An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations

Figures & data

Table 1. Summary of long-acting methylphenidate and amphetamine formulations approved in U.S. for the treatment of ADHD (past 20 years).

Brand Name (Manufacturer Name)	Manufacturer (as of March 2019)	Approval Date	FDA-approved Age	Available Dosing Strengths	Dosage Form	Administration	Formulation	Drug Delivery Platform	IR/ER (%)	Enantiomer/ Salt
Methylphenidate formulations
ADHANSIA XR (PRC-063) [78]	Adlon Therapeutics (Purdue Pharma)	February 2019	≥6 years	25, 35, 45, 55, 70, and 85 mg	Capsule (composite beads)	Oral (whole or sprinkled)	MPH-MLR	Multilayered beads	IR 20%; ER 80%	d,l-MPH
APTENSIO XR (RP-BP) [66]	Rhodes Pharmaceuticals	April 2015	≥6 years	10, 15, 20, 30, 40, 50, and 60 mg	Capsule (composite beads)	Oral (whole or sprinkled)	MPH-MLR	Multilayered beads	IR 40%; ER 60%	d,l-MPH
CONCERTA [40]	Janssen Pharmaceuticals	August 2000	≥6 years ≤65 years	18, 27, 36, and 54 mg	Tablet	Oral (whole)	OROS-MPH	OROS®	IR 22%; ER 78%	d,l-MPH
COTEMPLA XR-ODT (NT-0102) [19,72]	Neos Therapeutics	June 2017	6‒17 years	8.6, 17.3, and 25.9 mg	Orally disintegrating tablet	Oral (whole)	MPH XR-ODT	Ion-exchange resin microparticles	IR 25%; ER 75%	d,l-MPH
DAYTRANA (SPD485) [27,61]	Noven Therapeutics	April 2006	≥6 years	10 mg/9 hours (1.1 mg/h), 15 mg/9 hours (1.6 mg/h), 20 mg/9 hours (2.2 mg/h), 30 mg/9 hours (3.3 mg/h)	Transdermal patch	Topical (hip)	MTS	DOT Matrix® Transdermal	N/A	d,l-MPH
FOCALIN XR [57]	Novartis Pharmaceuticals	May 2005	≥6 years	5, 10, 15, 20, 25, 30, 35, and 40 mg	Capsule (mixed beads)	Oral (whole or sprinkled)	d-MPH-ER	SODAS®	IR 50%; ER 50%	d-MPH
JORNAY PM (HLD200) [75]	Ironshore Pharmaceuticals	August 2018	≥6 years	20, 40, 60, 80, and 100 mg	Capsule (composite beads)	Oral (whole or sprinkled)	DR/ER-MPH	DELEXIS®	N/A	d,l-MPH
METADATE CD [47]	UCB	April 2001	6‒15 years	10, 20, 30, 40, and 50 mg	Capsule (mixed bead)	Oral (whole or sprinkled)	MPH-CD	Diffucaps®	IR 30%; ER 70%	d,l-MPH
QUILLICHEW ER (NWP09) [70]	Tris Pharma	December 2015	≥6 years	20, 30, and 40 mg	Chewable tablet	Oral (chewed)	MPH-ERCT	Ion-exchange resin microparticles	IR 30%; ER 70%	d,l-MPH
QUILLIVANT XR (NWP06) [62]	Tris Pharma	September 2012	≥6 years	5 mg/mL in bottles containing 300, 600, and 750 mg of powder (to prepare 60, 120, and 150 mL suspensions, respectively)	Liquid oral suspension	Oral	MEROS	LiquiXR®	IR 20%; ER 80%	d,l-MPH
RITALIN LA [53]	Novartis Pharmaceuticals	June 2002	≥6 years	10, 20, 30, and 40 mg	Capsule (mixed beads)	Oral (whole or sprinkled)	MPH-LA	SODAS®	IR 50%; ER 50%	d,l-MPH
Amphetamine formulations
ADDERALL XR (SLI381) [37]	Shire	October 2001	≥6 years	5, 10, 15, 20, 25, and 30 mg	Capsule (mixed beads)	Oral (whole or sprinkled)	MAS-ER	SODAS®	IR 50%; ER 50%	Mixed salts of d- and l-AMP (ratio of 3:1)
ADZENYS ER (NT-0201) [97]	Neos Therapeutics	September 2017	≥6 years	1.25 mg/mL in 450 mL bottles	Liquid oral suspension	Oral	AMP XR-OS	Ion-exchange resin microparticles	IR 50%; ER 50%	Mixed salts of d- and l-AMP (ratio of 3:1)
ADZENYS XR-ODT (NT-0202) [94]	Neos Therapeutics	January 2016	≥6 years	3.1, 6.3, 9.4, 12.5, 15.7, and 18.8 mg	Orally disintegrating tablet	Oral (whole)	AMP XR-ODT	Ion-exchange resin microparticles	IR 50%; ER 50%	Mixed salts of d- and l-AMP (ratio of 3:1)
DYANAVEL XR (TRI102) [91]	Tris Pharmaceuticals	October 2015	≥6 years	2.5 mg/mL in 464 mL bottles	Liquid oral suspension	Oral	AMP EROS	LiquiXR®	NR	Mixed salts of d- and l-AMP (ratio of 3.2:1)
MYDAYIS (SPD465; SHP465) [101]	Shire	June 2017	≥13 years	12.5, 25, 37.5, and 50 mg	Capsule (mixed beads)	Oral (whole or sprinkled)	Triple-bead MAS-ER	Triple-bead	NR	Mixed salts of d- and l-AMP (ratio of 3:1)
VYVANSE (SPD489; NRP104) [36]	Shire	February 2007	≥6 years	10, 20, 30, 40, 50, 60, and 70 mg	Capsule (powder)	Oral (whole or sprinkled)	LDX	Prodrug	N/A	d-AMP
		April 2017		10, 20, 30, 40, 50, and 60 mg	Chewable tablet	Oral (chewed)

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AMP, amphetamine; AMP EROS, amphetamine extended-release oral suspension; AMP XR-ODT, amphetamine extended-release orally disintegrating tablet; AMP XR-OS, amphetamine extended-release oral suspension; d-MPH-ER, d-methylphenidate extended-release; DR/ER-MPH, delayed-release and extended-release methylphenidate; ER, extended-release; FDA, Food and Drug Administration; IR, immediate-release; LDX, lisdexamfetamine; MAS-ER, mixed amphetamine salts extended-release; MEROS, methylphenidate extended-release oral suspension; MPH, methylphenidate; MPH-CD, methylphenidate controlled-delivery; MPH-ERCT, methylphenidate extended-release chewable tablets; MPH-LA, methylphenidate long-acting; MPH-MLR, methylphenidate multilayer extended-release; MPH XR-ODT, methylphenidate extended-release orally disintegrating tablet; MTS, methylphenidate transdermal system; N/A, not applicable; NR, not reported; OROS-MPH, osmotic-release oral system methylphenidate; SODAS, spheroidal oral drug absorption system; US, United States.

Table 2. Summary of pharmacokinetic properties of long-acting methylphenidate formulations (FDA-approved doses only).

