Single ascending dose in healthy volunteers: parameters by dose

Parameter	10 mg (N = 6)	50 mg (N = 6)	100 mg (N = 6)	150 mg (N = 6)	200 mg (N = 6)
Cmax, mean (SD), ng/mL	“24.1 (10.728)”	“176 (52.786)”	“348.167 (141.832)”	“596.5 (117.527)”	“975.667 (253.995)”
Tmax, median (min, max), h	“3 (3, 3)”	“3 (2, 4)”	“3.01 (1, 4)”	“3 (3, 4)”	“1.75 (1.5, 3)”
t½, mean (SD), h	“13.75 (3.9375)”	“11.933 (1.7797)”	“14.146 (3.9617)”	“11.969 (1.8897)”	“12.997 (3.5854)”
AUC0-24, mean (SD), ng•h/mL	“198.807 (66.9513)”	“1336.105 (167.6764)”	“2303.664 (533.1684)”	“4067.23 (685.9163)”	“5983.093 (833.9816)”
AUC0-inf, mean (SD), ng•h/mL	“252.637 (69.857)”	“1595.938 (189.1599)”	“2809.785 (477.7622)”	“4363.577 (745.7299)”	“7002.109 (820.7252)”
CL/F, mean (SD), L/h	“42.44 (12.598)”	“31.7 (3.794)”	“36.56 (6.935)”	“33.05 (5.25)”	“28.89 (3.381)”

Absorption and half-life

“In Part A (SAD), LB-102 was rapidly absorbed and LB-102 concentration generally declined from peak in an apparent biphasic manner.” (opens the source at this quote in a new tab)

“The half-life of LB-102 was slightly greater than 12 hours, and maximum drug levels were observed approximately three hours after administration.” (opens the source at this quote in a new tab)

“A phase 1 trial demonstrated LB-102 has rapid absorption (time to peak drug concentration, [Tmax] approximately 3 hours), nearly dose-proportional exposure across 10 to 200 mg, and a terminal half-life of 12 to 14 hours, with transient prolactin elevation and mild extrapyramidal symptoms occurring when occupancy exceeded 80%.” (opens the source at this quote in a new tab)

Dose proportionality

“exposure (as measured by Cmax, AUC0-t, and AUC0-inf) increased in a slightly greater than dose-proportional manner” (opens the source at this quote in a new tab)
“Apparent clearance (CL/F) appeared to decrease as dose increased (42.44 L/h to 28.89 L/h).” (opens the source at this quote in a new tab)
“Exposure to LB-102 increased in a dose-proportional manner.” (opens the source at this quote in a new tab)
“Apparent clearance at steady state to LB-102 appeared to be similar as the dose increased.” (opens the source at this quote in a new tab)

Steady state and accumulation with twice-daily dosing

“In Part B (MAD), trough concentrations of LB-102 and amisulpride plateaued before the morning dose on Day 4.” (opens the source at this quote in a new tab)
“After multiple doses, there was slight to moderate accumulation of LB-102 across dose levels with mean accumulation ratio based on Cmax after the first dose and last dose (RCmax) values ranged from 1.121 to 1.798 and with mean accumulation ratio based on AUC after the first and last dose (RAUC) values ranged from 1.472 to 1.925.” (opens the source at this quote in a new tab)

Metabolism to amisulpride in humans

“In Part A (SAD), amisulpride was formed quickly over time after a single dose of LB-102 (median Tmax, range = 2 to 3.5 hours) and generally declined with an approximate biphasic disposition of comparable shape to LB-102 but at approximately 2.5% of LB-102 abundance.” (opens the source at this quote in a new tab)
“In fact, amisulpride was not detected in healthy volunteers taking 10 mg LB-102 QD (Cohort 2).” (opens the source at this quote in a new tab)
“Mean amisulpride t½ ranged from approximately 8.921 to 14.614 hours.” (opens the source at this quote in a new tab)
“Amisulpride had a higher accumulation than LB-102 across dose levels with mean RCmax values ranged from 1.317 to 2.016 and with mean RAUC values ranged from 1.801 to 2.232.” (opens the source at this quote in a new tab)

“The metabolism of LB-102 will be studied more completely in a subsequent study.” (opens the source at this quote in a new tab)

Metabolism in rodents

“N-demethylation of LB-102 (generating amisulpride) is the dominate elimination pathway.” (opens the source at this quote in a new tab)

“LB-102 displays a demethylation burst (possibly 1st pass) followed by a steady state having equal proportions of LB-102 and demethylated metabolite (amisulpride).” (opens the source at this quote in a new tab)

Plasma exposure compared with published amisulpride values

“We observed the plasma exposure of 50 mg of LB-102 to be 1,648 ng*h/mL.” (opens the source at this quote in a new tab)
“In a previous third-party study of amisulpride, plasma exposure was reported at 667 ng*h/mL.” (opens the source at this quote in a new tab)

“Plasma concentrations of LB-102 were ~2.5 times greater than published values of amisulpride at the same dose, suggesting LB-102 could be dosed substantially lower than amisulpride” (opens the source at this quote in a new tab)

Membrane permeability and brain penetration

“The ability of LB-102 to cross the BBB was estimated using a standard in vitro membrane permeability assay.” (opens the source at this quote in a new tab)
“In this assay, the permeability of LB-102 was approximately 200-fold greater than that of amisulpride.” (opens the source at this quote in a new tab)

“This may be due to the increased lipophilicity of LB-102 and increased residence time in brain, which may be due to more than just lipophilicity alone” (opens the source at this quote in a new tab)
“Future work may include more direct measurements of LB-102 in brain to further validate the hypothesis of its potential improved brain kinetics and potential to be an effective antipsychotic with antidepressant action while enjoying a low side effect potential.” (opens the source at this quote in a new tab)

Food effect: company expectation

“No expected food effect or DDIs” (opens the source at this quote in a new tab)

Class context: pharmacokinetics of oral amisulpride

“Absolute bioavailability is 48%.” (opens the source at this quote in a new tab)
“As plasma protein binding is low (16%) drug interactions are unlikely.” (opens the source at this quote in a new tab)
“Amisulpride is weakly metabolised: two inactive metabolites, accounting for approximately 4% of the dose, have been identified.” (opens the source at this quote in a new tab)
“The elimination half-life of amisulpride is approximately 12 hours after an oral dose.” (opens the source at this quote in a new tab)
“Amisulpride is eliminated unchanged in the urine.” (opens the source at this quote in a new tab)
“Kinetic profile of amisulpride is not influenced by diet.” (opens the source at this quote in a new tab)
“A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUCs, Tmax and Cmax of amisulpride but no changes were seen after a high fat meal.” (opens the source at this quote in a new tab)

Class context: excretion of intravenous amisulpride

“After intravenous administration of amisulpride, 74% and 23% of the administered dose was recovered in urine and feces, respectively.” (opens the source at this quote in a new tab)
“Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects suggesting that amisulpride undergoes active renal secretion.” (opens the source at this quote in a new tab)

Food effect study results for LB-102

No evidence found.

Absolute bioavailability, plasma protein binding, volume of distribution, mass balance, and routes of excretion of LB-102

No evidence found.

Pharmacokinetics of LB-102 in participants with schizophrenia

No evidence found.