Lisdexamfetamine: A pharmacokinetic review

    Lisdexamfetamine: A pharmacokinetic review Eloisa Comiran, F´elix Henrique Kessler, Pedro Eduardo Fr¨oehlich, Renata Pereira Limberger PII: DOI: Reference:

S0928-0987(16)30132-4 doi: 10.1016/j.ejps.2016.04.026 PHASCI 3551

To appear in: Received date: Revised date: Accepted date:

8 January 2016 23 April 2016 24 April 2016

Please cite this article as: Comiran, Eloisa, Kessler, F´elix Henrique, Fr¨oehlich, Pedro Eduardo, Limberger, Renata Pereira, Lisdexamfetamine: A pharmacokinetic review, (2016), doi: 10.1016/j.ejps.2016.04.026

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ACCEPTED MANUSCRIPT LISDEXAMFETAMINE: A PHARMACOKINETIC REVIEW

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Running title: Pharmacokinetics of lisdexamfetamine

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Eloisa Comiran*a, Félix Henrique Kesslerb, Pedro Eduardo Fröehlicha and

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Renata Pereira Limbergera

a

Graduate Studies Program in Pharmaceutical Sciences, Faculty of Pharmacy,

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Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; bCenter for Drug and Alcohol Research, Hospital de Clínicas of Porto Alegre - Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do

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Sul, Brazil

*

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Address correspondence to this author at the Graduate Studies Program in Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Rio

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Grande do Sul, 2752 Ipiranga Avenue, Santana, 90610-000, Porto Alegre, RS,

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Brazil; Tel/Fax: +55-51-3308-5762/+55-51-3308-5243; E-mail: [email protected]

ACCEPTED MANUSCRIPT LISDEXAMFETAMINE: A PHARMACOKINETIC REVIEW

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Running title: Pharmacokinetics of lisdexamfetamine

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Eloisa Comiran*a, Félix Henrique Kesslerb, Pedro Eduardo Fröehlicha and

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Renata Pereira Limbergera

a

Graduate Studies Program in Pharmaceutical Sciences, Faculty of Pharmacy,

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Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; bCenter for Drug and Alcohol Research, Hospital de Clínicas of Porto Alegre - Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do

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Sul, Brazil

*

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Address correspondence to this author at the Graduate Studies Program in Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Rio

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Grande do Sul, 2752 Ipiranga Avenue, Santana, 90610-000, Porto Alegre, RS,

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Brazil; Tel/Fax: +55-51-3308-5762/+55-51-3308-5243; E-mail: [email protected]

ACCEPTED MANUSCRIPT ABSTRACT

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Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to

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treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same

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as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific

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pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007- 2016) databases were searched for articles and their list of

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references. As for basic pharmacokinetics studies, since LDX is a newly

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developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the

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first robust review on this topic, gathering data from all clinical pharmacokinetics

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studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already wellknown pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice.

Key-words: lisdexamfetamine; amphetamine; clinical pharmacokinetics.

ACCEPTED MANUSCRIPT 1 INTRODUCTION Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used

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to treat the symptoms of Attention Deficit and Hyperactivity Disorder (ADHD),

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and Binge Eating Disorder (BED). ADHD is a neuropsychiatric disorder characterized by a pattern of inattention and/or hyperactivity/impulsivity

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(American Psychiatric Association, 2013). BED is a neuropsychiatric disorder

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characterized by episodes of compulsive eating occurring at least once a week for three months, together with a feeling of lack of control and no regular compensatory behaviors (American Psychiatric Association, 2013). The two disorders involve a certain degree of impulsivity, but in the second compulsive

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behavior predominates. This pro-drug has other potential uses that are still offlabel, and its use can be considered an intellectual potentiator. This use of

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amphetamine (AMPH) has already been characterized (Wood et al., 2013).

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AMPH appears to inhibit dopamine and norepinephrine reuptake and release these monoamines into the extraneuronal space relieving the symptoms

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of ADHD and BED (Heal et al., 2009; Mcelroy et al., 2015). Therefore the pharmacological treatment of these neuropsychiatric disorders mimics or increases the effects of catecholamines (Arnsten, 2009). The pro-drug does not cross the blood-brain barrier due to its characteristics and the lack of other biotransformation products of its own. Hence, it is assumed that the in vivo pharmacodynamics of LDX will be the same as that of its active product dAMPH

with

a

few

qualitative

and

quantitative

differences

due

to

pharmacokinetics (Hutson et al., 2014). Stimulants which have slow release preparations and/or are long-acting (Brams et al., 2008), such as methylphenidate, mixed salts of AMPH and LDX

ACCEPTED MANUSCRIPT dimesylate, take longer to reach the maximum concentration in plasma, reducing the levels of reinforcement. Furthermore, slow release helps reduce

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the drug potential for abuse and diversion of the drug to other purposes, since

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there is a great capacity to monitor and supervise its administration once a day (Bukstein and Horner, 2010).