							Pharmacokinetic Parameters^a
							AUC0-∞^b (ng∙h/mL)	Cmax (ng/mL)	Tmax (h)	t1/2 (h)
Drug	PK Profile	Population	Dose(s) tested (mg)	Single/multiple dosing	Fasted/fed/ sprinkled	Enantiomer	Mean ± SD (CV%)	Mean ± SD (CV%)	Median (range) or Mean ± SD (CV%)	Mean ± SD (CV%)
ADHANSIA XR	Two peaks	Healthy adults (n = 15) [77,78]	100 mg	Multiple (5 days)	Fasted	d-MPH	AUC0-24: 227.17 ± 83.61 (36.81%)^c	15.73 ± 4.54 (28.86%)^c	Tmax1: 1.5 (1–2.5) Tmax2: 11.5 (8.5–16)	~7
		Adolescents with ADHD (12–16 years) (n = 17) [77,78]	62.9 ± 19.8 mg (range: 25–85 mg)	Single	Fasted	d-MPH	205.80 ± 90.41 (43.93%)^c	13.64 ± 6.21 (45.53%)^c	Tmax1: 2 (1–4) Tmax2: 11.3 (8–14)	4.91 ± 3.04 (61.17%)^c
		Children with ADHD (6–12 years) [78]	NR	NR	NR	d,l-MPH	NR	NR	Tmax1: 2 (1–4) Tmax2: 10 (8–14)	4–7
APTENSIO XR^d	Two peaks	Healthy adults (n = 24–25) [66,67]	80 mg	Single	Fasted	d,l-MPH	258.1 ± 94.2 (36.50%)^c	23.47 ± 11.4 (48.57%)^c	Tmax1: 2 Tmax2: 8	5.09 ± 1.6 (31.43%)^c
					Sprinkled		258.0 ± 84.4 (32.71%)^c	21.78 ± 9.5 (43.62%)^c	Tmax1: 2 Tmax2: 8	5.43 ± 2.5 (46.04%)^c
		Healthy adults (n = 21) [69]	80 mg	Single	Fed	MPH	289.9 ± 90.8 (31.32%)^c	23.7 ± 6.4 (27.00%)^c	3.0 (2.0–10.0)	6.0 ± 5.4 (90.00%)^c
				Multiple (4 days)	Fed (standard breakfast)		305.4 ± 92.9 (30.42%)^c	28.1 ± 7.1 (25.27%)^c	2.0 (1.0–5.0)	5.4 ± 2.0 (37.04%)^c
		Children with ADHD (6–12 years) (n = 14) [68]	38.6 ± 17.7 mg/d (range: 20–80 mg)	Single	Fed	MPH	155.11 ± 71.16 (45.88%)^c	12.12 ± 5.76 (47.52%)^c	3.97 ± 2.61 (65.74%)^c	5.07 ± 1.47 (28.99%)^c
CONCERTA	Two peaks	Healthy adults (18–45 years) (n = 36) [40,41,43]	18 mg	Single	NR	MPH	41.8 ± 13.9 (36.47%)^c	3.73 ± 1.01 (27.08%)^c	Tmax1: ~1 Tmax2: 6.8 ± 1.8 (26.47%)^c	3.5 ± 0.4 (11.43%)^c
		Healthy adults (18–45 years) (n = 32) [41,43]	18 mg	Single	NR	MPH	32.9 ± 12 (33.25%)^c	2.81 ± 0.96 (34.16%)^c	7.4 ± 2.0 (27.03%)^c	3.9 ± 0.71 (18.21%)^c
				Multiple (6 days)	NR	MPH	AUC0-24: 35.2 ± 12 (34.09%)^c	3.00 ± 1.1 (36.67%)^c	6.6 ± 2.3 (34.85%)^c	3.9 ± 0.76 (19.49%)^c
		Healthy adults [40,44]	18 mg (n = 24)	Single	Fasted	MPH	37.6 ± 17.5 (46.54%)^c	3.3 ± 1.3 (39.39%)^c	6.1 ± 2.2 (36.07%)^c	4.0 ± 0.7 (17.50%)^c
					Fed		45.3 ± 20.8 (45.92%)^c	4.4 ± 1.9 (43.18%)^c	7.2 ± 1.3 (18.06%)^c	3.8 ± 0.7 (18.42%)^c
			36 mg (n = 31)	Single	Fasted		67.6 ± 23.7 (35.06%)	6.20 ± 2.2 (35.48%)	6.5 ± 1.0 (15.38%)^c	3.5 ± 0.5 (14.29%)^c
					Fed		79.0 ± 26.8 (33.92%)^c	6.87 ± 2.3 (33.48%)^c	7.4 ± 1.3 (17.57%)^c	3.3 ± 0.3 (9.09%)^c
		Healthy adults (18–43 years) (n = 33) [43,45]	18 mg	Single	Fasted	d-MPH	41.1 ± 15.9 (38.69%)^c	3.8 ± 1.8 (47.37%)^c	7.9 ± 1.7 (21.52%)^c	3.7 ± 0.9 (24.32%)^c
			36 mg				80.9 ± 30.8 (38.07%)^c	7.3 ± 2.8 (38.36%)^c	7.5 ± 1.3 (17.33%)^c	3.9 ± 0.7 (17.95%)^c
			54 mg				118.9 ± 45.9 (38.60%)^c	10.5 ± 3.4 (32.38%)^c	7.2 ± 1.5 (20.83%)^c	3.9 ± 0.7 (17.95%)^c
		Children with ADHD (6–12 years) (n = 32) [42,43]	18 mg (n = 3)	Single	Fasted	MPH	50.4 ± 7.8 (15.48%)^c	6.0 ± 1.3 (21.67%)^c	9.4 ± 0.02 (0.21%)^c	NR
			36 mg (n = 7)				87.7 ± 18.2 (20.75%)^c	11.3 ± 2.6 (23.01%)^c	8.1 ± 1.1 (13.58%)^c	NR
			54 mg (n = 3)				121.5 ± 37 (30.45%)^c	15.0 ± 3.8 (25.33%)^c	9.1 ± 2.5 (27.47%)^c	NR
			18 mg (n = 3)	Single	Fed	MPH	57.1 ± 2.8 (4.90%)^c	7.2 ± 0.5 (6.94%)^c	9.6 ± 1.7 (17.71%)^c	NR
			36 mg (n = 7)				92.6 ± 30.4 (32.83%)^c	12.5 ± 3.8 (30.40%)^c	8.0 ± 2.8 (35.00%)^c	NR
			54 mg (n = 3)				118.9 ± 45 (37.85%)^c	16.1 ± 4.9 (30.43%)^c	10.3 ± 2.0 (19.42%)^c	NR
COTEMPLA XR-ODT	Single peak	Healthy adults (n = 38) [38,72]	51.8 mg	Single	Fasted	d-MPH	169.1 ± 57.13 (33.78%)^c	20.8 ± 5.22 (25.10%)^c	4.98 (2.5–6.5)	4.00 ± 0.73 (18.25%)^c
		Adolescents with ADHD (13–17 years) (n = 8) [38,39,72]	51.8 mg	Single	Fasted	d-MPH	187.2 ± 62.05 (33.15%)^c	20.2 ± 5.79 (28.66%)^c	5.5 (3.5–8.0)	3.93 ± 0.33 (8.40%)^c
		Children with ADHD (6–12 years) (n = 24) [38,39,72]	51.8 mg	Single	Fasted	d-MPH	328.9 ± 90.21 (27.43%)^c	32.7 ± 9.83 (30.06%)^c	4.5 (2.0–8.0)	4.43 ± 1.00 (22.57%)^c
DAYTRANA [60,61]	Single peak	Children with ADHD (6–12 years) (n = 24)	12.5 cm^2/9 h (10 mg/9 h)	Single	N/A	d-MPH	99.2 ± 42.9 (43.25%)^c	9.30 ± 3.60 (38.71%)^c	10.0 (8.00–12.0)	5.01 ± 1.20 (23.95%)^c
		Adolescents with ADHD (13–17 years) (n = 11)					48.7 ± 21.9 (44.97%)^c	4.15 ± 2.59 (62.41%)^c	10.0 (6.00–12.0)	4.35 ± 0.788 (18.11%)^c
		Children with ADHD (6–12 years) (n = 11; 12)	12.5 cm^2/9 h (10 mg/9 h)	Multiple (up to 28 days)	N/A	d-MPH	163 ± 101 (61.96%)^c	15.7 ± 9.39 (59.81%)^c	9.00 (8.00–10.0)	N/A
			37.5 cm^2/9 h (up to 30 mg/9 h)	Multiple (up to 28 days)	N/A	d-MPH	447 ± 230 (51.45%)^c	42.9 ± 22.4 (52.21%)^c	8.00 (8.00–12.00)	N/A
		Adolescents with ADHD (13–17 years) (n = 12; 10)	12.5 cm^2/9 h (10 mg/9 h)	Multiple (up to 28 days)	N/A	d-MPH	85.7 ± 50.0 (58.34%)^c	8.32 ± 4.60 (55.29%)^c	10.0 (6.00–24.0)	N/A
			37.5 cm^2/9 h (up to 30 mg/9 h)	Multiple (up to 28 days)	N/A	d-MPH	167 ± 66.0 (39.52%)^c	16.5 ± 6.94 (42.06%)^c	9.00 (1.00–10.00)	N/A
FOCALIN XR	Two peaks	Healthy adults (19–45 years) (n = 24) [55,57,58]	20 mg	Single	Fasted	d-MPH	119.1 ± 40.7 (34.1%)	Cmax1: 13.7 ± 4.6 (34.0%) Cmax2: 14.9 ± 4.0 (26.8%)	Tmax1: 1.5 (1.0–2.0) Tmax2: 6.5 (4.5–7.0)	3.26 ± 0.51 (15.81%)
