Pediatric trazodone compositions and methods of treatment thereof

Abstract

The present invention relates to trazodone for use in the treatment of insomnia in pediatric populations, said pediatric populations suffering from intellectual or neurodevelopmental disorders. The present invention also relates to a pediatric formulation comprising 0.1-4% trazodone concentration and pediatric-appropriate excipients.

Description

[Technical Field]

[0001] The present invention relates to methods for treating insomnia in the pediatric population and the development of stable pharmaceutical compositions suitable for administration to the pediatric population. [Background technology]

[0002] Trazodone is an antidepressant that exerts its activity as a serotonin antagonist and reuptake inhibitor. It is primarily indicated for the treatment of depression in patients who have not responded to antidepressants, including selective serotonin reuptake inhibitors. Due to its combined serotonergic receptor antagonism and serotonin reuptake inhibition, trazodone has demonstrated unique therapeutic flexibility, allowing it to potentially be used for a wide range of comorbid conditions in major depressive disorder, as well as off-label conditions, including insomnia. Trazodone's hypnotic effects are achieved rapidly and may have beneficial effects on sleep architecture and quality in patients with depression.

[0003] Trazodone also exhibits sedative effects, and one review indicates that insomnia is the most common reason for its off-label prescription and use in adult and pediatric populations (Blackmer A. B, and Feinstein JA “Management of Sleep Disorders in Children with Neurodevelopmental Disorders: A Review”, Pharmacotherapy 2016, 36(1): 84-98 2016).

[0004] Indeed, insomnia is a common problem in children with neurodevelopmental disorders, affecting the quality of life of both the child and their family and contributing to the worsening of behavioral disorders.

[0005] Owens JA et al., "Use of pharmacotherapy for insomnia in child psychiatry practice: A national survey," Sleep Medicine 2010, 11: 692-700, discloses that trazodone is the most commonly prescribed off-label insomnia treatment for children with mood and anxiety disorders (MD and AD) and the second most commonly prescribed drug for children with both attention deficit hyperactivity disorder (ADHD) and mental retardation / developmental delay (MR / DD).

[0006] Despite favorable anecdotal reports regarding the use of trazodone in pediatric insomnia, controlled clinical trials to evaluate its efficacy and safety and subsequently assess appropriate dosing in children are still lacking. Indeed, although the clinical pharmacokinetics (PK) of trazodone has been extensively studied in adults, details related to trazodone's metabolism remain unclear. In vitro studies have shown that it is primarily metabolized by CYP3A4 and CYP3A5 to the active metabolite m-chlorophenylpiperazine (mCPP), with CYP2C19 and CYP2D6 also contributing to the metabolism of trazodone to other (inactive) metabolites. Therefore, studies in children, whose metabolic pathways may differ significantly from those in adults, are warranted.

[0007] Liquid trazodone compositions have been described and are commercially available. For example, WO 2009 / 016069 discloses liquid pharmaceutical compositions containing trazodone HCl at concentrations of 6% w / v or 1% w / v. Furthermore, Indian Patent Application 1242 / MUM / 2005 discloses liquid pharmaceutical compositions containing trazodone at a concentration of at least 0.5-5% w / v.

[0008] A 6% w / w solution of trazodone is commercially available and is stable in the pH range of 5-6 and is stable for up to 3 years for adult administration.

[0009] There is a much-felt need in the art to develop stable, palatable pediatric pharmaceutical compositions with low trazodone concentrations that contain pediatric-acceptable excipients and allow for fine-tuning of the dose in this highly heterogeneous population. Summary of the Invention

[0010] Detailed Description of the Invention According to a first embodiment, the present invention relates to a method for treating insomnia in the pediatric population, preferably caused by a neurodevelopmental disorder, with low doses of trazodone.

[0011] This embodiment provides trazodone for use in pediatric populations. According to this embodiment, trazodone is used at a dose of 0.2 to 0.6 mg / kg in pediatric patients with insomnia secondary to intellectual disability (ID) or neurodevelopmental disorders (NDD), particularly NDDs such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).

[0012] Other IDs that may benefit from treating insomnia are TIC disorder, fragile X syndrome, cerebral palsy, Angelman syndrome, learning disabilities, conduct disorder, Down syndrome, and Rett syndrome (Thapar A, Cooper M, Rutter M. Neurodevelopmental disorders. Lancet Psychiatry. 2017 Apr;4(4):339-346; Angriman M, Caravale B, Novelli L, Ferri R, Bruni O. Sleep in children with neurodevelopmental disabilities. Neuropediatrics.2015 Jun;46(3):199-210 ).