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In this way, considering the specific pharmacokinetics of the long-acting

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stimulants, the present article is a review of pharmacokinetic studies on LDX, the most recent AMPH pro-drug. Some review articles explore in some sections the pharmacokinetics of LDX (Childress and Sallee, 2012; Cowles, 2009; J. C. Ermer et al., 2010; Mattingly, 2010; Mattos, 2014; Najib, 2009; Popovic et al.,

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2009; Steer et al., 2012). The objective was to gather the results found in literature, besides updating knowledge on the subject. A virtual search of the “lisdexamfetamine

pharmacokinetics”

was

performed

in

the

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term

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Medline/PubMed, Science Direct and Biblioteca Virtual em Saúde (Lilacs e Ibecs) databases (2007- 2016) for articles in English, Spanish and Portuguese.

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Additional references were identified through the reference list of those articles. This review included articles with pre-clinical data that help understand the absorption, biotransformation and elimination phases of LDX and all the original articles of clinical pharmacokinetics studies.

2 PHARMACOKINETICS REVIEW

2.1 ABSORPTION After oral administration, the biotransformation product d-AMPH is usually detected in the portal blood for a short period, indicating rapid

ACCEPTED MANUSCRIPT metabolism of LDX to d-AMPH, during or immediately after absorption. Absorption from the lumen of the gastrointestinal tract occurs through carrier-

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mediated transport present in the small bowel. This is consistent with its

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physico–chemical properties of high aqueous solubility and low lipophilia, which foresee low passive diffusion through the biological membranes. Since the

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molecule includes the essential aminoacid lysine in its constitution, it is a substrate for the peptide transporting proteins, mainly PEPT1 which is

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expressed in the small bowel and is related to rapid, efficient intestinal absorption, even with a damaged mucosa (Pennick, 2010). The absorption of PEPT1 substrates does not appear to be affected by the intake of foods, corroborating the results that show that the bioavailability of LDX is not impaired

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in the fed state (Krishnan and Zhang, 2008; Pennick, 2010).

regarding

the

pharmacokinetic

parameters

of

oral

single

dose

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LDX

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Ermer and collaborators (Ermer et al., 2012) studied the absorption of

administration compared to the release of the medication directly into the

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proximal small bowel, distal small bowel and ascending colon. The absorption (systemic exposure) of intact LDX was similar after oral administration and release into the small bowel resulting in similar plasma and pharmacokinetic concentration profiles of d-AMPH. However, the intact LDX presented lower absorption after release into the colon compared with the other administrations, resulting in smaller concentrations of intact LDX and d-AMPH. As to the influence of eating and the way the medication is administered – in the form of a capsule or as a solution – it was found that fasting and capsule dissolution do not affect the bioavailability of LDX in terms of the area under the curve from time 0 to the last time of concentration determined (AUC 0-

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however, eating diminishes the maximum concentration (Cmax) and prolongs

the time to attain maximum concentration (tmax) compared to fasting. For the

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AMPH that results from LDX administration, the fed/fasted status and

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dissolution of the capsule do not influence systemic exposure (area under the curve - AUC and Cmax), however, a fat rich diet delays tmax by 1 hour. The fast

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tmax for LDX under all conditions studied shows its quick absorption, and increasing the fed state by 1 hour did not affect the resulting absorption of d-

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AMPH which was bioequivalent under the three conditions. Therefore, changes in normal gastrointestinal transit time do not affect the end result of the medication and it can be ingested both in a fed and fasted state. These results also show that the capsules can be opened and their content dissolved in water

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without any loss of effect (Krishnan and Zhang, 2008). Further, in vitro tests in

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buffered aqueous solutions demonstrated that the pH of the medium does not affect the solubility profile of LDX within the biological range of pH 1-8, and

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when administered together with the medication called omeprazole, the

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pharmacokinetic profile does not undergo any changes, on the contrary of what happens with other medications for ADHD that use systems sensitive to pH. Thus, both results indicate that the gastric pH does not alter LDX absorption and, consequently there is no interaction with medications that reduce gastric pH (Goodman, 2010; Haffey et al., 2009).

2.2 BIOTRANSFORMATION LDX is not converted in vitro by enzymes that simulate conditions in the gastrointestinal tract, such as gastric and bowel fluids and by trypsin, suggesting that its cleavage in the gastrointestinal tract in vivo is probably

ACCEPTED MANUSCRIPT minimal. Thus, it is absorbed predominantly intact from the small bowel to the portal circulation with posterior enzyme conversion into d-AMPH and l-lysine in

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the blood (Pennick, 2010). Presystemic conversion was demonstrated in rats

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based on two observations: (1) LDX levels in portal blood, approximately 10 times greater than in systemic plasma and (2) area under the curve of LDX and

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d-AMPH similarly in portal plasma, but approximately 3.2 times greater for dAMPH in systemic plasma. Liver microsome assays and assays with isolated

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fresh hepatocytes show that the red blood cells of the portal circulation are responsible for this pre-conversion, not the liver (Pennick, 2010). The biotransformation of LDX occurs only in the red blood cells, not in

