**3. Pediatric dosing considerations**

#### **3.1. Medical cannabis dosage forms**

processes. To ensure appropriate clinical care, then, dosing recommendations need to consider age-related changes in PK and PD. This becomes particularly important for new therapeutics, which have limited clinical trial data and experience of use in the pediatric population.

Medical *Cannabis* herbal extracts are being considered as new therapeutics for the management of pediatric conditions refractory to standard of care therapies. With no DIN (Drug Identification Number) designation, though, these herbal extracts have limited safety and efficacy data in the pediatric population. The small number of clinical pharmacology trials with pharmaceutical grade cannabinoid products as well as anecdotal use lends some support for medical *Cannabis* in such conditions, but no rational pediatric dosing recommendations are available for these products. The known age-related changes in drug PK and PD, differences further complicated by existing comorbidities and concurrent medications likely to influence drug PK and PD, have left treating caregivers uncertain and reluctant to recommend an appropriate medical *Cannabis* dosage regimen to their patient. A greater understanding of the developmental changes in cannabinoid PK and PD, though, may help to mitigate these

This chapter will mainly address issues of developmental maturation of PK and PD processes as key determinants of medical *Cannabis* herbal extract dosage regimens (henceforth referred to as *Cannabis* extracts). The chapter will first summarize the therapeutic applications for *Cannabis* extracts in pediatric populations. It then will highlight the key physiological determinants of PK and PD that undergo change with postnatal maturation and how such changes might lead to age-related cannabinoid PK and PD differences based on current understandings from adult populations. Superimposed with normal developmental programming, dose selection must also consider the influence of pharmacogenetics, disease, and drug-cannabinoid interactions, and these are briefly discussed. This chapter will underscore developmental maturation of PK and PD processes as paramount to considerations of medical *Cannabis* dos-

Many studies report the use of *Cannabis* to aid treatment of a diverse range of health conditions and symptoms. Although *Cannabis*' medical use dates back centuries with the first written records in China and India around 2900 BC and 900 BC, respectively, *Cannabis* was introduced to western medicine only in the nineteenth century [1, 2]. Today, potential indications for medical *Cannabis* include appetite stimulation, chronic pain, spasticity from multiple sclerosis or paraplegia, depression, anxiety, sleep problems, psychosis, glaucoma, Tourette's syndrome, epilepsy, dementia, cancer, post-traumatic stress disorder, and osteoarthritis [3].


uncertainties.

182 Recent Advances in Cannabinoid Research

ing of the pediatric patient.

Δ9

**2. Therapeutic applications**

Commercially available medical *Cannabis* includes the purified pharmaceutical preparations and the herbal extracts. The extracts contain well-defined proportions of the major psychoactive cannabinoids, THC and CBD, and poorly documented quantities of other cannabinoids and terpenoids [4, 8, 9]. Nonmedical or recreational *Cannabis* have unknown contents of THC, CBD, and other components and should be avoided when used for medical benefit. Much of the anecdotal and observational human trial data usually correlates therapeutic benefit with content of THC or CBD or some ratio of THC to CBD [10]. Given the differences in the pharmacology of THC and CBD, different THC:CBD ratios are promoted within the range of possible clinical indications for medical *Cannabis*. For the pediatric patient, the choice of THC:CBD ratio, though, must acknowledge the known dose-related intoxicating effects of THC and the potential for adverse neurodevelopmental effects with cannabinoid exposure [11]. As well, the selection of *Cannabis* product should consider the presence of the secondary components that often contribute to the more unique characteristics of *Cannabis* extracts [4]. Little is known about the pharmacology of these secondary cannabinoids and terpenes and age-related differences in their PK and PD properties [4, 9]. With the current absence of product quality control on the composition of these other active *Cannabis* components, dose optimization of *Cannabis* extracts for different pediatric indications will need to principally focus on the specific THC:CBD ratio for now.

At present, age-appropriate formulations of *Cannabis* extracts are limited to oil-based oral products. Oral dosing is a challenging route of administration in the pediatric population as issues with incomplete dose ingestion and product refusal negatively impact therapeutic outcomes [12, 13]. Often formulation development considers the adult patient and when used in the pediatric patient can be associated with reduced therapeutic efficacy and safety. For example, some excipients commonly used in adult formulations have well known safety concerns in the pediatric patient such as the common pharmaceutical formulation excipients propylene glycol, benzyl alcohol, and ethanol [14]. As well, factors such as ability to swallow, taste, texture, and smell that determine acceptability of an oral dosage formulation undergo developmental changes such that acceptable formulations in one pediatric age group may not be acceptable in another age group [12, 13]. Currently, medical *Cannabis* companies are actively pursuing product formulation development. Whether these efforts consider the unique requirements of the pediatric patient is uncertain, which will necessitate the treating caregiver to exercise caution when considering *Cannabis* product formulations for their pediatric patients.

size (and age) to predict dosages in pediatric patients is also limited by the complexity of these modeling approaches that precludes general application to many drugs [16–18]. Hence, we seem left with the current self-titration dosing model where doses, based on weight adjusted adult doses, begin low to moderate and are increased slowly, along with adjustments in dosing interval, until the desired effect is achieved [19]. This empirical "trial-and-error" approach will not likely result in optimal dosing guidelines for the different pediatric age strata due to

Pediatric Dosing Considerations for Medical *Cannabis* http://dx.doi.org/10.5772/intechopen.85399 185