[0013] In the methods of the present invention, the pediatric population is between 2 and 17 years of age and includes two subpopulations: a first subpopulation between 6 and 17 years of age (up to their 18th birthday) and a subpopulation between 2 and 5 years of age (up to their 6th birthday).

[0014] Patients who may benefit from this therapeutic treatment and who may have insomnia episodes and other symptoms of ID and NDD resolved are pediatric patients with intellectual disabilities (ID) or neurodevelopmental disorders (NDD) as described above, particularly neurodevelopmental disorders such as autism spectrum disorder (ASD), intellectual disability, and attention-deficit / hyperactivity disorder (ADHD).

[0015] Doses that have been preliminarily found to increase sleep time in pediatric populations with NDD are, inter alia, 0.4 and 0.5 mg / kg / day via drops or equivalent doses via syrup.

[0016] The present invention also encompasses all intermediate doses such as 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, up to 0.6 mg / kg daily. For example, a pediatric treatment scheme may involve the administration of 5 to 30 drops of a drop composition of either the 1.5% or 3% w / V liquid formulation daily, preferably for at least one week, or even more preferably chronically, depending on the age group, patient weight, disease severity, etc.

[0017] These doses and associated treatment schedules in the pediatric population for the treatment of insomnia secondary to the above-mentioned ID and NDD pathologies can be adapted to other routes of administration with low trazodone dose compositions.

[0018] Trazodone is preferably administered before bedtime in a pharmaceutical formulation suitable for children, such as a tasteful syrup or drops that are diluted in a drink, creamer, or semi-solid food composition typically enjoyed by children.

[0019] Trazodone may be co-administered with other drugs typically used in ID or NDD. According to this further embodiment, trazodone is administered with at least one drug selected from the group consisting of a first-generation antipsychotic such as haloperidol, a second-generation antipsychotic such as olanzapine, an antidepressant such as amitriptyline, a benzodiazepine such as lorazepam, an antiepileptic such as gabapentin, a mood stabilizer such as lithium, a psychostimulant such as methylphenidate, and an anticonvulsant such as biperiden and atomoxetine.

[0020] With the aim of providing a means for pediatric use of trazodone, a pharmaceutical composition with a low trazodone concentration was developed that is stable, palatable, avoids specific excipients or co-solvents such as ethanol, only contains pediatric-acceptable excipients, and allows fine-tuning of the dose in children according to age, weight, disease and its severity.

[0021] As is known, this is a critical task because certain excipients acceptable for adult formulations, such as ethanol in oral liquids or benzyl alcohol in intravenous formulations, may not be appropriate, especially for neonates. Indeed, pediatric patients may not be able to metabolize and excrete ingredients as well as adults, potentially leading to adverse side effects (CHMP, 2006). The toxicity of excipients may differ between adult and pediatric patients, as well as among subsets of children. For example, neonates have been shown to metabolize propylene glycol less efficiently than other pediatric populations, potentially leading to accumulation and adverse events (FDA, 2011). Furthermore, children receiving multiple medications may be exposed to multiple potentially toxic excipients during their usual multiple treatment regimens, posing a higher risk of adverse effects. For example, coadministration of benzyl alcohol, propylene glycol, and polysorbate 80 has resulted in various toxicological syndromes in pediatric populations, particularly neonates.

[0022] According to this embodiment, pediatric liquid solutions, either drops or syrups, are developed that contain pediatric-acceptable excipients, provide a maximum daily intake (MDI) well below the acceptable daily intake (ADI), are ethanol-free, and preferably contain the following co-solvent combinations: PEG400 and propylene glycol for drop compositions, or glycerol, sucrose and PEG400, and reduced amounts of propylene glycol for syrups.

[0023] Preliminary data indicate that pediatric pharmaceutical trazodone compositions with 0.1%-4% w / V trazodone concentrations are useful for treating insomnia due to neurodevelopmental disorders such as autism spectrum disorder (ASD), intellectual disability, and attention-deficit / hyperactivity disorder (ADHD), and are very well tolerated by children due to their sweet taste.