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other fractions of human blood such as leukocytes and platelets (Pennick, 2010). These cells have high hydrolytic activity and, consequently, the capacity

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to biotransform LDX, even with a low hematocrit. Hence, the d-AMPH release

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rate appears to be controlled by the biotransformation process, and not by the dissolution of intact LDX (Pennick, 2010). The blood concentrations of LDX in a

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4-hour time period in in vitro samples from normal donors and donors with sickle cell anemia were higher than the plasma concentrations observed in pharmacokinetic studies of therapeutic doses in healthy volunteers. In vitro hydrolysis is robust and is not affected by sickle red blood cells, therefore the depuration would not be compromised. However, in vivo the renal system also can be affected in this pathology and modify LDX depuration (Pennick, 2013). In this way, the mechanism by which the red cells biotransform LDX is still being studied, but it is probably a high capacity system that is not affected by calcium dependent enzymes and a red blood cell pathology. Several hypotheses were raised in this respect, such as the interaction with

ACCEPTED MANUSCRIPT glycoproteins in the membranes of these cells with enzymatic activity for peptides due to the structural similarity of LDX with dipeptides. Also, since the

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structure of AMPH is similar to that of the catecholamines, it could be

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transported actively into the red blood cells through the choline exchange system (Pennick, 2013). Recent, more detailed in vitro studies suggest that LDX

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is hydrolyzed in the cytosol of red cells and not in the membrane (Häge et al., 2014; Sharman and Pennick, 2014). Although this activity is probably due to an

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aminopeptidase, the enzyme responsible has not yet been identified (Sharman and Pennick, 2014). Also, the administration of LDX results in a slow release of d-AMPH through different routes of administration and a broad interval of doses substantially supports the idea that the onset of d-AMPH depends on the rate of

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conversion that limits the LDX, and thus there is no saturation of the depuration

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capacity (Ermer et al., 2012, 2011; Pennick, 2010).

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Since ADHD and BED can be accompanied by comorbidities and the individuals being treated may need other medications due to transient

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conditions, it is very possible that medicines will be co-administered. In such cases, it is important to know the interactions among the medications, especially regarding cytochromes that are responsible for the biotransformation of most drugs. On the contrary of most drugs, LDX is not metabolized by the enzymes of cytochrome P450 (Shire, 2015). The inhibition of CYP2D6 by AMPH and the inhibition of CYP1A2, CYP2D6, and CYP3A4 by one or more of their metabolites have been observed, but no induction of CYP1A2, CYP2B6 and CYP3A4/5 occurred in tests performed with human hepatocytes at concentrations of 1, 10 and 100 μM. The hydrolysis of LDX results in exposure to d-AMPH, therefore it could be predicted that LDX has a similar potential for

ACCEPTED MANUSCRIPT drug interaction. In vitro tests using human liver showed that LDX does not inhibit isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19,

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CYP2D6 and CYP3A4 of the P450 cytochrome and at concentrations of 1, 10

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and 100 μM does not induce CYP1A2, CYP2B6 or CYP3A4/5, suggesting a low potential for interaction with other drugs. Therefore, any interactions would

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probably be caused by AMPH and its biotransformation products and not by intact LDX. Hence, neither LDX nor AMPH inhibit glycoprotein-P at

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concentrations below 300 μM and are not their substrates at concentrations below 100 μM (Hutson et al., 2014; Krishnan and Moncrief, 2007).

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2.3 ELIMINATION

Pharmacokinetics and metabolism studies using the drug marked with 14

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C and liquid scintigraphy found that after oral administration the LDX is

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eliminated 96.4% through the urine in a 120 hour period. In 48 hours 79.4% of the dose was recovered, 41.5% of d-AMPH, 24.8% of hippuric acid, 2.2% of

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benzoic acid, 2.2% of intact LDX and 8.9% not identified. Fecal excretion of LDX corresponds to less than 0.3% (Krishnan et al., 2008).

3 CLINICAL PHARMACOKINETICS

3.1 PHARMACOKINETICS IN PATIENTES Tables 1 and 2 show a summary of the data from single dose pharmacokinetics studies performed in humans for LDX administered alone (Table 1) or in combination with other drugs (Table 2). All the studies have in

ACCEPTED MANUSCRIPT common the use of plasma as a matrix for analysis and liquid chromatography tandem mass spectrometry (LC-MS/MS) as a technique with the same limits of

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quantification (LOQ) of 2 ng/mL for AMPH and 1 ng/mL for LDX. Sample

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extraction varies among articles, from extraction with a non specified organic solvent (Boellner et al., 2010; Krishnan and Zhang, 2008) and liquid-liquid

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extraction (Ermer et al., 2013a, 2013b, 2012, 2011; Roesch et al., 2013) until protein precipitation (Ermer et al., 2016, 2015), and using plasma aliquots of

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100 μL or 200 μL. In Table 1 we can see that although the pharmacokinetic parameter values were close, they have a variation that is probably due to the different study conditions, such as population, age, dosage and others. As already reported in the literature tmax may be influenced by eating (Krishnan and

