Dexmethylphenidate

Absorption

Serdexmethylphenidate is a prodrug of dexmethylphenidate. Following a single dose administration of 52.3 mg/10.4 mg AZSTARYS and 40 mg of an dexmethylphenidate hydrochloride extended-release (ER) capsule in healthy volunteers under fasted conditions:
The mean peak plasma concentration (C
max) of dexmethylphenidate was 14.0 ng/mL and 28.2 ng/mL, respectively;
The mean area under concentration curve (AUC) of dexmethylphenidate was 186 hour*ng/mL and 248 hour*ng/mL, respectively.
The plasma PK profiles of dexmethylphenidate following administration of AZSTARYS or dexmethylphenidate hydrochloride extended-release (ER) capsule are presented in
Figure 1.
Figure 1: Mean Dexmethylphenidate Plasma Concentration-Time Profiles After A Single Dose Administration of AZSTARYS or Dexmethylphenidate Hydrochloride Extended-Release (ER) Capsule in Healthy Adults Under Fasted Conditions
Approximate linear PK was demonstrated for dexmethylphenidate following single dose administration of AZSTARYS in the dose range of 26.1 mg/5.2 mg to 52.3 mg/10.4 mg. Steady state of dexmethylphenidate was approached after the third once-daily dose. At steady-state, dexmethylphenidate mean exposures (C
maxand AUC
0-24h) were approximately 37% higher relative to a single-dose administration of AZSTARYS. No accumulation of serdexmethylphenidate was observed after once-daily administration of AZSTARYS. The mean relative exposure of serdexmethylphenidate to dexmethylphenidate based on molar concentrations for C
max, C
min, and AUC
0-24hrwas about 101%, 8.5%, and 55.7%, respectively, following multiple once-daily oral dosing under fasted conditions.
Absorption
Cross-study calculation estimated an absolute oral bioavailability for serdexmethylphenidate of less than 3%. The median time to reach C
maxof serdexmethylphenidate and dexmethylphenidate (T
max) is about 2 hours following a single dose administration of AZSTARYS under fasted conditions. Following oral administration of serdexmethylphenidate single moiety alone, dexmethylphenidate T
maxis reached at about 8 hours post dose.
Effect of Food
No clinically meaningful differences in the exposure of dexmethylphenidate were observed when administered after an overnight fast, with a high-fat, high-caloric meal, or sprinkled onto applesauce or water. The median time to peak plasma concentration (T
max) was lengthened from 2 to 4-4.5 hours in the presence of food.
Distribution
Plasma protein binding of serdexmethylphenidate and dexmethylphenidate is approximately 56% and 47%, respectively, at 5 µM (about 60-fold higher than the therapeutic concentrations at the highest recommended dose). The mean apparent volume of distribution for serdexmethylphenidate was about 29.3 L/kg after AZSTARYS administration. Dexmethylphenidate shows a mean volume of distribution of 2.65 L/kg after intravenous administration.
Elimination
The mean plasma terminal elimination half-life of serdexmethylphenidate and dexmethylphenidate in healthy adult subjects was about 5.7 hours and 11.7 hours, respectively, following a single dose of 52.3 mg/10.4 mg AZSTARYS. The mean apparent clearance for serdexmethylphenidate was about 3.6 L/hr/kg after AZSTARYS administration. Dexmethylphenidate was eliminated with a mean clearance of 0.40 L/hr/kg after intravenous administration.
Metabolism
Serdexmethylphenidate is a prodrug of dexmethylphenidate and is likely converted to dexmethylphenidate mainly in the lower gastrointestinal tract. Enzymes involved in the conversion process are not identified.
Dexmethylphenidate is metabolized primarily via de-esterification to
d-α-phenyl-piperidine acetic acid (also known as
d-ritalinic acid). Ritalinic acid has little or no pharmacological activity. There is no in vivo interconversion to the
l-threo-enantiomer observed.
Excretion
After oral dosing of radiolabeled serdexmethylphenidate in humans, about 62% and 37% of the radioactivity was recovered in urine and feces, respectively. Metabolite ritalinic acid accounted …