[0024] The pediatric population that benefits from this treatment is aged 2 to 17 years, up to their 18th birthday. Two subpopulations have been identified: the first aged 6 to 17 years, and the second aged 2 to 5 years. The first subpopulation can be treated with a 3% w / w trazodone solution, and the second subpopulation with a 1.5% w / V trazodone solution.

[0025] Another administration via syrup composition is also suitable for administration to children who enjoy the sweet taste of this pharmaceutical form.

[0026] Indeed, in the field of pediatric medicine and therapeutic treatment, especially insomnia, there is a much-felt need to develop stable compositions that contain most of the pediatric approved excipients, that easily allow for lower doses in younger children, and that conveniently mask the bitter taste of trazodone, preferably in the form of drops or syrups as described above.

[0027] Drops, which are typically diluted in a liquid, have to overcome the technical challenge of being stable in liquids (or semi-solid food compositions) and beverages typically preferred by children, such as fruit juices, yogurt, cream, or soft drinks, i.e. food compositions which contain a wide variety of additives such as emulsifiers, preservatives, etc.

[0028] These are problems encountered during the development of pediatric compositions in addition to the known drawbacks of liquid trazodone solutions, the physical aspects of which can turn yellow due to oxidation phenomena and have an extremely bitter taste, which have hitherto strongly limited their possible use in children.

[0029] Furthermore, trazodone, which has a pKa of 6.61, is only fully soluble at acidic pH and precipitates at near-neutral pH values.

[0030] Thus, according to one embodiment, the present invention relates to a pediatric drop composition comprising a trazodone salt in a concentration comprised between 0.1% w / V and 4% w / V. Preferably, the trazodone is trazodone HCl, having a concentration of 1% w / V or more, more preferably 1-3% w / V. The pediatric drop composition does not contain alcohol as a solvent or cosolvent, is stable in more concentrated forms, does not turn yellow over time, and is stable when diluted in liquids suitable for administration to children, such as fruit juice or sugar water, yogurt, or cream.

[0031] In the trazodone compositions developed by the applicant, the excipients are approved for use in pediatric populations and have no known contraindications. The excipients, when administered to provide an adequate trazodone dose, are present at a maximum daily intake (MDI) well below the acceptable daily intake (ADI) according to competent authorities. The ADIs and MDIs for most of the excipients used in the pharmaceutical compositions of the present invention are shown in Table 1.

[0032] [Table 1]

[0033] Notably, the trazodone solution in drops suitable for administration to children is compatible with liquid beverages typically enjoyed by children, such as fruit juice, sugar water, yogurt, and cream.

[0034] [Table 2]

[0035] As an alternative co-solvent, the composition may include glycerol-PEG200, PEG6000, or other PEGs. As an alternative antioxidant, it may contain: Ascorbic Acid Vitamin E - Ascorbyl Palmitate. Alternative sweeteners may include: sucrose, aspartame, neotem saccharin, stevia, sodium cyclamate, acesulfame K. Alternative chelating agents may include: citric acid-tartaric acid. Alternative buffering agents may include: sodium citrate-K-phosphate.

[0036] Thus, according to a preferred embodiment, the drop formulation comprises: ·Active ingredients Glycol, preferably propylene glycol, in an amount of 5-45% (w / v), preferably 20-40%, optionally in combination with a sugar such as sucrose or sucralose. Simple polyols such as glycerol can also be used as cosolvents, for example together with alditols such as sucrose.

[0037] The drop formulation has a pH value of 4.5 to 5.5, more preferably 4.5 to 5.2, and more preferably 4.5 to 5.0, and preferably contains at least two cosolvents in a total amount of 50 to 60% w / V, preferably selected from the group consisting of the following mixtures: propylene glycol + PEG 200, propylene glycol + PEG 400, propylene glycol + PEG 6000, propylene glycol + PEG 200 + PEG 6000, propylene glycol + PEG 400 + PEG 6000, PEG 200 + PEG 6000, and PEG 400 + PEG 6000. A preferred combination is propylene glycol + PEG 400. An oligosaccharide, preferably sucralose, may be present as a sweetener.

[0038] In particular, the drop composition according to the invention is preservative-free.