		Healthy adults (19–45 years) [56–58]	5 mg (n = 21)	Single	Fasted	d-MPH	24.3 (30.7%)	Cmax1: 2.68 (37.1%) Cmax2: 3.18 (27.5%)	Tmax1: 2.0 (1.5–4.0) Tmax2: 5.5 (4.1–7.1)	2.86 (21.6%)
			10 mg (n = 23)				45.9 (30.2%)	Cmax1: 5.00 (35.7%) Cmax2: 5.84 (27.7%)	Tmax1: 1.5 (1.1–4.0) Tmax2: 6.0 (4.5–8.0)	2.93 (24.0%)
			20 mg (n = 23)				96.4 (35.5%)	Cmax1: 10.8 (41.9%) Cmax2: 12.5 (31.7%)	Tmax1: 2.0 (0.52–4.0) Tmax2: 5.5 (4.5–7.0)	3.11 (22.2%)
			30 mg (n = 24)				144 (33.3%)	Cmax1: 15.7 (38.4%) Cmax2: 17.7 (31.6%)	Tmax1: 1.5 (1.0–4.0) Tmax2: 6.0 (4.5–7.0)	3.03 (16.5%)
			40 mg (n = 23)				195 (30.9%)	Cmax1: 20.6 (40.9%) Cmax2: 23.6 (29.0%)	Tmax1: 1.5 (1.0–4.0) Tmax2: 6.5 (4.5–8.0)	3.20 (23.3%)
JORNAY PM	Single peak	Healthy adults (n = 20) [74,75]	20 mg	Single	Fasted	MPH	AUC0-t: 33.4 (38.9%) AUC0-∞: 34.7 (40.5%)	2.56 (34.4%)	14 (13–19) 14.25 (12.7%)	6.51 (32.3%)
			100 mg	Single	Fasted	MPH	176.7 (34.0%)	12.31 (36.5%)	14 (13–20) 14.85 (12.0%)	6.40 (34.5%)
		Healthy adults (n = 18) [74,75]	100 mg	Single	Fasted	MPH	183.0 (44.3%)	14.17 (46.5%)	14.00 (11.50–18.05) 14.31 (11.9%)	5.90 (41.6%)
					Fed (evening meal)		178.7 (43.4%)	12.21 (41.3%)	16.50 (13.00–20.00) 16.67 (11.3%)	5.94 (23.5%)
					Sprinkled		187.4 (40.0%)	13.71 (39.5%)	14.00 (11.50–20.02) 14.64 (14.2%)	6.25 (27.2%)
		Healthy adults (n = 12) [73,75]	54 mg	Single	Fasted	MPH	AUC0-t: 83.4 (27.1%)	5.99 (24.0%)	16 (13–18) 15.6 (11.1%)	NR
		Adolescents with ADHD (13–17 years) (n = 18) [73,75]	54 mg	Single	Fasted	MPH	109.6 (30.8%)	7.17 (23.7%)	16.2 (13.9–22.1) 17.1 (14.5%)	NR
		Children with ADHD (8–12 years) (n = 11) [73,75]	54 mg	Single	Fasted	MPH	210.1 (38.5%)	11.64 (36.3%)	18.2 (12.4–22) 17.7 (14.1%)	NR
METADATE CD^e	Two peaks	Children with ADHD (7–12 years) [47–49]	20 mg (n = 12)	Multiple	NR	MPH	AUC0-9: 63.0 ± 16.8 (26.67%)^c	Cmax1: 8.6 ± 2.6 (30.23%)^c Cmax2: 10.9 ± 3.9 (35.78%)^c	Tmax1: 1.5 (2.2 ± 0.7) Tmax2: 4.5 (5.1 ± 1.0)	NR
			40 mg (n = 9)				AUC0-9: 119.7 ± 39.6 (33.08%)^c	Cmax1: 16.8 ± 5.1 (30.36%)^c Cmax2: 15.1 ± 5.8 (38.41%)^c	Tmax1: 1.5 (1.9 ± 1.0) Tmax2: 4.5 (5.2 ± 0.8)
		Healthy adults (20–50 years) (n = 18) [47–49]	40 mg	Single	Fasted	d-MPH	99.7 ± 41.3 (41.42%)^c	8.9 ± 3.0 (33.71%)^c	4.8 ± 1.2 (25.00%)^c	NR
					Fed		116.5 ± 48.0 (41.20%)^c	11.7 ± 4.6 (39.32%)^c	5.7 ± 1.7 (29.82%)^c
		Healthy adults (21–40 years) (n = 26) [46,47]	20 mg	Single	Fasted	MPH	45.62 ± 20.05 (43.95%)^c	4.58 ± 1.97 (43.01%)^c	4.58 ± 1.17 (25.55%)^c	6.42 ± 1.43 (22.27%)^c
					Sprinkled		47.15 ± 20.30 (43.05%)^c	4.78 ± 1.88 (39.33%)^c	4.39 ± 1.39 (31.66%)^c	6.27 ± 1.80 (28.71%)^c
		Healthy adults (21–40 years) (n = 23) [50]	10 mg	Single	Fasted	d,l-MPH	25.77 ± 10.77 (41.80%)	2.34 ± 0.99 (42.19%)	5.00 (1.00–6.00) 4.72 ± 1.16 (24.51%)	5.61 ± 0.85 (15.16%)
			20 mg				50.66 ± 21.98 (43.39%)	4.80 ± 2.23 (46.35%)	5.00 (1.00–6.00) 4.52 ± 1.30 (28.77%)	6.06 ± 1.42 (23.36%)
			30 mg				76.03 ± 31.62 (41.59%)	7.38 ± 3.14 (42.47%)	5.00 (3.00–6.00) 5.00 ± 0.60 (12.06%)	5.75 ± 0.79 (13.83%)
QUILLICHEW ER	Single peak	Healthy adults (18–55 years) (n = 31) [70,71]	40 mg	Single	Fasted	MPH	118.1 (30%)	12.5 (29%)	5 (NR) 4.2 (28%)	5.2 (15%)
QUILLIVANT XR	Single peak	Healthy adults (18–68 years) (n = 28) [62,64]	60 mg	Single	Fasted	d-MPH	143.65 (50.67%)	13.61 ± 5.8 (42.56%)	5.00 (1.67–6.00)	5.65 ± 0.848 (15.01%)
		Healthy adults (n = 27) [62,65]	60 mg	Single	Fed	d-MPH	163.2 ± 80.3 (49.20%)^c	17.0 ± 7.7 (45.29%)^c	4.00 (1.3–7.3)	5.24 ± 1.05 (20.04%)^c
		Adolescents with ADHD (13–15 years) (n = 4) [62,65]	20 mg	Single	Fed	MPH	82.4 ± 4.76 (5.78%)^c	9.22 ± 0.560 (6.07%)^c	2.00 (1.98–4.00)	5.18 ± 0.227 (4.38%)^c
			60 mg				178 ± 54.2 (30.45%)^c	21.1 ± 5.9 (27.96%)^c	2.00 (1.98–4.00)	5.04 ± 0.214 (4.25%)^c
		Children with ADHD (6–12 years) (n = 3) [62,65]	20 mg	Single	Fed	MPH	101 ± 4.23 (4.19%)^c	11.5 ± 2.17 (18.87%)^c	2.99 (1.98–4.08)	5.27 ± 0.665 (12.62%)^c
			60 mg				378 ± 175 (46.30%)^c	34.4 ± 14.0 (40.70%)^c	4.05 (3.98–6.00)	5.19 ± 0.0832 (1.60%)^c
RITALIN LA	Two peaks	Healthy adult males (n = 8) [53]	20 mg	Single	NR	d,l-MPH	45.8 ± 10.0 (21.83%)^c	Cmax1: 5.3 ± 0.9 (16.98%)^c Cmax2: 6.2 ± 1.6 (25.81%)^c	Tmax1: 2.0 ± 0.9 (45.00%)^c Tmax2: 5.5 ± 0.8 (14.55%)^c	3.3 ± 0.4 (12.12%)^c
		Children with ADHD (7–12 years) (n = 18) [53]	20 mg	Single	NR	d,l-MPH	86.6 ± 64.0 (73.90%)^c	Cmax1: 10.3 ± 5.1 (49.51%)^c Cmax2: 10.2 ± 5.9 (57.84%)^c	Tmax1: 2.0 ± 0.8 (40.00%)^c Tmax2: 6.6 ± 1.5 (22.73%)^c	2.4 ± 0.7 (29.17%)^c
		Healthy adults [51]	40 mg	Single	Fasted (n = 18)	d,l-MPH	105.72 ± 22.42 (21.21%)^c	Cmax1: 12.47 ± 2.60 (20.85%)^c Cmax2: 14.84 ± 2.71 (18.26%)^c	Tmax1: 1.56 ± 0.74 (47.44%)^c Tmax2: 5.44 ± 0.62 (11.40%)^c	NR
					Fed (n = 18)		111.33 ± 18.14 (16.24%)^c	Cmax1: 12.75 ± 4.38 (34.35%)^c Cmax2: 11.42 ± 3.52 (30.82%)^c	Tmax1: 2.42 ± 1.23 (50.83%)^c Tmax2: 5.33 ± 1.44 (27.02%)^c	NR
					Sprinkled (n = 17)		101.97 ± 20.56 (20.16%)^c	Cmax1: 12.95 ± 3.56 (27.49%)^c Cmax2: 13.10 ± 2.84 (21.68%)^c	Tmax1: 1.26 ± 0.31 (24.60%)^c Tmax2: 5.76 ± 0.59 (10.24%)^c	NR