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Zhang, 2008) and therefore an interval of 2.5 to 6h can be seen for AMPH and

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0.8 to 2 h for LDX, considering the oral administration of LDX in a capsule. However, in a study on the fasted condition, a tmax of 6 h was found for AMPH

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corresponding to supratherapeutic doses of LDX, while the tmax of LDX was not

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altered by the dose increase. For a same dosage, AUC differs among the studies, as for instance the AUC of the AMPH corresponding to 70 mg of LDX in a study (Biederman et al., 2007) which has values equal to 50 mg of another study (Boellner et al., 2010) with very similar characteristics. In the studies that looked at several dosages, systemic exposure increased with the dose. Data on multiple dose pharmacokinetics, analyzed more carefully with respect to multiple dose parameters, in humans were found in one article (Krishnan and Stark, 2008). Eleven adults (men and women aged 18 to 55 years) took a 70 mg capsule of LDX when fasting. The blood was collected predose on days 1, 5, 6 e 7 and post dose on day 7 at times 0.5, 1, 1.5, 2, 3, 4, 5,

ACCEPTED MANUSCRIPT 6, 7, 8, 10, 12, 16, 24, 48, 72 h. The matrix used, as well as the equipment and LOQ for AMPH and LDX were the same as the methods mentioned previously.

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The tmax, maximum concentration observed in the stationary state (Cmax,ss),

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mean concentration in the stationary state (Cmed) and minimum concentration observed in the stationary state (Cmin,ss) attained for AMPH were 3.0 h, 90.1

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ng/mL, 46.4 ng/mL and 18.2 ng/mL, respectively, and for LDX 1.0 h, 47.9 ng/mL, 2.5 ng/mL and 0.0 ng/mL, respectively. On the other hand the area

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under the time curve 0 to 24 hours (AUC0-24) and the Fluctuation Index (FI) found for AMPH were 1110.0 ng·h/mL and 164 %, respectively, and for LDX they were 60.7 ng·h/mL and 1900 %, respectively. Also, in this study, which is concordant with the reality of ADHD treatment, it was observed that the

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administration of a single daily dose of 70 mg of LDX orally produces stationary

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state concentrations of d-AMPH on the fifth day after the first administration. There is no accumulation of LDX and AMPH in the stationary state, and the

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AUC of intact LDX is approximately 5% of the d-AMPH. The levels of intact LDX

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fall below the detectable level in approximately 6 hours after the final dose, and 95% of the AMPH is eliminated in 48 hours after the final dose (Krishnan and Stark, 2008).

3.2 DRUG INTERACTIONS As it was seen in section 2.2, LDX can be co-administered with other medication due some comorbidity or transient condition. Although in vitro tests have been performed, it is necessary to study some important pharmacokinetic interactions in vivo. Table 2 shows that when administered with other

ACCEPTED MANUSCRIPT medications, the pharmacokinetic parameters do not vary much, probably because the conversion does not occur in cytochrome P450.

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The drugs that have been studied in vivo so far together with LDX are

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guanfacine because it is biotransformed by CYP3A4 (Roesch et al., 2013), venlafaxine because it is biotransformed by CYP2D6 (Ermer et al., 2013b),

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omeprazole because it is a proton-pump inhibitor and affects the gastric pH (Haffey et al., 2009) and antipsychotics (Martin et al., 2014). In addition, a joint

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study of the substrates of CYP1A2, CYP2D6, CYP2C19 and CYP3A caffeine, dextromethorfan, omeprazole and midazolam, respectively, was performed, administered alone in the form of a Cooperstown cocktail, or combined with LDX (Ermer et al., 2015).

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The use of LDX together with guanfacine (Childress, 2012; Roesch et al.,

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2013) and antipsychotics (Martin et al., 2014) did not lead to relevant pharmacokinetic changes compared to isolated treatments, and the co-

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administration with omeprazole (Haffey et al., 2009) also did not impair

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exposure to the drug. The co-administration of LDX with venlafaxine also did not speed up exposure to d-AMPH, but it increased exposure to venlafaxine and diminished its biotransformation product, and did not alter the sum total (Ermer et al., 2013b). In the study of interaction with Cooperstown cocktail, LDX did not alter the activity of enzymes CYP1A2, CYP2D6 and CYP3A in healthy volunteers, suggesting that the co-administration of drugs that are metabolized by these enzymes with LDX would not result in drug interactions. As to CYP2C19, there might be a small reduction of Cmax (Ermer et al., 2015), which must be further evaluated for conclusions, since another study with omeprazole (Haffey et al., 2009) did not show a change in exposure to the drug.

ACCEPTED MANUSCRIPT As previously mentioned by Steer and collaborators (Steer et al., 2012), there is still a lack of studies combining LDX (long-acting stimulant) and short-

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acting stimulants or other psychotropic drugs that there are frequently

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associated. Nevertheless, a review article (Najib, 2009) resumes summarized in

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table format some possible interactions with several drugs.