[0039] In a further embodiment, the applicant has developed a trazodone syrup formulation for direct administration in the pediatric population, which has a lower trazodone concentration than the drop formulation. In the syrup composition, trazodone or a salt thereof has a concentration comprising 0.1% to 0.9% w / V, preferably 0.2% to 0.4% w / V, more preferably 0.24% to 0.3% w / V, and even more preferably 0.26% w / V.

[0040] Alternatively, the syrup composition has a trazodone concentration of 0.1-0.9 mg% (w / V), preferably 0.18%-0.3%. These low concentration solutions have been shown to be relatively stable from a chemical and physical standpoint (under stress tests at 70°C and 4°C for 1 week), similar to the drop formulation disclosed above and summarized below.

[0041] The syrup composition also preferably contains excipients selected from those suitable for pediatric use. As mentioned above for the drop composition, many references provide pediatric guidance and define acceptable daily intakes (ADIs) for excipients in the pediatric population, as summarized in Table 1 above. To avoid possible interactions between excipients, the composition is kept as simple as possible.

[0042] Syrups are aqueous compositions in which the trazodone salt is present in a concentration of 0.1-0.9% w / V and has a pH value of 4-5.5. Sucrose is present in a concentration of 25-38%, preferably 30-36%. Advantageously, these compositions are stable and palatable, and do not require the addition of any flavor, although this may optionally be present without altering the stability of the composition, as described in more detail in the experimental section.

[0043] The co-solvent or co-solvent mixture has a concentration w / V comprised between 10 and 60%, preferably between 10 and 40% w / V. A preferred combination is glycerol 20-30% w / V, propylene glycol containing less than 9% w / V, preferably between 5 and 8% w / V, and PEG-400 at 1-5%, preferably between 2 and 3% w / V.

[0044] Indeed, syrup compositions to be administered undiluted have been developed containing reduced concentrations of propylene glycol, advantageously less than 9% w / V. In these compositions, sucrose can be used at % w / V higher than 30%, providing the required palatability and trazodone stability.

[0045] The syrup composition preferably contains an antioxidant, a buffer, and a preservative, preferably selected from the group consisting of methyl and propyl parahydroxybenzoates, potassium sorbate, and mixtures thereof. Potassium sorbate, or alternatively sodium benzoate, is preferred. The antioxidant is selected from the group consisting of propyl gallate and EDTA, and mixtures thereof. Preferably, the buffer is citrate.

[0046] Preferably, these solutions contain trazodone HCl as the trazodone salt.

[0047] The above syrup composition is highly palatable and can be used by oral or transmucosal routes of administration in the pediatric population.

[0048] According to the above preferred embodiments, the present invention also relates to a pharmaceutical composition, either an infusion or a syrup, for use in treating insomnia and its symptoms (e.g., anxiety, agitation or confusion, motor agitation in children with intellectual or neurodevelopmental disabilities), wherein the child is between 2 and 17 years of age (up to their 18th birthday), and wherein the therapeutic treatment involves oral or transmucosal administration of the preferred composition in the preferred form, i.e., drops diluted in the child's most preferred liquid, or a syrup administered neat, suitable to provide a dose of 0.2 to 0.6 mg / kg prior to sleep.

[0049] An exemplary syrup composition is disclosed in Table 3 below. [Table 3]

[0050] In summary, the syrup composition preferably comprises the following excipients: PEG w / V 0-5%, preferably PEG400 2-4%w / V Glycerol 20-30% w / V, preferably 23-28% w / V Propylene glycol 5-10% w / V, preferably 6-8% w / V Sucrose 30-40% w / V, preferably 33-38% w / V

[0051] Notably, the syrup composition contains very low concentrations of PEG, preferably PEG-400, propylene glycol and preservatives (ie, sodium benzoate, methylparaben or potassium sorbate), and the MDI is significantly lower than the ADI.

[0052] Patients who may benefit from the use of these compositions in the treatment of insomnia include pediatric patients with intellectual disabilities and neurodevelopmental disorders, such as autism spectrum disorder (ASD), intellectual disability, and attention-deficit / hyperactivity disorder (ADHD). Three different doses, 0.25, 0.4, and 0.5 mg / kg, may be used in drops, or equivalent doses in syrup. For example, a pediatric treatment regimen may involve the administration of 5 to 30 drops of either a 1.5% or 3% w / V liquid formulation, depending on the age group, patient weight, and disease severity.