Footnotes: ^aArithmetic mean ± SD (CV%) except for time to maximum observed plasma concentration (T_max), for which the median (range) is reported, unless specified otherwise; ^bAUC_0-∞, unless specified otherwise; ^cCV was derived using the following formula: CV% = (SD/mean) *100%; ^dWhile 80 mg is not an approved dose, the FDA’s evaluation was based on these pharmacokinetic studies; ^eIn the multiple-dose pharmacokinetic study of METADATE CD evaluated in children with ADHD, approximately 25%–30% of participants had only one peak. The C_max data reported in the FDA Pharmacology Review differs from the label (i.e. at 20 mg, C_max1 was 8.6 ± 2.6 and C_max2 was 9.6 ± 3.8, and at 40 mg, C_max1 was 15.4 ± 8.1 and C_max2 was 17.0 ± 4.4). These data discrepancies may due to differences in accounting for participants that did not have a second peak.

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AUC_0-∞, area under the plasma concentration–time curve from zero to infinite time; AUC_0–9, area under the plasma concentration–time curve from zero to 9 hours; AUC_0–24, area under the plasma concentration–time curve from zero to 24 hours; AUC_0–t, area under the plasma concentration–time curve from zero to the time point with the last quantifiable concentration; C_max, peak plasma concentration; C_max1, first peak plasma concentration; C_max2, second peak plasma concentration; CV, coefficient of variation; FDA, Food and Drug Administration; MPH, methylphenidate; N/A, not applicable; NR, not reported; SD, standard deviation; t_1/2, half-life; T_max, time to peak plasma concentration; T_max1, first time to peak plasma concentration; T_max2, second time to peak plasma concentration.

Table 3. Summary of pharmacokinetic properties of long-acting amphetamine formulations (FDA-approved doses only).