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3.3 PHARMACOKINETS IN SPECIAL PATIENT GROUPS Systemic exposure to intact LDX in children appears to be greater in girls than in boys, even when AUC and Cmax are normalized by dose per weight (Boellner et al., 2010). In adults up to the age of 55 years, when the exposure

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parameters (AUC and Cmax) were normalized by body weight, the systemic exposure to d-AMPH and LDX was not affected by gender (Krishnan and

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Zhang, 2008). In adults over 55 years of age the results obtained in the

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pharmacokinetic parameters for both genders were considered similar, both for d-AMPH and for LDX, but without normalization according to weight (Ermer et

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al., 2013a).

Since part of the AMPH is excreted intact in the urine, it is expected that age related diminished renal function will affect pharmacokinetics. When the renal function of healthy adults over 55 years of age to whom LDX was administered was evaluated, it was found that the depuration of creatinine and d-AMPH tend to diminish with age. However, no clear relationship was detected between these parameters, which contrasts with other studies probably due to the different criteria for the selection and exclusion of the individuals in each study (Ermer et al., 2013a). Recently, a study evaluated individuals with impaired renal function and it was found that d-AMPH elimination decreases as

ACCEPTED MANUSCRIPT kidney injury increases. Also, this same study evaluated if d-AMPH and LDX molecules are dialyzable. Through their tests, the researchers reached the

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dialysate, they are not dialyzable (Ermer et al., 2016).

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conclusion that, since almost no LDX e little d-AMPH were recovered in the

Other special groups are generally not included in the studies. This

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makes it difficult to establish the pharmacokinetics and possible safety, beyond

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what is already established for AMPH, in individuals belonging to special groups such as psychiatric disorders comorbidities, extremes of weight, major neurological and cardiovascular conditions, pregnant women, nursing mothers and individuals with problems or propensity to abuse. Also, pediatric patients

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are advised to monitor weight and height (Coghill et al., 2014; Shire, 2015).

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4 OTHER PHARMACOKINETIC CHARACTERISTICS

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The therapeutic oral doses of 30 to 70 mg LDX result in a

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pharmacokinetics that is proportional to the dose for systemic exposure and peak of exposure to d-AMPH, but not to intact LDX. The plasma concentrations of LDX present a more than proportional increase with the increase of oral doses of LDX (Boellner et al., 2010). Identical results of proportionality for dAMPH were found up to supratherapeutic doses of LDX of 50 to 250 mg in healthy adults, indicating that there is no enzyme saturation in the conversion of LDX into d-AMPH. Consequently, larger doses of LDX result in higher blood levels of d-AMPH, demonstrating that there is no protection against superdosages at least up to 250 mg of LDX (Childress and Sallee, 2012; J. Ermer et al., 2010; Martin et al., 2014).

ACCEPTED MANUSCRIPT The low intra and interindividual variability of the pharmacokinetic parameters in therapeutic and supratherapeutic doses (Biederman et al., 2007;

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Boellner et al., 2010; J. Ermer et al., 2010; Ermer et al., 2011; Krishnan et al.,

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2008), measured by the coefficient of variation (% CV), may be a result of LDX being a pro-drug and thus not depending on typical release mechanisms

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connected to the formulation (Biederman et al., 2007; Boellner et al., 2010). Other factors may also be responsible for this low variability and for the

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consistent delivery of d-AMPH among patients, such as the high solubility in water, resistance to changes in the gastric environment and pH on absorption/conversion, the gradual enzymatic conversion of LDX into d-AMPH and not saturable in therapeutic doses and high capacity metabolism through

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the red blood cells (Pennick, 2010). Pharmacokinetics proportional to the dose

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of active product with low interindividual variability found in studies with a small number of participants may be useful to optimize the dosage and tolerability in a

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diverse population (Boellner et al., 2010).

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The route of administration may affect the pharmacokinetic parameters of a substance and increase its reinforcement properties by beginning action faster focusing on its potential for abuse. This is especially the case of the smoked, injected and inhaled forms of administration, whose action begins much faster than by oral route, which has a lower addictive potential but can also act as reinforcement, especially at a high dose (Compton and Volkow, 2006). LDX dimesylate is approved for oral administration, but like other stimulant medications it may be misused or abused by intranasal administration. Therefore, the pharmacokinetics of LDX by intranasal administration was studied and compared with the oral route of administration. In oral

ACCEPTED MANUSCRIPT administration there was a correlation between the absorption of intact LDX and the appearance of d-AMPH, while intranasally, the rapid absorption and

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redistribution of intact LDX was followed by a second, slower absorption phase,

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without generating two peaks of d-AMPH absorption. Hence, the plasma concentrations and systemic exposure related to d-AMPH were similar in both

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routes studied (Ermer et al., 2011).