[0053] These doses and associated treatment schedules in the pediatric population for insomnia secondary to the above-mentioned intellectual and neurodevelopmental disorders may be adapted to other routes of administration and low trazodone dose compositions and may be administered chronically or for at least 1 week.

[0054] The pharmaceutical syrup compositions of the present invention can be prepared in suitable mono-predilution and pre-fill forms.

[0055] However, other low-dose forms can be prepared by those skilled in the art to provide a daily dose of 0.2-0.6 mg / kg per pediatric patient. For example, low-dose tablets, capsules, lozenges, sugar drops, lollipops, coated tablets, granules, or the above solutions and syrups can be provided for oral administration; medicinal patches can be provided for transdermal administration; and suppositories and injectable sterile solutions can be provided for rectal administration.

[0056] Other suitable dosage forms are modified release dosage forms and liposome-based dosage forms for oral, injectable or transdermal or transmucosal administration. Particularly preferred alternative administration routes and compositions are transmucosal routes and transdermal patches.

[0057] The dosage form may also contain other traditional ingredients such as preservatives, stabilizers, surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, sweeteners, colorants, flavors, etc., and is suitable for pediatric use.

[0058] The dosage and frequency of administration may vary over a range depending on factors such as the type of condition or symptom, the severity of the disease, the patient's weight and age, metabolic rate, the appropriate pharmaceutical dosage form, and the route of administration. Doses range from 0.2 to 0.6 mg / kg, with preferred doses of 0.3, 0.35, 0.4, 0.45, 0.5, and 0.55 mg / kg of trazodone being useful for once-daily use in children, preferably administered before bedtime. Higher doses of 0.4 to 0.6 mg / kg are particularly preferred.

[0059] A physician skilled in the art can determine how best to adapt the present invention to the particular condition of a pediatric patient with a neurodevelopmental disorder. [Example]

[0060] Experimental part Example 1 Preparation of Trazodone Composition (Drops) Two formulations were developed as oral drop solutions containing two different concentrations of trazodone hydrochloride as the active ingredient: Trazodone HCl 15mg / ml (1.5% w / V) Trazodone HCl 30mg / ml (3% w / V)

[0061] It is useful for treating pediatric populations aged 2-6 years and 6-17 years, respectively.

[0062] The formulation has been developed in accordance with the requirements of the EMA guidelines on the development of medicines for paediatric use.

[0063] Drops are particularly suitable for dosing flexibility and can be mixed with juice or sugar water to improve patient compliance.

[0064] Table 4 below reports two drop formulations [Table 4]

[0065] According to this embodiment, preferred drop compositions having a trazodone concentration of 1-3% w / V further comprise the following excipients: propylene glycol 20-40% w / V, preferably 25-35% w / V, PEG, preferably PEG400 20-30% w / V, propyl gallate as an antioxidant, and citric acid as a buffer. Notably, these compositions do not contain any preservatives.

[0066] Toxicological evaluation A toxicological risk assessment of the formulations was performed to evaluate the safety of excipients used in two oral drops for children. The assessment was performed in accordance with the EMA guideline for the development of medicinal products for children (EMA / CHMP / QWP / 805880 / 2012 Rev.2).

[0067] The evaluation was carried out considering two target populations: Trazodone HCl 1.5% oral solution for children 2 years of age Trazodone HCl 3.0% Oral Solution for Children 6 Years and Older and consider chronic use of this product once daily before sleep as a function of the proposed maximum daily therapeutic dose of up to 0.5 mg / kg / day.

[0068] The results of the evaluation were that all selected excipients were considered safe and without potential toxicological risks under the intended conditions of use in the pediatric population. Indeed, the selected excipients are safe to use in pharmaceutical formulations and foods and in accordance with the relevant Ph. Eur. Monograph.

[0069] Finally, no specific warnings for the pediatric population were identified for the selected excipients. Indeed, for each excipient, the MDI (Maximum Daily Intake) is below the recommended ADI (Acceptable Daily Intake) or regulatory limit, where available, as reported in Table 5 below.

[0070] [Table 5]

[0071] Table 6 below shows the specifications for two trazodone drop formulations. [Table 6]

[0072] Notably, both solutions are preservative-free formulations and are considered toxicologically safe for children in the target age ranges of interest (2 to 5 years, up to their 6th birthday, and 5 to 17 years, up to their 18th birthday).

