Pharmacokinetic parameters at steady state: prescribing information

Parameter	Prescribing information
Presentation of values	“Levacetylleucine pharmacokinetic parameters at steady state are presented as mean (SD) unless otherwise specified.”
Maximum concentration and exposure	“Levacetylleucine maximum concentration (Cmax) and area under the curve from time 0 to 24 hours (AUC0-24hrs) were 8.3 (3.3) µg/mL and 33.2 (12.5) h*µg/mL.”
Accumulation	“No levacetylleucine accumulation occurs after repeated administration.”
Absorption	“Levacetylleucine time to Cmax (Tmax) is 1 hour (ranging from 0.5 to 2.5 hours).”
Distribution	“Levacetylleucine apparent (oral) volume of distribution (Vss/F) is 253 (125) L.”
Elimination	“Levacetylleucine estimated half-life is around 1 hour and the apparent (oral) clearance is 139 (59) L/h.”
Metabolism	“Levacetylleucine is metabolized into acetate and L-leucine by ubiquitously expressed enzymes, which are used endogenously in catabolic and metabolic pathways.”
Cytochrome P450 involvement	“Cytochrome P450 enzymes are not involved in the metabolism of levacetylleucine.”

Covariates: age, sex, race, and body weight

“No clinically significant differences in pharmacokinetics of levacetylleucine were observed based on age (range 4 to 67 years), gender (female 47%, male 53%), or race/ethnicity (White 92%, Asian 3%, Other or not specified 5%).” (opens the prescribing information at this quote)
“The volume of distribution and clearance of levacetylleucine increases with increasing body weight (21 kg to 109 kg), but these effects on pharmacokinetics are minimized by the recommended weight-based dosing.” (opens the prescribing information at this quote)

Pharmacokinetics: European summary of product characteristics

“After oral administration, levacetylleucine is rapidly absorbed.” (opens the source at this quote in a new tab)
“Mean, dose-normalised (per gram of levacetylleucine) Cmax and area under the curve from time 0 to 24 hours (AUC0-24hrs) were 4 mcg/mL/g and 9 h*mcg/mL/g. The absolute oral bioavailability is unknown.” (opens the source at this quote in a new tab)
“No studies on food effect on absorption have been conducted.” (opens the source at this quote in a new tab)
“Levacetylleucine is taken up by ubiquitously expressed monocarboxylate transporters, thereby delivering levacetylleucine to all tissues including the central nervous system.” (opens the source at this quote in a new tab)
“No or only minor accumulation was observed after repeat administration.” (opens the source at this quote in a new tab)

Clinical pharmacology program

“Another Phase II study IB1001-203 is ongoing but was not included as part of this application. No Phase I studies were performed.” (opens the source at this quote in a new tab)
“Only a single dose level was evaluated in humans and consequently the range of linear PK could not be determined.” (opens the source at this quote in a new tab)

Rich sampling in the phase 2 NPC study

“Following single dose of levacetylleucine (Commercial formulation, Visit 7B, n=14) in subjects from Study IB1001-201, absorption was reasonably rapid with a Cmax approximately achieved at a median (min-max) Tmax of 1h (0.5-2 h).” (opens the source at this quote in a new tab)
“Following multiple doses of levacetylleucine (Commercial formulation, Visit 9B, n=19) in subjects from Study IB1001-201, absorption was reasonably rapid with a Cmax approximately achieved at a median (min-max) Tmax of 1h (0.75-1.3 h).” (opens the source at this quote in a new tab)
“Based on study IB1001-201, after multiple doses, geometric mean Vss/F was 227 L.” (opens the source at this quote in a new tab)
“Based on study IB1001-201, after multiple doses, geometric mean CLss/F was 128 L/h.” (opens the source at this quote in a new tab)

Protein binding, bioavailability, metabolism, and excretion

“Based on in vitro investigation (Study ADM-20-2970b), levacetylleucine tested at a concentration of 1, 10 and 100 µg/mL has a protein binding near 0%.” (opens the source at this quote in a new tab)
“No information was provided with regards to levacetylleucine absolute bioavailability” (opens the source at this quote in a new tab)
“Interconversion between the L to the D enantiomer is unlikely.” (opens the source at this quote in a new tab)
“Only minor amounts of levacetylleucine are excreted via the urine.” (opens the source at this quote in a new tab)

Population pharmacokinetic analysis

“The PPK of levacetylleucine was based on PK results pooling 3 clinical studies from patients aged 4 years and over (IB1001-201/202/301).” (opens the source at this quote in a new tab)
“Overall, 185 subjects with 567 PK observations were included.” (opens the source at this quote in a new tab)
“The final PPK model consisted of a one compartment PK model parameterized with first order absorption and lag time and linear elimination, in terms of Ka, Tlag, CL/F and Vd/F.” (opens the source at this quote in a new tab)
“Body weight allometric scaling with fixed exponents to theoretical values was considered on both CL/F and Vd/F.” (opens the source at this quote in a new tab)
“Based on the PPK analysis IIV CL/F and Vd/F were 38.7% and 83%.” (opens the source at this quote in a new tab)

Variability and reliability of pharmacokinetic sampling

“The inter-subject variability in exposure of levacetylleucine in patients with NPC was moderate to high (from single to multiple dose) with range from 30% to 47 % for Cmax and 36% to 39 %for AUC0-24.” (opens the source at this quote in a new tab)
“Considering the findings related to findings for the PK sampling/bioanalysis observed during the GCP inspection for study IB1001-301, the reliability of the PK samples measurement could be questioned and the potential impact of endogenous PK levels cannot be fully excluded” (opens the source at this quote in a new tab)

Enantiomer pharmacokinetics after oral dosing in mice

“When administered as the racemate, both the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer.” (opens the source at this quote in a new tab)
“When administered as the racemate, the ratio of D/L enantiomer was about 25 for both Cmax (Fig 5H; 26 versus 1, p = 0.014) and AUC (Fig 5I, 25 vs 1, p = 0.015).” (opens the source at this quote in a new tab)
“Elimination (ke and T1/2) was similar for both enantiomers.” (opens the source at this quote in a new tab)
“These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation.” (opens the source at this quote in a new tab)
“In brain and muscle, N-acetyl-L-leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-leucine and utilization by normal leucine metabolism.” (opens the source at this quote in a new tab)

Deacetylation in human and mouse liver fractions

“The time course revealed that the disappearance of 1 µM N-acetyl-dl-[2H10]leucine asymptotically approached 50% of the initial concentration (i.e., 0.5 µM) and correlated well with the appearance of l-leucine for both human (Fig. 4f) and mouse (Fig. 4g) fractions.” (opens the source at this quote in a new tab)
“Kinetic data fit to the Michaelis–Menten equation yielded a Km values of 216 and 69 µM and Vmax values of 6.8 and 2.6 µmol/min/mg protein for human and mouse, respectively (Fig. 4h).” (opens the source at this quote in a new tab)

Brain distribution of the radiolabeled racemate in monkeys

“An important uptake of radioactivity is localized in the cortical structures and in several tisses such as nuclei of the vestibular system, including the inner ear.” (opens the source at this quote in a new tab)