AUC_last, area under the plasma concentration curve from time 0 to the last detectable time point; AUC_last,ss, area under the plasma concentration curve from time 0 to the last detectable time point at the steady state; C_max, maximum plasma concentration; C_max,ss, maximum steady-state plasma concentration.