Alterations of gastric pH or gastrointestinal transit do not appear to affect LDX solubility. The bioavailability of d-AMPH as a result of pro-drug administration is bioequivalent when given in the form of a capsule or solution,

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and fasted or fed, although foods reduce Cmax and prolong tmax. This difference in the fed state for the parameters mentioned may be partly the cause of the

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different values obtained for the studies in the table. LDX is absorbed intact

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from the small bowel and biotransformed into d-AMPH in the red blood cells. Systemic exposure to d-AMPH increases with the dose of LDX. This is

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an extremely important factor in clinical practice to titer dosage and patient adaptation. As previously mentioned, when administered together with other drugs, pharmacokinetic parameters do not vary much, probably because the conversion does not occur in cytochrome P450, thus showing the suitability of joint use with some drugs in clinical practice when necessary in comorbidities. Elimination is predominantly renal, and almost half this excretion occurs in the form of AMPH.

4 CONCLUSIONS

ACCEPTED MANUSCRIPT This review showed that LDX pharmacokinetics was studied under various conditions. However, so far there have been no studies showing the

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enzymes responsible for the biotransformation of LDX in the red blood cells, nor

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studies on the distribution of this drug in the body. Looking at the available data, there is a lack of studies and research in the literature on the analysis of other

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biological matrices to help gain a better understanding of the behavior of this drug in the human body. This knowledge is needed to help the toxicological

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analyses regarding the possibility of detection in other biological matrices and to interpret results related to time of detection and biotransformation. Interindividual variability is a major factor in a uniform response to treatments, despite the broad spectrum of psychic disorder presentations. In

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general, the articles report a small variability of the data obtained. However,

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when equal dosages are compared in similar studies, systemic exposure to the drug presents a certain difference. This occurs even if the methods of analysis

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used are very similar or applied at the same site. The articles evaluate

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variability in their studies and report that it is low, possibly because the conditions are the same among intrastudy volunteers. However, when studies from different articles are compared, variability may be greater than reported and a more complex and critical evaluation are needed for a better conclusion. This result would require the process of developing a dosage regime for groups of patients. There was a comprehensive review of literature for data on the pharmacokinetics of LDX, focusing on data from original clinical studies. The objective of gathering the results from literature besides updating knowledge on the subject was accomplished. This is the first robust review on this topic with

ACCEPTED MANUSCRIPT data from all clinical pharmacokinetic studies available in the literature. The specific pharmacokinetics of LDX plays a major role in studying this pro-drug,

T

since this knowledge was essential to understand some reports on clinical

RI P

effects in the literature, e.g. the small likelihood of reducing the effect by interactions, the long duration effect and the still questionable reduction of the

SC

potential for abuse. In general, the already well known pharmacokinetic

LDX in clinical practice.

ACKNOWLEDGEMENTS

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properties of the AMPH make LDX relatively predictable, simplifying the use of

The authors thank Conselho Nacional de Desenvolvimento Científico e

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Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de

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Nível Superior (Capes) for the support and scholarships and Fundo de Incentivo

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à Pesquisa e Eventos (FIPE/HCPA) for the support.

REFERENCES

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Goodman, D.W., 2010. Lisdexamfetamine dimesylate (Vyvanse), a prodrug stimulant for attention-deficit/hyperactivity disorder. Pharm. Ther. 35, 273– 87.

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ACCEPTED MANUSCRIPT

Table 1: Pharmacokinetic studies of single dose in humans. Difference from c other studies

Collection interval (h)

AMPH a tmax (h)

tmax (h)a

AMPH Cmax a (ng/mL)

LDX Cmax a (ng/mL)

AMPH AUC0-t a (ng·h/mL)

25

Adults (18-55 years)

Intravenous administration

Pre-dose to 24

2.5

Chart

20.7

Chart

319.5

30

Adults (18-85 years)

Pre-dose to 96

3.5

1.1

32.2

15.7

527.9

30

Children (6-12 years)

ADHD subjects

Pre-dose to 48

3.41

0.97

53.2

21.9

30

Adults (18-85 years)

Mild to severe renal impairment

Pre-dose to 96

3.9-4.3

1.0-1.5

27.5-35.1

12.8-16

30

Adults (18-85 years)

End-stage renal disease – Dose predialysis

Pre-dose to 72

3.3

1.1

25.5

30

Adults (18-85 years)

End-stage renal disease – Dose postdialysis

Pre-dose to 48

4.5

9.8

20.1

50

Adults (18-65 years)

Pre-dose to 72-96

3-5

1.0-1.2

36.5-45.0

50

Children (6-12 years)

ADHD subjects

Pre-dose to 48

3.58

0.98

50

Adults (18-55 years)

Intravenous administration

Pre-dose to 24

2.5

50

Adults (18-65 years)

Intranasal administration Phamaceutical form: Solution

Pre-dose to 72

4.8

50

Adults (≥55 years)

Older adults

Pre-dose to 72

50

Adults (18-65 years)

Oral administration with release in the proximal small bowel

50

Adults (18-65 years)

Oral administration with release in the distal small bowel

LDX AUC0-t a (ng·h/mL)

AMPH AUC0-∞ a (ng·h/mL)

LDX AUC0-∞ a (ng·h/mL)

AMPH

LDX

t½ (h)a

t½ (h)a

REFERENCES (Jasinski and Krishnan, 2009)