							Pharmacokinetic Parameters^a
							AUC0-∞^b (ng∙h/mL)	Cmax (ng/mL)	Tmax (h)	t1/2 (h)
Drug	PK Profile	Population	Dose(s) Tested (mg)	Single/multiple dosing	Fasted/ fed/ sprinkled	Enantiomer/ entity	Mean ± SD (CV%)	Mean ± SD (CV%)	Median (range) or Mean ± SD (CV%)	Mean ± SD (CV%)
ADDERALL XR	Single peak	Healthy adults (n = 19) [37,79,83]	20 mg	Single	Fed	d-AMP	566.62 ± 114.30 (20%)	28.13 ± 8.84 (31%)	6.95 ± 2.35 (33.81%)^c	11.83 ± 2.74 (23.16%)^c
						l-AMP	203.12 ± 46.04 (23%)	8.67 ± 2.80 (32%)	8.15 ± 4.44 (54.48%)^c	13.72 ± 2.83 (20.63%)^c
		Healthy adults (n = 19) [37,79,83]	30 mg	Single	Fasted	d-AMP	851.17 ± 213.51 (25.08%)^c	44.33 ± 11.10 (25.04%)^c	7 (NR) 5.20 ± 1.96 (37.69%)^c	10.40 ± 2.31 (22.21%)^c
						l-AMP	288.59 ± 79.17 (27.43%)^c	13.32 ± 3.66 (27.48%)^c	7 (NR) 5.55 ± 2.09 (37.66%)^c	12.71 ± 3.30 (25.96%)^c
					Fed	d-AMP	822.56 ± 200.18 (24.34%)^c	39.70 ± 8.84 (22.27%)^c	7.67 ± 2.31 (30.12%)^c	10.34 ± 1.98 (19.15%)^c
						l-AMP	273.56 ± 68.98 (25.22%)^c	11.98 ± 2.89 (24.12%)^c	8.33 ± 2.89 (34.69%)^c	12.50 ± 2.56 (20.48%)^c
					Sprinkled	d-AMP	855.98 ± 179.68 (20.99%)^c	43.51 ± 9.61 (22.09%)^c	5.50 ± 1.76 (32.00%)^c	10.39 ± 2.05 (19.73%)^c
						l-AMP	290.38 ± 64.49 (22.21%)^c	13.04 ± 3.20 (24.54%)^c	5.60 ± 1.73 (30.89%)^c	12.73 ± 2.83 (22.23%)^c
		Healthy adults (n = 20) [37,80]	30 mg	Multiple	Fasted	d-AMP	1294.37 ± 290.45 (22.44%)^c	66.88 ± 13.8 (20.63%)^c	4.18 ± 1.18 (28.23%)^c	11.28 ± 1.12 (9.93%)^c
						l-AMP	506.17 ± 125.05 (24.71%)^c	21.72 ± 4.60 (21.18%)^c	4.30 ± 1.12 (26.05%)^c	13.77 ± 3.3 (23.97%)^c
		Adolescents with ADHD (13–17 years; ≤75 kg) (n = 15) [37,82]	10 mg	Single	Fasted	d-AMP	351 ± 56.9 (16.21%)^c	18.4 ± 2.96 (16.09%)^c	3.93	10.8 ± 2.65 (24.54%)^c
						l-AMP	129 ± 28.6 (22.17%)^c	5.80 ± 0.86 (14.83%)^c	4.00	12.9 ± 4.54 (35.19%)^c
			20 mg			d-AMP	689 ± 128 (18.58%)^c	34.1 ± 7.80 (22.87%)^c	4.99	11.0 ± 2.28 (20.73%)^c
						l-AMP	267 ± 62.7 (23.48%)^c	11.3 ± 2.45 (21.68%)^c	5.01	13.5 ± 3.62 (26.81%)^c
		Adolescents with ADHD (13–17 years; >75 kg) (n = 6) [37,82]	20 mg	Single	Fasted	d-AMP	589 ± 84.2 (14.30%)^c	29.4 ± 2.70 (9.18%)^c	5.00	12.4 ± 2.05 (16.53%)^c
						l-AMP	225 ± 39.1 (17.38%)^c	9.60 ± 0.97 (10.10%)^c	4.98	15.0 ± 2.78 (18.53%)^c
		Children with ADHD (6–12 years) (n = 48) [37,81,83]	20 mg	Single	NR	d-AMP	936.7 ± 319 (34.06%)^c	48.8 ± 13.5 (27.66%)^c	6.8 ± 3.2 (47.06%)^c	9.5 ± 2.4 (25.26%)^c
						l-AMP	309.0 ± 115 (34.06%)^c	14.8 ± 4.3 (29.05%)^c	6.9 ± 3.3 (47.83%)^c	10.9 ± 3.1 (28.44%)^c
		Children with ADHD (6–12 years) [37,81,83]	10 mg (n = 8)	Multiple	NR	d-AMP	AUC0-24: 431.9 ± 123 (28.48%)^c	28.8 ± 6.2 (21.53%)^c	6.4 ± 3.5 (54.69%)^c	NR
						l-AMP	AUC0-24: 138.3 ± 40 (28.92%)^c	8.8 ± 1.9 (21.59%)^c	6.4 ± 3.5 (54.69%)^c	NR
			20 mg (n = 9)			d-AMP	AUC0-24: 777.2 ± 304 (39.11%)^c	54.6 ± 18.8 (34.43%)^c	5.8 ± 1.8 (31.03%)^c	NR
						l-AMP	AUC0-24: 261.6 ± 120 (45.87%)^c	17.2 ± 6.8 (39.53%)^c	5.7 ± 2.2 (38.60%)^c	NR
			30 mg (n = 6)			d-AMP	AUC0-24: 1364.3 ± 364 (26.68%)^c	89.0 ± 15.6 (17.53%)^c	5.5 ± 2.1 (38.18%)^c	NR
						l-AMP	AUC0-24: 443.5 ± 134 (30.21%)^c	28.1 ± 6.5 (23.13%)^c	5.5 ± 2.1 (38.18%)^c	NR
ADZENYS ER	Single peak	Healthy adults (20–70 years) (n = 42) [97,99]	18.8 mg (15 mL)	Single	Fasted	d-AMP	925.2 ± 209.0 (22.59%)	47.2 ± 7.68 (16.26%)	5.00 (3.00‒7.50)	11.41 ± 2.27 (19.92%)
						l-AMP	350.2 ± 87.02 (24.85%)	14.9 ± 2.40 (16.09%)	5.00 (3.00‒8.00)	14.11 ± 3.52 (24.95%)
		Healthy adults (20–68 years) (n = 30) [97,98]	18.8 mg (15 mL)	Single	Fasted	d-AMP	996.3 ± 193.7 (19.44%)^c	51.9 ± 9.02 (17.38%)^c	5.00 (3.00‒7.00) 4.95 ± 0.99 (20.00%)^c	11.82 ± 1.83 (15.48%)^c
						l-AMP	370.9 ± 83.23 (22.49%)^c	16.4 ± 2.97 (18.11%)^c	5.00 (3.00‒7.50) 5.16 ± 1.02 (19.77%)^c	14.47 ± 2.80 (19.35%)^c
					Fed	d-AMP	961.5 ± 176.8 (18.39%)^c	45.9 ± 7.98 (17.39%)^c	5.50 (2.00‒10.00) 5.47 ± 1.91 (34.92%)^c	12.12 ± 1.90 (15.68%)^c
						l-AMP	357.4 ± 76.22 (21.33%)^c	14.6 ± 2.61 (17.88%)^c	6.00 (3.00‒12.02) 5.88 ± 2.16 (36.73%)^c	14.84 ± 3.07 (20.69%)^c
		Children with ADHD (6–12 years) (n = 29) [97,99]	18.8 mg (15 mL)	Single	Fasted	d-AMP	1599 ± 784.4 (49.05%)	68.0 ± 12.3 (18.06%)	5.33 ± 1.59 (29.81%)	12.70 ± 6.36 (50.11%)
						l-AMP	642.1 ± 576.7 (89.81%)	23.5 ± 4.10 (17.46%)	5.93 ± 1.97 (33.24%)	15.3 ± 14.44 (94.27%)
ADZENYS XR-ODT	Single peak	Healthy adults (n = 39) [97,99]	18.8 mg	Single	Fasted (n = 39)	d-AMP	876.9 ± 182.4 (20.81%)	44.9 ± 8.94 (19.94%)	5 (3–12)	11.25 ± 2.02 (17.95%)
						l-AMP	320.7 ± 69.96 (21.81%)	14.5 ± 3.00 (20.74%)	5.25 (3.00–12.00)	12.94 ± 2.72 (20.99%)
					Fed (n = 40)	d-AMP	856.3 ± 166.1 (19.40%)	36.3 ± 6.85 (18.88%)	7 (3–16)	11.33 ± 2.00 (17.61%)
						l-AMP	310.7 ± 62.11 (19.99%)	11.7 ± 2.27 (19.32%)	7.50 (3.05–16.00)	13.18 ± 2.67 (20.23%)