[0073] The drop delivery device chosen is the same for both, but due to the high dose flexibility, it can be considered the better system for its range. All doses are covered by administering 5 to 30 drops. Also, accuracy and precision have been studied and demonstrated.

[0074] Both developed products are stable when stored for two years under ICH stability conditions. In-use stability studies were performed with good results. To further improve the product's taste and, consequently, patient acceptance, the stability of the drops diluted in a number of beverages and liquids, such as sugar water or orange juice, prior to administration was also demonstrated.

[0075] Example 2. Preparation of Trazodone Composition (Syrup) A number of syrup formulations were developed using the same concentration of trazodone hydrochloride (0.26% w / V) and are reported in Table 7 below, numbered 4, 5 and 6.

[0076] [Table 7]

[0077] Other syrup formulations were developed and tested as described in the table below:

[0078] [Table 8]

[0079] Notably, the pH of all formulations was approximately 4.5.

[0080] Formulations F and G were evaluated as being palatable without the addition of flavorings. However, as a test, berry flavor was also added to Formulations F and G up to 0.15% w / V to improve palatability. The stability of these flavored formulations under the same test conditions was confirmed.

[0081] As reported in the table above, two different formulations ("F" and "G"), both containing 0.2% active pharmaceutical ingredient (API), were considered the best products meeting all the initial requirements of the product in terms of solubility and stability.

[0082] The solubility issue of the API was overcome by selecting appropriate co-solvents and their final concentrations, also considering the ADI (acceptable daily dose) of each excipient for the target population.

[0083] The amount of sucrose was reduced in order to overcome instability issues accentuated by the browning effect of the final formulation when stored at elevated temperatures.

[0084] The sweetness of the product was improved by using a very low concentration of sucralose, a safer excipient and no interactions with the active ingredient.

[0085] Two different preservative systems were also selected: the first by using only sodium benzoate and the second by using a combination between methylparaben and potassium sorbate, the latter being more suitable for the pediatric population.

[0086] Example 3. Pediatric Dose Design The approach used to estimate an appropriate starting dose of trazodone to support the conduct of clinical trials in children was physiologically based pharmacokinetic (PBPK) modeling.

[0087] The Simcyp Population-Based Simulator (Version 14 release 1) was used for all simulations (Simcyp Ltd, Sheffield, UK). The Simcyp Caucasian Healthy Volunteer population model was used for adult simulations, and the Simcyp Pediatric Population Model was used for simulations of children aged 2-6 years, >6-12 years, and >12-17 years. A PBPK model for trazodone was developed based on available physicochemical parameters, data from in vitro experiments, clinical PK parameters, and prediction parameters. The derivation of key parameters is described below. The final parameters used in the model are shown in Table 9.

[0088] [Table 9]

[0089] Trazodone is extensively metabolized by hepatic cytochromes, and available evidence suggests that CYP3A4 is primarily involved in its metabolic pathway. Consequently, estimates of CYP3A4-mediated metabolism are based on (fm CYP3A4 = 70%) and was included in the model to account for trazodone elimination.

[0090] Similarly, trazodone absorption parameters were estimated, and based on the observed bioequivalence between the oral solution and immediate-release (IR) tablet formulations, a first-order absorption model for the IR tablet was used to describe the absorption kinetics of the trazodone oral solution model.

[0091] The model developed for adults was then validated by comparing simulated plasma concentrations with observed clinical data for: A single oral dose of 50 mg IR tablets or 30 mg, 60 mg, or 90 mg oral solution IR tablets 100 mg orally, 3 times daily for 7 days.

[0092] Notably, all of the aforementioned simulations were consistent with the corresponding clinical studies.

[0093] The trazodone model demonstrated comparable steady-state exposure (peak plasma concentration, C) in adults following daily administration of 30, 75, and 150 mg IR (immediate-release) trazodone. (max) The dose estimates for pediatric patients were refined by adapting the dose estimates for each age group (i.e., 2 to 6 years, >6 to 12 years, and >12 to 17 years). These doses were selected as the lowest and middle doses of the 30 to 90 mg / day range tested for the treatment of sleep disorders in adults, with 30 mg and 75 mg, respectively, representing the lowest and middle doses, whereas 150 mg represents the starting dose in the approved dose range for the treatment of major depressive disorder in adults.

[0094] Furthermore, predictions considered gastrointestinal physiological changes in the pediatric population (ADAM module) and were comparable to simulations with a first-order absorption model.