23.7

12.1

0.5

(Ermer et al., 2016)

745.3

25.54

844.6

27.88

8.90

0.50

(Boellner et al., 2010)

577.1-779.5

15.5-19.2

637.7-856.9

17.9-31.4

12.819.8

0.6-0.7

(Ermer et al., 2016)

60.7

741.8

1244.3

1065.9

24

40.9

0.7

(Ermer et al., 2016)

37.7

623.8

864.5

1126.3

NA

38.2

NA

(Ermer et al., 2016)

19.8-26.1

719.1-763.1

23.4-28.1

686.9-818.1

25.2-62.1

9.7-11.6

0.5-0.6

(J. Ermer et al., 2010; Ermer et al., 2012, 2011; Haffey et al., 2009) (Roesch et al., 2013)

93.3

46.0

1448.0

56.20

1510.0

57.90

8.61

0.60

(Boellner et al., 2010)

Chart

38.9

Chart

562.7

NA

NA

NA

NA

NA

(Jasinski and Krishnan, 2009)

0.5

35.9

50.4

690.5

48.3

746.2

49.3

NA

NA

(Ermer et al., 2011)

3.5-5.5

1.0-1.8

44.2-64.3

24.7-43.0

NA

NA

915.0-1347.8

28.5-51.9

12.215.0

0.5-0.9

(Ermer et al., 2013a)

Pre-dose to 72

4

0.8

40.5

28.2

771.2

33.4

839.8

35.1

11.8

0.5

(Ermer et al., 2012)

Pre-dose to 72

5

0.8

38.7

36.6

752.4

45.9

811.9

47.1

11.2

0.5

(Ermer et al., 2012)

TE

D

MA

NU S

597.9

AC

17.5

CE P

LDX

PT

Population studied

CR I

Presentation (mg)

ACCEPTED MANUSCRIPT

Difference from c other studies

Collection interval (h)

AMPH a tmax (h)

50

Adults (18-65 years)

Oral administration with release in the ascending large bowel

Pre-dose to 72

8

tmax (h)

AMPH Cmax a (ng/mL)

LDX Cmax a (ng/mL)

AMPH AUC0-t a (ng·h/mL)

0.8

25.7

2.8

574.3

LDX a

LDX AUC0-t a (ng·h/mL)

AMPH AUC0-∞ a (ng·h/mL)

LDX AUC0-∞ a (ng·h/mL)

AMPH

LDX

t½ (h)a

t½ (h)a

3.0

635.3

12.7

11.5

0.7

PT

Population studied

CR I

Presentation (mg)

a

REFERENCES (Ermer et al., 2012)

Only the means of the pharmacokinetic parameters were extracted from the studies and included in the table for ranges. Multiple dose study with pharmacokinetic measurement on the last day of drug intake. C Studies standards are the capsule pharmaceutical form ingested in fasted feeding status via oral administration in healthy subjects. tmax = time to reach maximum (peak) concentration following drug administration; Cmax = maximum (peak) concentration; AUC0–t = area under the curve from time zero to the last time of concentration determined; AUC0-∞ = area

NU S

b

AC

CE P

TE

D

MA

under the curve from time zero to infinity; t½ = elimination half-life; NA = data not available.

ACCEPTED MANUSCRIPT

Population studied

70

Adults (18-55 years)

70

Children (6-12 years)

70

Collection interval (h)

AMPH tmax a (h)

LDX tmax a (h)

AMPH Cmax a (ng/mL)

LDX Cmax a (ng/mL)

AMPH AUC0-t a (ng·h/mL)

LDX AUC0-t (ng·h/mL)a

AMPH AUC0∞ (ng·h/mL)a

LDX AUC0-∞ (ng·h/mL)a

59.47-65.5

1110

107.40

AMPH a

LDX a

REFERENCES

t½ (h)

t½ (h)

66.84

9.6910.4

0.4-0.41

(Ermer et al., 2013b ; Krishnan and Zhang, 2008)

2157.0

108.90

8.64

0.51

(Biederman et al., 2007b; Boellner et al., 2010)

b

3.5-3.78

1.11.15

69.3-88.9

48.0-49.1

10201143.4

ADHD subjects

Pre-dose to 12-48

3.46-4.5

1.07

134-155

89.5

13262088.0

Adults (18-55 years)

Feeding Status: Fed

Pre-dose to 72

4.72

2.08

65.3

26.2

972

53.68

1038

58.81

9.59

0.63

(Krishnan and Zhang, 2008)

70

Adults (18-55 years)

Phamaceutical form: Solution

Pre-dose to 72-120

3.003.33

0.971.00

68.4-80.3

45.6-58.2

1007-1260

53.07-70.21

1074-1342

55.10-67.04

9.3710.39

0.44-0.47

(Krishnan and Zhang, 2008; Krishnan et al., 2008)

100

Adults (18-55 years)

Supratherapeutic dose

Pre-dose to 96

4

1.0

84.6

63.8

1485.1

96.0

1548.2

94.0

11.1

0.7

(J. Ermer et al., 2010)