		Children with ADHD (6–12 years) (n = 28) [93]	18.8 mg	Single	Fasted	d-AMP	1486.0 ± 232.3 (15.63%)^c	86.7 ± 19.5 (22.49%)^c	5.6 ± 86.7^d	9.5 ± 1.7 (17.89%)^c
						l-AMP	529.1 ± 95.9 (18.13%)^c	27.0 ± 5.2 (19.26%)^c	5.9 ± 2.1 (35.59%)^c	11.0 ± 2.1 (19.09%)^c
DYANAVEL XR	Single peak	Healthy adults (n = 29) [91,92]	18.8 mg	Single	Fasted	d-AMP	1197.321 (22%)	54.128 (19%)	4.00 (2.00–7.00)	12.36 ± 2.95 (23.87%)^c
						l-AMP	461.544 (23%)	17.286 (19%)	4.00 (2.00–7.00)	15.12 ± 4.40 (29.10%)^c
					Fed	d-AMP	1125.248 (20%)	55.031 (18%)	5.00 (3.00–8.00)	NR
						l-AMP	425.849 (21%)	17.683 (19%)	5.00 (3.00–8.00)	NR
		Children with ADHD (n = 12) [91,92]	10 mg	Single	Fasted	d-AMP	1061.199 ± 309.200 (29.14%)	54.879 ± 15.221 (27.74%)	3.43 (2.92–5.93) 4.04 ± 1.37 (33.84%)	10.59 ± 2.01 (19.01%)
						l-AMP	380.533 ± 112.234 (29.49%)	17.148 ± 5.206 (30.36%)	4.05 (2.92–7.93) 4.85 ± 1.96 (40.52%)	12.46 ± 3.15 (25.31%)
MYDAYIS	Single peak	Healthy adults (19–51 years) (n = 20) [100–102]	37.5 mg	Single	Fasted	d-AMP	1084.9 ± 196.2 (18.08%)^c	50.3 ± 7.5 (14.91%)^c	8.0 (NR) 8.2 ± 2.0 (24.39%)^c	10.1 ± 1.3 (12.87%)^c
						l-AMP	372.8 ± 73.5 (19.72%)^c	14.7 ± 2.2 (14.97%)^c	8.0 (NR) 8.4 ± 2.1 (25.00%)^c	12.5 ± 1.7 (13.60%)^c
		Healthy adults (n = 14) [101,102]	50 mg	Single	Fasted (n = 14)	d-AMP	1589.5 ± 360.0 (22.65%)^c	72.3 ± 13.7 (18.95%)^c	7.0 (6.0–10.0)	10.9 ± 2.6 (23.85%)^c
						l-AMP	545.2 ± 147.9 (27.13%)^c	21.1 ± 3.7 (17.54%)^c	7.5 (6.0–12.0)	13.6 ± 3.7 (27.21%)^c
					Fed (n = 16)	d-AMP	1433.8 ± 339.5 (23.68%)^c	60.0 ± 7.1 (11.83%)^c	12.0 (8.0–14.0)	10.5 ± 2.1 (20.00%)^c
						l-AMP	481.7 ± 138.4 (28.73%)^c	17.6 ± 2.2 (12.50%)^c	12.0 (8.0–14.0)	12.8 ± 3.3 (25.78%)^c
					Sprinkled (n = 16)	d-AMP	1497.9 ± 300.8 (20.08%)^c	67.3 ± 7.7 (11.44%)^c	7.5 ± (5.0–9.0)	10.6 ± 2.2 (20.75%)^c
						l-AMP	511.4 ± 127.1 (24.85%)^c	20.0 ± 2.5 (12.50%)^c	8.0 (5.0–12.0)	13.0 ± 3.2 (24.62%)^c
		Adolescents with ADHD (13–17 years) (n = 14) [101,102]	25 mg	Single	Fasted	d-AMP	651.97 ± 174.282 (26.7%)	40.57 ± 9.255 (22.8%)	8.00 (6.00–10.00) 7.496 ± 1.4454 (19.3%)	11.3666 ± 1.95137 (17.2%)
						l-AMP	326.09 ± 92.866 (28.5%)	12.88 ± 3.205 (24.9%)	8.00 (6.00–11.00) 7.738 ± 1.7332 (22.4%)	13.1525 ± 2.90674 (22.1%)
VYVANSE (capsule)	Single peak	Children with ADHD (6–12 years) (n = 17) [35,36,84,86]	30 mg (n = 16)	Single	Fasted	d-AMP	844.6 ± 116.7 (13.8%)	53.2 ± 9.62 (18.1%)	3.41 ± 1.09 (31.9%)	8.90 ± 1.33 (15.0%)
						LDX	27.88 ± 9.29 (33.3%)	21.9 ± 5.97 (27.3%)	0.97 ± 0.14 (14.4%)	0.50 ± 0.19 (37.9%)
			50 mg (n = 17)			d-AMP	1510.0 ± 241.6 (16.0%)	93.3 ± 18.2 (19.5%)	3.58 ± 1.18 (33.0%)	8.61 ± 1.04 (12.1%)
						LDX	57.90 ± 21.03 (36.3%)	46.0 ± 20.7 (44.9%)	0.98 ± 0.06 (6.2%)	0.60 ± 0.44 (72.8%)
			70 mg (n = 17)			d-AMP	2157.0 ± 383.3 (17.8%)	134 ± 26.1 (19.4%)	3.46 ± 1.34 (38.6%)	8.64 ± 1.32 (15.3%)
						LDX	108.90 ± 50.46 (46.3%)	89.5 ± 38.5 (43.0%)	1.07 ± 0.17 (16.3%)	0.51 ± 0.19 (37.6%)
		Healthy adults (18–55 years) (n = 18) [85,86]	70 mg	Single	Fasted	d-AMP	1110 ± 314.2 (28.31%)^c	69.3 ± 14.3 (20.63%)^c	3.78 ± 1.01 (26.72%)^c	9.69 ± 1.96 (20.23%)^c
						LDX	66.84 ± 23.61 (35.32%)^c	48.0 ± 23.8 (49.58%)^c	1.15 ± 0.28 (24.35%)^c	0.41 ± 0.07 (17.07%)^c
					Fed	d-AMP	1038 ± 238.6 (22.99%)^c	65.3 ± 13.4 (20.52%)^c	4.72 ± 1.07 (22.67%)^c	9.59 ± 1.89 (19.71%)^c
						LDX	58.81 ± 15.26 (25.95%)^c	26.2 ± 11.9 (45.42%)^c	2.08 ± 0.65 (31.25%)^c	0.63 ± 0.20 (31.75%)^c
					Sprinkled (in solution)	d-AMP	1074 ± 220.8 (20.56%)^c	68.4 ± 14.6 (21.35%)^c	3.33 ± 1.19 (35.74%)^c	9.37 ± 2.06 (21.96%)^c
						LDX	55.10 ± 16.97 (30.80%)^c	45.6 ± 17.0 (37.28%)^c	0.97 ± 0.27 (27.84%)^c	0.44 ± 0.10 (22.73%)^c
		Healthy adults (18–55 years) (n = 11) [85,86]	70 mg	Multiple (7 days)	Fasted	d-AMP	AUC0-∞: 1453 ± 645.7 (44.44%)^c AUC0-24: 1110 ± 397 (35.7%)	90.1 ± 29.6 (32.8%)	3.0 (1.5–7.0) 3.68 ± 1.42 (38.5%)	NR
						LDX	AUC0-∞: 61.06 ± 20.63 (33.79%)^c AUC0-24: 60.7 ± 21.0 (34.6%)	47.9 ± 18.6 (38.8%)	1.0 (1.0–2.0) 1.14 ± 0.32 (28.5%)	NR
VYVANSE (chewable)	Single peak	Healthy adults (n = 36) [36,89]	60 mg	Single	Fasted	d-AMP	1168 ± 270 (23.12%)^c	56.9 ± 14.7 (25.83%)^c	4.4 ± 1.2 (27.27%)^c	12.7 ± 2.3 (18.11%)^c
						LDX	AUC0-t: 35.7 ± 8.9 (24.93%)^c	32.3 ± 8.3 (25.70%)^c	1.0 ± 0.2 (20.00%)^c	NR
		Healthy adults (n = 35) [36,89]	60 mg	Single	Fasted	d-AMP	1073 ± 201 (18.73%)^c	54.9 ± 11.7 (21.31%)^c	3.9 ± 1.0 (25.64%)^c	12.3 ± 2.1 (17.07%)^c
						LDX	AUC0-t: 33.9 ± 29.3 (86.43%)^c	32.3 ± 30.2 (93.50%)^c	0.97 ± 0.17 (17.53%)^c	NR
					Fed	d-AMP	1025 ± 199 (19.41%)^c	52.5 ± 10.3 (19.62%)^c	4.9 ± 0.8 (16.33%)^c	12.5 ± 2.9 (23.20%)^c
						LDX	AUC0-t: 39.9 ± 11.1 (27.82%)^c	20.7 ± 8.4 (40.58%)^c	1.36 ± 0.36 (26.47%)^c	NR