[0095] DDIs with medications frequently used in children with neurodevelopmental disorders (i.e., atomoxetine) were also evaluated and found to be negligible.

[0096] In summary, the PBPK model provides the area under the plasma concentration-time curve (AUC) and C max PK parameters such as were found to be reliable and predictive when compared with available data in healthy adults for both IR formulations at all doses tested (i.e., 50 mg tablet and 30, 60, or 90 mg oral solution). This was particularly demonstrated by the calculated ratios of predicted:observed PK parameters, which were always within 1.5-fold, indicating acceptable recovery of clinical data by the trazodone PBPK model.

[0097] Furthermore, the predicted concentration-time profiles were compared with those observed in clinical trials (visual inspection), which showed an acceptable correspondence.Final predictions for the pediatric population were then obtained corresponding to adult exposures after relevant doses of 30, 75, and 150 mg (mg / kg qd), as disclosed in Table 10 (Oggianu).

[0098] Pediatric dose prediction should be based on the equivalent steady-state C values ​​in adults to minimize the potential risk of QT / QTc alterations. max However, the corresponding AUCs were also assessed and shown to be within the corresponding adult range.

[0099] Table 4 shows that for exposures equivalent to adult doses of 30, 75, and 150 mg once daily, the doses for the following age groups were predicted as follows: · 2-6 age group, doses 0.35, 0.8 and 1.6 mg / kg QD, respectively; ·>6-12 age group, doses 0.4, 1.0 and 1.9 mg / kg QD, respectively; In the >12-17 age group, the doses were 0.4, 1.1, and 2.1 mg / kg QD, respectively. QD: Once a day

[0100] [Table 10]

[0101] In the absence of clinical data on the PK and efficacy of trazodone in children, the PBPK model was useful for initial dose prediction to enable ethical and regulatory approval for clinical trials.

[0102] In fact, traditional allometric methods of dose prediction in children are often inaccurate because they are based on body weight (BW) changes without considering the effects of early childhood maturation on the ontogeny of body composition, organ maturation, and elimination enzymes, which are generally nonlinear with age.

[0103] Example 4. Clinical evaluation of treatment with low-dose trazodone in a pediatric population Three doses, 0.25, 0.4, and 0.5 mg / kg / day, were administered in fruit juice (volume approximately 200 mL) at bedtime in a pediatric population aged 2 to 17 years.

[0104] A multicenter, randomized, parallel-group, single-blind, Phase II study was designed based on the predictions described in Example 3 above to evaluate the pharmacokinetics and PKPD relationships of trazodone after single and multiple oral doses in children aged 2 to 17 years who suffer from insomnia affected by neurodevelopmental disorders (NDD: autism spectrum disorder, intellectual disability, or attention deficit hyperactivity disorder). The single-blind Phase II study is still ongoing.

[0105] The primary objective of this study was to evaluate the pharmacokinetics (PK) of trazodone after single and multiple doses in patients aged 2 to 17 years.

[0106] Secondary objectives of the study include establishing the pharmacokinetic-pharmacodynamic (PKPD) relationship of trazodone as assessed by actigraphy and defining the dosing basis in children and adolescents aged 2 to 17 years, taking into account the therapeutic exposure range in adults.

[0107] Parent diaries will also be used to assess outcomes.

[0108] This Phase II clinical trial is designed to evaluate the PK and PD of three dose levels of trazodone in children with insomnia and NDD. At least 36 patients will be randomized (at least 30 evaluable patients, 10 in each treatment group; at least 10 evaluable patients aged 2 to 5 years, 10 evaluable patients aged 6 to 11 years, and 10 evaluable patients aged 12 to 17 years; at least 3 in each age group and treatment group).

[0109] Patients will be initially assigned to one of three treatment arms. Patients in arms 2 and 3 will receive 0.25 mg / kg / day for 3 days, followed by a higher maintenance dose for 7 days: Treatment group 1: 0.25 mg / kg / day (days 1 to 10) Treatment group 2: 0.4 mg / kg / day (0.25 mg / kg / day on days 1-3, 0.4 mg / kg / day on days 4-10) Treatment group 3: 0.5 mg / kg / day (0.25 mg / kg / day on days 1-3 and 0.5 mg / kg / day on days 4-10). Patients who were eligible for study participation at Visit 1 (Day 1, randomization - first dose) were admitted for two of the three visits according to a patient-specific PK sampling scheme. Due to the need for sporadic sampling, each patient will provide a total of five PK samples.