150

Adults (18-55 years)

Supratherapeutic dose

Pre-dose to 96

4

1.0

126.6

99.5

2429.3

135.1

2503.4

151.7

10.9

0.7

(J. Ermer et al., 2010)

200

Adults (18-55 years)

Supratherapeutic dose

Pre-dose to 96

6

1.0

127.7

3265.5

188.9

3336.2

214.9

11.3

0.9

(J. Ermer et al., 2010)

250

Adults (18-55 years)

Supratherapeutic dose

Pre-dose to 96

6

185.6

5056.8

307.6

5132.5

345.8

12.4

0.9

(J. Ermer et al., 2010)

1.5

NU S

D

TE 168.8

246.3

CR I

Pre-dose to 24-72

CE P

a

Difference from other studiesc

MA

Presentation (mg)

PT

Table 1: Pharmacokinetic studies of single dose in humans (cont.).

AC

Only the means of the pharmacokinetic parameters were extracted from the studies and included in the table for ranges. Multiple dose study with pharmacokinetic measurement on the last day of drug intake. C Studies standards are the capsule pharmaceutical form ingested in fasted feeding status via oral administration in healthy subjects. tmax = time to reach maximum (peak) concentration following drug administration; Cmax = maximum (peak) concentration; AUC0–t = area under the curve from time zero to the last time of concentration determined; AUC0-∞ = area b

under the curve from time zero to infinity; t½ = elimination half-life; NA = data not available.

Table 2: Pharmacokinetic studies on joint administration with other medications in humans. AMPH a tmax (h)

LDX a tmax (h)

AMPH Cmax a (ng/mL)

LDX Cmax a (ng/mL)

Adults (18-45 years)

Pre-dose to 96

3

NA

46.3

NA

LDX 70 mg/day + VXR 225 mg/day with initial LDX alone

Adults (18-55 years)

Pre-dose to 24

3.2

1.1

88.9

49.8

LDX 70 mg/day + VXR 225 mg/day with initial VXR alone

Adults (18-55 years)

Pre-dose to 24

3.1

1.0

85.3

LDX 50 mg + GXR 4 mg

Adults (18-45 years)

Pre-dose to 72

3.9

1.1

36.50

LDX 50 mg + antipsychotic

Adults (18-65 years)

Schizophrenia subjects

Pre-dose to 12

3.8

1.3

51.7

LDX 70 mg+ antipsychotic

Adults (18-65 years)

Schizophrenia subjects

Pre-dose to 12

3.8

1.3

LDX 100 mg + antipsychotic

Adults (18-65 years)

Schizophrenia subjects

Pre-dose to 12

3.9

1.3

LDX 150 mg + antipsychotic

Adults (18-65 years)

Schizophrenia subjects

Pre-dose to 12

4.3

1.2

LDX 200 mg + antipsychotic

Adults (18-65 years)

Schizophrenia subjects

Pre-dose to 12

4.8

LDX 250 mg + antipsychotic

Adults (18-65 years)

Schizophrenia subjects

Pre-dose to 12

LDX 70 mg + caffeine 200 mg + dextromethorphan 30 mg + omeprazole 40 mg + midazolam 0.025 mg/Kg

Adults (18-45 years)

a

Pre-dose to 72

761.6

NA

NU S 50.8

27.13

708.4

AMPH AUC0-τ a (ng·h/mL)

LDX AUC0- τ a (ng·h/mL)

1049.2

60.8

9.7

0.4

11.2

NA

NA

35.0

1139.8

43.7

109.0

50.6

1712.2

80.5

153.6

90.3

2465.0

144.9

207.0

133.3

3402.5

230.2

4397.9

301.5

D

74.8

181.5

4.4

1.5

74.60

43.88

1310.3

62.0

NA 0.4

25.6

266.3

10.4 9.8

801.8

1.4

LDX a t½ (h)

63.9

21.9

4.6

AMPH a t½ (h)

1135.4

MA

1.4

LDX AUC0-∞ a (ng·h/mL)

AMPH AUC0-∞ a (ng·h/mL)

CR I

Collection interval (h)

TE

LDX 50 mg + omeprazole 40 mg

Difference from c other studies

CE P

Population studied

REFERENCES (Haffey et al., 2009)

(Ermer et al., b 2013b)

(Roesch et al., 2013)

(Martin et al., 2014)b

11.09

0.56

(Ermer et al., 2015)

AC

Combination

PT

ACCEPTED MANUSCRIPT

Only the means of the pharmacokinetic parameters were extracted from the studies and included in the table for ranges. Multiple dose study. c Studies standards are the capsule pharmaceutical form ingested in fasted feeding status via oral administration in healthy subjects. b

tmax = time to reach maximum (peak) concentration following drug administration; Cmax = maximum (peak) concentration; AUC0-∞ = area under the curve from time zero to infinity; AUC0-τ = area under the curve during a dosage interval; t½ = elimination half-life; GXR = guanfacine; VXR = venlafaxine; NA = data not available.

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA NU

SC

RI P

T

Graphical abstract