Footnotes: ^aArithmetic mean ± SD (CV%) except for time to maximum observed plasma concentration (T_max), for which the median (range) is reported, unless specified otherwise; ^bAUC_0-∞, unless specified otherwise; ^cCV was derived using the following formula: CV% = (SD/mean) * 100%; ^dThis standard deviation is likely a typo in the publication and there are no supporting documents to verify.

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AMP, amphetamine; AUC_0-∞, area under the plasma concentration–time curve from zero to infinite time; AUC_0–24, area under the plasma concentration–time curve from zero to 24 hours; AUC_0–t, area under the plasma concentration–time curve from zero to the time point with the last quantifiable concentration; C_max, peak plasma concentration; CV, coefficient of variation; FDA, Food and Drug Administration; LDX, lisdexamfetamine; N/A, not applicable; NR, not reported; SD, standard deviation; t_1/2, half-life; T_max, time to peak plasma concentration.

Table 4. Investigational long-acting stimulant formulations in the pipeline for the treatment of ADHD.

			Pharmacokinetic Properties
				AUC (ng∙h/mL)	Cmax (ng/mL)	Tmax (h)	t1/2 (h)
Drug/ Company	Phase/ FDA Status	Formulation/Delivery System	Profile	Mean ± SD (CV%)	Mean ± SD (CV%)	Median (range)	Mean ± SD (CV%)
Methylphenidate formulations
KP415/ KemPharm [103–105]	Phase III/NDA planned for Q1 2019	30% IR d-MPH and 70% serdexmethylphenidate (SDX), a d-MPH prodrug (utilizing a LAT^TM [Ligand Activated Therapy] platform technology; capsule)	Single peak	Healthy adults: AUC0-24: 207.6 ± 54.4 (steady state after 7 days on 56/12 mg) Adolescents with ADHD (13–17 years): AUC0-24: 171.1 ± 19.4 (single dose of 56/12 mg) Children with ADHD (9–12 years): AUC0-24: 294.1 ± 98.2 (single dose of 56/12 mg)	Healthy adults: 20.9 ± 3.1 (steady state after 7 days on 56/12 mg) Adolescents with ADHD (13–17 years): 14.0 ± 1.7 (single dose of 56/12 mg) Children with ADHD (9–12 years): 25.9 ± 9.7 (single dose of 56/12 mg)	Healthy adults: 1.8 ± 0.6 (steady state after 7 days on 56/12 mg) Adolescents with ADHD (13–17 years): 4 Children with ADHD (9–12 years): 4	Healthy adults: 8.9 ± 2.2 (steady state after 7 days on 56/12 mg) Adolescents with ADHD (13–17 years): NR Children with ADHD (9–12 years): NR
KP484/ KemPharm	Unknown/ IND filed in September 2017	‘Super’ extended-release d-MPH prodrug (utilizing a LAT^TM platform technology; capsule)	Single peak	NR	NR	NR	NR
CTx-1301/ Cingulate [106,107]	Phase I/II IND planned for EOY 2018	Triple-release, multicore formulation of d-MPH (utilizing OralogiK^TM technology; tablet)	Three peaks	AUC8-24: 29.2 and 31.6	Cmax (0–4 h): 4.9 and 5.3 Cmax (4–24 h): 6.6 and 6.9	Tmax (0–4 h): 1.6 and 1.9	4.5 and 4.3
Amphetamine formulations
HLD100/Ironshore Pharmaceuticals [109]	Phase II completed	Delayed-release and extended-release formulation of AMP (DR/ER-AMP; utilizing DELEXIS® technology; capsule)	Single peak following an 8-hour delay	Adolescents with ADHD: AUC0-∞ (15 mg): 536.6 (24.0%) AUC0-∞ (25 mg): 1195.7 (42.7%) AUC0-t (15 mg): 476.2 (16.8%) AUC0-t (25 mg): 1022.8 (42.7%) Children with ADHD: AUC0-∞ (15 mg): 1039.5 (18.7%) AUC0-∞ (25 mg): 1752.7 (26.2%) AUC0-t (15 mg): 1034.7 (31.5%) AUC0-t (25 mg): 1513.0 (27.3%)	Adolescents with ADHD: 15 mg: 22.0 (11.6%) 25 mg: 47.9 (36.5%) Children with ADHD: 15 mg: 44.18 (29.0%) 25 mg: 70.80 (19.3%)	~8-hour delayed release Adolescents with ADHD: 18 Children with ADHD: 18	NR
AMP ER TAB/Tris Pharma [110]	Unknown	Extended-release AMP chewable tablet containing a 3.2:1 ratio of mixed d- and l-AMP salts (utilizing LiquiXR® technology)	Single peak	NR	NR	NR	NR
CTx-1302/ Cingulate	Phase I/II IND planned for EOY 2018	Triple-release, multicore formulation of d-AMP	Three peaks	Not published	Not published	Not published	Not published
d-ATS/ Noven Pharmaceuticals [108]	Phase II completed/ Unknown	d-AMP patch	Not published	Not published	Not published	Not published	Not published