Changes in body size and maturation of the physiological and biochemical processes determining PK and PD must be considered during dosage selection. Normal growth results in a decreasing ratio of body weight to body surface area with age making it difficult to recommend dosing according to patient body weight or body surface area consistent with adult guidelines [22]. For example, in an analysis of pediatric patients, dosing adjustments of hydrophobic drugs (cannabinoids are hydrophobic) based on body weight provided better clinical outcomes in patients between 1 month and 1 year of age, while dosing based on body surface area was best in older children [18]. As well, within and between the age strata maturational changes in PK and PD processes occur at considerably different rates and patterns suggesting that dosage adjustments with long-term therapy may be necessary to ensure efficacy and avoid risk of adverse events [23, 24]. Other clinical and demographic variables such as puberty, which bring hormonal changes known to influence PK in adolescents, and the patient's clinical state, are known to influence dosing requirements [25]. Only with a greater understanding of the impact of such factors can we hope to rationally identify doses for different pediatric populations, particularly in the absence of robust clinical data. The following section addresses a key determinant of dosing requirements, the age-related changes in the

For many drugs, dosage regimens are designed to attain and maintain drug concentrations within a therapeutic window, the range of concentrations that produce a desired effect. Pediatric therapeutic windows may be quite different from the adult due to PD differences, such as receptor ontogeny (maturation of receptor number and functionality), and organ specific distributional differences resulting in different tissue concentrations of drug to elicit pharmacological activity. Such differences can result in differences in efficacy and toxicity which brings into question use of pediatric therapeutic ranges based on adult clinical data. However, the absence of dose-concentration-response data in children results in a void of evidence that risks the development of arbitrary therapeutic ranges. This was evident with theophylline for neonatal apnea where the therapeutic range adopted in the early 1980s was inadequate and a considerable number of neonates were under-dosed [26]. Understanding the

diverse developmental periods within this population [20, 21].

PK processes acting upon a dose exposure.

**4.1. Exposure and exposure route**

**4. Ontogeny of pharmacokinetic processes**

**3.3. Accounting for growth and development in dosage selection**

#### **3.2. Current dosing guidelines**

Medical *Cannabis* dosing guidelines are largely unavailable for the pediatric patient. Such guidelines, though, should consider specific age strata since development and maturation result in age-dependent dosing requirements [15]. Recommended pediatric age strata are: pre-term newborn infants (born at less than 36 weeks of gestation), term newborn infants (age 0 to <28 days), infants and toddlers (age 28 days to 23 months; infants >28 days to 12 months and toddlers >12 months to 23 months), children (age 2–11 years; preschool children 2–5 years and school age children 6–11 years), and adolescents (12–18 years). As with other drugs, the safety and effectiveness of the cannabinoids likely will vary between the different age strata. Consequently, pediatric clinical trials that determine plasma cannabinoid concentrationeffect relationships, efficacy, and safety within specific age strata will be required to develop optimal age-specific dosing recommendations.

In the absence of pediatric PK and clinical trial data, adult data become a starting point for pediatric dose selection. For simplicity, doses may be normalized to body weight and, in some cases, to body surface area. Dose scaling by body weight (or body surface area) requires dose adjustment according to the patient's clinical state and clinical response until a dose is titrated to appropriate effect. This process could take some time to identify an appropriate dosage regimen for the pediatric patient, if at all. Furthermore, given possible ceiling effects of the cannabinoids, where dosing beyond a certain amount per body weight may not yield further pharmacological benefit, this approach has risk of adverse therapeutic outcomes.

Other approaches exist to improve upon the simple extrapolation of body weight-adjusted adult doses. Allometric scaling approaches use body surface or body weight ratios and allometric models to extrapolate adult doses to the pediatric patient [16]. An important limitation of this approach is an assumption of a linear correlation between demographic covariates and the dose, which is not the case for the pediatric patient due to developmental maturation of PK and PD processes [16–18]. Children differ not only in body weight but also show changes in body composition, organ size, and maturation, which influence PK as well as result in differences in the therapeutic window (range of exposure concentrations that result in drug efficacy) due to PD changes with age. The use of exponential scaling factors adjusted by body size (and age) to predict dosages in pediatric patients is also limited by the complexity of these modeling approaches that precludes general application to many drugs [16–18]. Hence, we seem left with the current self-titration dosing model where doses, based on weight adjusted adult doses, begin low to moderate and are increased slowly, along with adjustments in dosing interval, until the desired effect is achieved [19]. This empirical "trial-and-error" approach will not likely result in optimal dosing guidelines for the different pediatric age strata due to diverse developmental periods within this population [20, 21].

#### **3.3. Accounting for growth and development in dosage selection**

Changes in body size and maturation of the physiological and biochemical processes determining PK and PD must be considered during dosage selection. Normal growth results in a decreasing ratio of body weight to body surface area with age making it difficult to recommend dosing according to patient body weight or body surface area consistent with adult guidelines [22]. For example, in an analysis of pediatric patients, dosing adjustments of hydrophobic drugs (cannabinoids are hydrophobic) based on body weight provided better clinical outcomes in patients between 1 month and 1 year of age, while dosing based on body surface area was best in older children [18]. As well, within and between the age strata maturational changes in PK and PD processes occur at considerably different rates and patterns suggesting that dosage adjustments with long-term therapy may be necessary to ensure efficacy and avoid risk of adverse events [23, 24]. Other clinical and demographic variables such as puberty, which bring hormonal changes known to influence PK in adolescents, and the patient's clinical state, are known to influence dosing requirements [25]. Only with a greater understanding of the impact of such factors can we hope to rationally identify doses for different pediatric populations, particularly in the absence of robust clinical data. The following section addresses a key determinant of dosing requirements, the age-related changes in the PK processes acting upon a dose exposure.