[0110] Sleep latency and total sleep time were recorded by actigraphy for 3 consecutive days before the first visit until the end of treatment.

[0111] An interim analysis was performed after completion of 18 patients to assess whether the collected data allowed the relevant PK parameters to be measured with adequate precision. The 18 patients were distributed according to treatment group: 3 in arm 1, 5 in arm 2, and 10 in arm 3.

[0112] Preliminary Pharmacokinetic Conclusions: The pharmacokinetics of trazodone could be described using a population pharmacokinetic model based on adult data. Interindividual variability in clearance estimates was found to be significantly higher than that previously observed in adult patients. Overall, the pharmacokinetics of trazodone was dose-proportional, and no deviations were observed that suggested additional sources of variability in drug distribution in the pediatric population.

[0113] Preliminary conclusions: PKPD correlation Actigraphy data showed that sleep latency was zero in many patients at baseline, despite a diagnosis of insomnia. Exploratory analysis of the data indicated that a significant proportion of patients enrolled in the trial had high total sleep time at baseline (≥7 hours). It is possible that treatment effects may be more difficult to detect in this subgroup of patients.

[0114] Despite all these considerations, correlations were observed between secondary PK parameters and the relative change from baseline in total sleep time. Primary PK parameters of trazodone after single and repeated oral administration include the apparent oral clearance (CL / F), apparent volume of distribution (Vd / F), and absorption rate constant (Ka). Secondary parameters are derived from the model-predicted profile: area under the plasma concentration curve (AUC) extrapolated to infinity, maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), maximum plasma concentration at steady state (Css), trough plasma concentration (Ctrough), and time to reach Cmax (Tmax).

[0115] Assessment of cumulative total sleep time suggests slightly longer sleep times in patients with higher exposure to trazodone. The increase in total sleep time was evident by a shift in the total sleep time distribution at visit 3, during which a small proportion of patients assigned to the 0.4 and 0.5 mg / kg doses achieved a total sleep time of more than 9 hours.

[0116] Example 5. Treatment Scheme (Prophetic Example) For the treatment of acute and chronic insomnia, different treatment schemes and doses are defined depending on the target NDD population, as follows:

[0117] For the treatment of acute and chronic insomnia, various treatment schemes and doses are defined depending on the target NDD population: 0.2-0.6 mg / kg / day, preferably 0.4-0.6 mg / kg / day for patients aged 2-17 years (up to their 18th birthday).

[0118] However, given the chronic nature of insomnia in NDD, and because trazodone has proven effective already on the first day of use (Jaffer KY, Chang T, Vanle B, et al. Trazodone for Insomnia: A Systematic Review. Innov Clin Neurosci. 2017; 14(7-8):24-34), trazodone may be used with greater success in chronic treatment regimens and may be periodically reassessed based on patient needs.

Claims

1. A pharmaceutical composition comprising trazodone or a salt thereof for treating insomnia in a pediatric population suffering from intellectual disability or neurodevelopmental disorder (NDD), wherein trazodone or a salt thereof is administered at a dose of 0.2-0.6 mg / kg of patient.

2. 2. The pharmaceutical composition of claim 1, wherein the NDD is selected from the group comprising autism spectrum disorder (ASD), intellectual disability and attention deficit hyperactivity disorder (ADHD).

3. 3. The pharmaceutical composition according to claim 1, wherein trazodone or a salt thereof is administered once a day.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein trazodone or a salt thereof is administered before going to bed.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein trazodone or a salt thereof is used for co-administration with at least one drug selected from the group consisting of first generation antipsychotics, second generation antipsychotics, antidepressants, benzodiazepines, antiepileptics, mood stabilizers, psychostimulants, and anticonvulsants.

6. The pharmaceutical composition described in claim 5, wherein the first generation antipsychotic is haloperidol, the second generation antipsychotic is olanzapine, the antidepressant is amitriptyline, the benzodiazepine is lorazepam, the antiepileptic is gabapentin, the mood stabilizer is lithium, the psychostimulant is methylphenidate, and the anticonvulsant is biperiden or atomoxetine.

7. The pharmaceutical composition of claim 1, which is used for chronic administration.

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