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AMP, amphetamine; AUC, area under the plasma concentration–time curve; AUC_0-∞, area under the plasma concentration–time curve from zero to infinite time; AUC_0–t, area under the plasma concentration–time curve from zero to the time point with the last quantifiable concentration; AUC_0–24, area under the plasma concentration–time curve from zero to 24 hours; AUC_8–24, area under the plasma concentration–time curve from 8 to 24 hours C_max, peak plasma concentration; CV, coefficient of variation; EOY, end of year; IND, investigational new drug; IR, immediate-release; MPH, methylphenidate; NDA, new drug application; NR, not reported; Q1, first quarter; SD, standard deviation; SDX, serdexmethylphenidate,t_1/2, half-life; T_max, time to peak plasma concentration.

Table 5. Dose proportionality, comparative bioavailability, multiple dose pharmacokinetics, and the effect of food, alcohol, age, and gender on the pharmacokinetic properties of long-acting stimulants.

			Food effect
Brand Name	Dose proportionality	Comparative bioavailability	High-fat meal	Sprinkled	Alcohol effect	Age effect	Gender effect	Multiple dose
Methylphenidate formulations
ADHANSIA XR [77,78]	NR	At steady state, increased Cmax1 by 22% and no difference in Cmax2, increased AUC0-24 by 50%, and increased Cmin by 288% at 100 mg qd vs. IR MPH at 20 mg tid	AUC: No effect Cmax1/Cmax2: No effect Tmax1/Tmax 2: Delayed by 1 h	No effect on absorption or exposure (100 mg dose)	In vitro: No increase in release at 5%, 20%, and 40% in the first hour and at 5% and 20% in the second hour. At 40% alcohol, 71% and 61% of MPH release in the second hour at 70 mg and 100 mg doses, respectively. In vivo: At 40% alcohol, 1.4-fold increase in Cmax and 1.3-fold increase in AUC at 70-mg dose.	When adjusted for body weight, PK profile of children (6–12 years) is comparable to adolescents (13–17 years) and adults	Insufficient experience to detect gender variations	Steady state after 3 days
APTENSIO XR [66,67,69,125]	Not studied	Comparable relative bioavailability to IR MPH tid (80 mg qd vs. 25 mg tid)	Decreased Cmax2, but increased average Cmax by 28% and AUC by 19%	No effect on Cmax, AUC, and Tmax (80 mg dose)	At 40% alcohol, 96% of MPH was released within 2 hours	PK profile qualitatively similar in children with ADHD (6–12 years) and healthy adults	Insufficient experience to detect gender variations	Steady state on day 4 After 4 days, Cmax increased by 16%^a and AUC increased by 5%^a in healthy adults dosed 80 mg
CONCERTA [40,41,44,45]	Dose proportional Cmax and AUC0-∞ of d-MPH at doses of 18, 36, and 54 mg; however, Cmax and AUC0-∞ of l-MPH increased disproportionately (plasma concentrations of l-MPH were 1/40 to d-MPH)	Comparable relative bioavailability to IR MPH tid (18 mg qd vs. 5 mg tid)	Cmax: Increased by 12% to 30% AUC: Increased by 20% Tmax: Delayed by 1 hour	N/A	In vitro: At 40% alcohol, no increased release of MPH in the first hour at 18 mg dose	Increase in age resulted in increased apparent oral clearance (58% increase in adolescents vs. children), which could be explained by body weight differences	No difference in mean dose-adjusted AUC0-∞ between men and women (36.7 vs. 37.1 ng∙h/mL)	No accumulation: No differences in PK, including AUC and t1/2, after single- and multiple-dose administration of doses between 18 and 144 mg
COTEMPLA XR-ODT [38,72]	NR	Cmax and AUC were 26% and 6% higher, respectively, at 51.8 mg qd vs. 60 mg qd of MPH-CD	AUC0-∞: Increased by 16% Cmax: Decreased by 24% Tmax: Shortened by 0.5 h	N/A	In vitro: Dose dumping potential at 40% alcohol	Cmax: Higher in children vs. adults (57%^a higher), but similar between adolescents vs. adults AUC: Higher in children vs. adults (95%^a higher), but similar between adolescents vs. adults Clearance: When body weight normalized, similar in children, adolescents, and adults	Insufficient experience to detect gender variations	NR
DAYTRANA [27,60,61]	Dose proportional Cmax and AUC of d-MPH, and Cmax of l-MPH at doses of 10 mg/9 h to 30 mg/9 h. AUC of l-MPH was slightly greater than proportional to patch dose.	Children with ADHD (6–12 years): Cmax and AUC were 19%^a and 5%^a higher for d-MPH, respectively, at 10 mg/9 h vs. 18 mg of OROS-MPH. Adolescents with ADHD (13–17 years): Cmax and AUC were 16%^a and 19%^a lower for d-MPH, respectively, at 10 mg/9 h vs. 18 mg of OROS-MPH.	N/A	N/A	N/A	Cmax: 124%^a higher in children vs. adolescents at 10 mg/9 h AUC0-∞: 104%^a higher in children vs. adolescents at 10 mg/9 h	No difference after adjusting for body weight differences	Steady state likely after 14 days. After 28 days, Cmax increased by 69% and 100%, and AUC increased by 64% and 76% in children and adolescents with ADHD, respectively, dosed 10 mg/9 h.
FOCALIN XR [55–58]	Healthy adults: Dose proportional at 5, 10, 20, 30, and 40 mg	Similar AUC (102%) and Cmax1 (106%), lower Cmax2 (82%), and fewer peak and trough fluctuations at 20 mg qd vs. 10 mg of IR d-MPH bid.	Not studied	Not studied	Not studied	Not studied in children <18 years	Cmax1 was 45% higher and Cmax2 was slightly, but not significantly, higher in women; these patterns remained even after adjusting for body weight.	Not studied
JORNAY PM [73–75,126]	Dose proportional Cmax (104%) and AUC (96%) between 20 and 100 mg	Relative bioavailability of 73.9% at similar dose of IR MPH given tid	AUC: No effect (decreased 3%) Cmax: Decreased 14% Tmax: Delayed by 2.5 h	No effect on Cmax (decreased 2%), AUC (increased 3%), and Tmax at 100 mg dose	In vitro: At 40% alcohol, 97% of MPH released in 2 hours. No increase in MPH release observed in the presence of 5% to 20% alcohol.	When adjusted for body weight and dose, PK profile is comparable in children (8–12 years), adolescents (13–17 years), and adults.	Not studied	Simulated steady state after 2 days
METADATE CD [46–48,50]	Children with ADHD: dose proportional at doses of 20 and 40 mg Healthy adults: dose proportional between 10 and 60 mg	Cmax and AUC were slightly lower at 20 mg qd vs. IR MPH at 10 mg bid dosed at 0 and 4 h	AUC: Increased 16.8% Cmax: Increased 32.3% Tmax: Delayed by 1 h	No effect on Cmax (increased 6%) and AUC (increased 4%)	In vitro: At 40% alcohol, 84% of MPH released in the first hour at 60 mg dose.	NR	Single-dose PK was similar in adult men and women.	Studied in children; did not report on accumulation or steady state
QUILLICHEW ER [70,71,127]	NR	Healthy adults: Cmax and AUC were 20% and 11% lower, respectively, at 40 mg qd vs. IR MPH (chewable) at 20 mg bid dosed 6 h apart	AUC: Increased 4% Cmax: Increased 20% Tmax: No effect	N/A	At 40% alcohol, 90% of MPH released in the first 30 minutes at 40 mg dose.	Not studied in children <18 years	Insufficient experience to detect gender variations	NR
QUILLIVANT XR [62,64,128]	NR	Relative bioavailability of 95% at 60 mg qd vs. IR MPH (oral solution) at 30 mg bid dosed 6 h apart	AUC: Increase 19% Cmax: Increase 28% Tmax: Shortened by 1 h	N/A	In vitro: At 20% alcohol, 20% increase in MPH exposure. No effect at 5% and 10% alcohol.	Cmax: ~2-hold higher in children (9–12 years) vs. adults, but similar in adolescents (13–15 years) vs. adults	Insufficient experience to detect gender variations	NR
RITALIN LA [51,53,54]	Healthy adults: Slight upward trend in AUC and Cmax1 and Cmax2 at 20 mg to 40 mg	Comparable to same total dose of IR-MPH given in 2 doses 4 hours apart	AUC: No effect Cmax: No effect on Cmax1 and Decreased Cmax2 by 25% Tmax: Variable delay in Tmax1 and Tmax2	No effect	In vitro: At 40% alcohol, 98% of MPH released in the first hour at 40 mg dose.	Cmax: 2-hold higher in children (7–12 years) vs. adults (18–35 years) at 20 mg dose	No apparent PK difference between healthy male and female adults	No accumulation is expected
Amphetamine formulations
ADDERALL XR [37,79–83]	Linear PKs between 20 and 60 mg in adults and adolescents (>75 kg), between 10 and 40 mg in adolescents (≤75 kg), and between 5 and 30 mg in children (6–12 years)	Comparable PK profiles of both d-AMP and l-AMP at 20 mg qd vs. IR AMP 10 mg bid dosed 4 hours apart	AUC: No effect (3%^a and 5%^a decrease in d- AMP and l-AMP, respectively) Cmax: 10%^a decrease in both d- AMP and l-AMP Tmax: Prolongs by 2.5 h for d-AMP and 2.7 h for l-AMP at 30 mg dose	No effect	NR	When adjusted for body weight and dose, children had 30% less exposure vs. adults	20%–30% greater exposure in women vs. men; however, no difference after adjusting for body weight	Accumulation not expected at steady state in children
ADZENYS ER [97–99]	NR	Comparable bioavailability to MAS ER (18.8 mg qd vs. 30 mg qd)	AUC: No effect (96.78% and 96.60% for d- and l-AMP) Cmax: 11% reduction (88.68% and 89.63% for d- and l-AMP, respectively) Tmax: 5 vs. 5.5 h for d-AMP and 5 vs. 6 h for l-AMP	N/A	In vitro: Substantial increase in AMP release at 40% alcohol, but not 5%, 10%, and 20%.	Based on PK of MAS-ER (ADDERALL XR)	Based on PK of MAS-ER (ADDERALL XR)	NR
ADZENYS XR-ODT [94–96,124]	Not studied	Comparable bioavailability (AUC: 99% and 103% for d-AMP and l-AMP, respectively; Cmax: 97% and 99% for d-AMP and l-AMP, respectively) to MAS-ER (18.8 mg qd vs. 30 mg qd)	AUC: No effect (99% and 98% for d- and l-AMP, respectively) Cmax: 19% reduction (81% and 82% for d- and l-AMP, respectively) Tmax: Prolonged by 2 h for d-AMP and 2.25 h for l-AMP	N/A	In vitro: Substantial increase in AMP release at 40% alcohol, but not 5%, 10%, and 20%. In vivo: No dose dumping or change in the extent of absorption at 4%, 20%, or 40% alcohol.	Based on PK of MAS-ER (ADDERALL XR)	Based on PK of MAS-ER (ADDERALL XR)	Not studied
DYANAVEL XR [91,92]	NR	Relative bioavailability of 106% and 111% for d-AMP and d-AMP, respectively, at an equal dose of IR MAS	AUC: Decreased by 5.7% for d-AMP and 7.4% for l-AMP Cmax: 2% increase in both d- AMP and l-AMP Tmax: Delayed by 1 h for both d-AMP and l-AMP	N/A	In vitro: Alcohol-induced dose dumping at 40% alcohol, but not observed at lower concentrations.	NR	NR	Steady state achieved on day 4
MYDAYIS [100–102]	Linear dose proportionality between 12.5 and 50 mg	Comparable PK profiles of both d-AMP (Cmax 101.0%; AUC 104.4%) and l-AMP (Cmax 90.9%; AUC 95.3%) at 37.5 mg vs. MAS-ER at 25 mg qd plus 12.5 mg IR MAS given 8 h later	AUC: no effect (91.1% and 88.7% for d-AMP and l-AMP, respectively) Cmax: decreased by 15% (85.3% and 85.2% for d-AMP and l-AMP, respectively) Tmax: prolonged by 5 h for d-AMP and 4.5 h for l-AMP	No effect on AUC (95.8% and 94.8% for d-AMP and l-AMP, respectively) or Cmax (95.8% and 96.9% for d-AMP and l-AMP, respectively)	In vitro: Increased AMP release at 20% alcohol, and more noticeably, at 40% alcohol.	Cmax and AUC were 21%–31% higher for d-AMP and l-AMP in adolescents (13–17 years) vs. adults (19–51 years)	Similar exposure to d-AMP and l-AMP in women (n = 41) and men (n = 61)	Steady state achieved between 7–8 days, with a mean accumulation ratio of 1.6
VYVANSE (capsule) [34,36,84,85,88]	Linear PK between 30 and 70 mg in children (6–12 years) and between 50 and 250 mg in adults.	30%^a higher AUC and Cmax for d-AMP at 70 mg LDX vs 30 mg MAS-ER	AUC: no effect (95.93% for d-AMP) Cmax: no effect (94.26% for d-AMP) Tmax: prolonged by 1 h for d-AMP [Note: no effect of yogurt or orange juice on AUC and Cmax of d-AMP]	No effect on AUC (99.40% for d-AMP) or Cmax (98.57% for d-AMP)	NR	When adjusted for body weight and dose, AUC and Cmax were similar in children with ADHD (6–12 years) as adults (single doses of 30 to 70 mg)	AUC and Cmax for d-AMP and LDX higher in women; however, similar when adjusted for dose and body weight	Steady state achieved by day 5 No accumulation at steady state
VYVANSE (chewable) [36,89]	Not studied in children	LDX: Cmax and AUC 15% lower at 60 mg qd of VYVANSE chewable vs. capsule d-AMP: Cmax and AUC similar between the VYVANSE chewable and capsule]	Exposure (AUC and Cmax) 5% to 7% lower for d-AMP Tmax: prolonged by 1 h]	N/A	NR	Not studied	Not studied	Not studied

Footnotes: ^aDerived using the following formula: % increase or decrease = (treatment/reference) * 100%.

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AMP, amphetamine; AUC, area under the plasma concentration–time curve; AUC_0-∞, area under the plasma concentration–time curve from zero to infinite time; AUC_0–t, area under the plasma concentration–time curve from zero to the time point with the last quantifiable concentration; AUC_0–24, area under the plasma concentration–time curve from zero to 24 hours; bid, twice daily; C_max, peak plasma concentration; C_max1, first peak plasma concentration; C_max2, second peak plasma concentration; ER, extended-release; IR, immediate-release; LDX, lisdexamfetamine; MAS, mixed amphetamine salts; MAS-ER, mixed amphetamine salts extended-release; MPH, methylphenidate; MPH-CD, methylphenidate controlled-delivery; N/A, not applicable; NR, not reported; OROS-MPH, osmotic-release oral system methylphenidate; PK, pharmacokinetic; qd, once daily; t_1/2, half-life; tid, thrice daily; T_max, time to peak plasma concentration; T_max1, first time to peak plasma concentration; T_max2, second time to peak plasma concentration.

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