For patients who fail conventional therapies, ability to access medical Cannabis may offer a therapeutic alternative that addresses their unmet clinical need. However, a paucity of clinical trial evidence has led to ambiguous pediatric dosing guidelines for medical Cannabis, a situation further complicated by the impact of developmental maturation of the pharmacokinetic (PK) and pharmacodynamic (PD) processes governing drug effect and dosing requirements. The pediatric population is very heterogeneous, and dissimilar developmental trajectories result in important differences in the rate and extent of cannabinoid absorption, distribution, elimination, and response both between and within pediatric age group classifications. These developmental changes will require the prescribing caregiver to consider age-specific dosage regimens that may demand continual modification as the child ages. The chapter that follows emphasizes the impact of age-related changes in PK and PD processes as important considerations in pediatric dosing recommendations for medical Cannabis.
- medical Cannabis
Optimal dose selection is fundamental to appropriate clinical care. A comprehensive understanding of drug pharmacokinetics (PK) and pharmacodynamics (PD) and the factors that can influence the drug exposure-response (PK-PD) relationship is important to facilitate the optimization of dosage regimens. In the pediatric patient, though, normal growth and maturation complicates dose selection and optimization. Experience has demonstrated that the usual practice of adjusting dose size according to body weight often results in inappropriate pediatric doses as this practice ignores the impact of developmental changes on drug PK and PD 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.
This chapter will mainly address issues of developmental maturation of PK and PD processes as key determinants of medical
2. Therapeutic applications
Many studies report the use of
Limited information is available on the therapeutic use of
3. Pediatric dosing considerations
3.1. Medical cannabis dosage forms
Commercially available medical
At present, age-appropriate formulations of
3.2. Current dosing guidelines
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 . 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, 17, 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, 17, 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 . 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 . 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 . 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 . 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.
4. Ontogeny of pharmacokinetic processes
4.1. Exposure and exposure route
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 . Understanding the therapeutic range of the cannabinoids for the different pediatric age-strata will be necessary to optimize dosing guidelines for
The attainment of plasma concentrations within the therapeutic window depends on route of administration, dosing frequency, size of dose, and the PK acting on the administered dose. Knowledge of the volume of distribution (Vd) is necessary in the design of a loading dose (the dose needed to quickly produce therapeutic concentrations, CTher), where Vd and the bioavailable dose (F × Dose) determine the plasma concentration (Eq. (1)). Following a chronic dosing regimen, the mean steady state therapeutic concentration (CSS,Ther) is the result of the bioavailable dose, dosing interval (τ), and systemic clearance (ClS) (Eq. (2)).
With extravascular dosing (e.g., oral dosing), compounds must undergo absorption into the systemic circulation. Typically, less than 100% of the administered dose becomes available to the systemic circulation as presystemic mechanisms can limit the fraction of the oral dose that enters the systemic circulation as an unmodified compound (i.e., bioavailability (F)). Once absorbed into the blood supply, compounds distribute to the tissues of the body while systemic clearance mechanisms function to eliminate the compound. Hence, systemic exposure is determined by the extent of absorption (bioavailability) and by the efficiency of the systemic clearance mechanisms, while organ specific exposure additionally depends upon tissue distribution properties of the compound. Age-related changes occur with all these PK processes such that a standard dosage regimen will produce different systemic and tissue-specific exposure levels during pediatric development.
4.2. Oral absorption
The most common route of administration for pediatric patients is the oral route. The rate and extent of oral absorption is determined by the interaction of the physicochemical properties of the cannabinoid and its formulation with the physiological processes governing absorption. With oral ingestion of cannabinoids, time (Tmax) to maximum concentrations (Cmax) varies on average from 1 to 6 h, and bioavailability is low and quite variable (4–12%) in adults due to extensive first pass effects [27, 28]. As well, first-pass metabolism following an oral administration results in production of active metabolites (e.g., 11-hydroxy-THC, 7-hydroxy-CBD) with potent psychoactive effects that contribute to the pharmacology of the cannabinoids . Age-related differences in Tmax, Cmax, and F may cause important differences in the onset and intensity of effect of an oral cannabinoid dose.
Growth and maturation of gastrointestinal absorption processes variably influence both absorption rate and extent (i.e., bioavailability), a key determinant of the effective dose. pH dependent passive diffusion, biliary excretion, and gastrointestinal (GIT) transit times undergo considerable change with maturation . Gastric pH is high at birth, becomes acidic in the first 24 h, returns to neutral pH values within the first 10 days of life, and subsequently decreases to adult pH levels within the first year or two of life . Intestinal tract pH tends to be similar with the adult at all pediatric age groups . Although impact of pH is likely limited on cannabinoid bioavailability (as these are neutral compounds), the higher gastric pH might reduce the extent of THC degradation . Biliary excretion, though, is lower in the neonate (2–4 mM) than the adult (5–6 mM) in the first weeks of life, which is due to immaturity of the hepatic transporters responsible for their biliary excretion rather than ability to synthesize bile salts [32, 33]. As hydrophobic molecules, this may reduce cannabinoid bioavailability due to lower GIT solubilization in the first months of life. Gastrointestinal motility is also reduced at birth and gastric emptying and intestinal peristaltic function likely become similar to adults in the first weeks of life [34, 35]. This suggests Tmax is likely to be similar with adults within a month of birth, although differences in motility may not influence Cmax.
Other gastrointestinal physiological factors that have importance on the extent of absorption (i.e., bioavailability) include gastrointestinal permeability and first pass effects. All cannabinoids undergo passive permeation across the gastrointestinal epithelium. Intestinal permeability is initially high at birth given the leakiness of the epithelial tight junctions, but with junction closure within the first week of birth overall permeability becomes lower than adult due to a smaller intestinal absorptive surface area . Passive transport mechanisms likely reach adult values within 4 months of birth. First-pass effects have a longer maturational trajectory. First pass effects include the activity of microbiota and gut luminal enzymes, enzymes and transporters of the gastrointestinal epithelia and liver. In adults, the low and variable bioavailability of CBD and THC is due to pre-systemic elimination by cytochrome P450 enzymes, principally CYP3A4 and CYP2C’s, expressed in the intestinal and hepatic epithelium . Intestinal and hepatic CYP3A4 expression and hepatic CYP2C expression principally contribute to considerable first-pass metabolism and the low oral bioavailability of cannabinoids . With development, hepatic CYP2C expression reaches adult levels by 6 months, exceeds adult levels in childhood, and returns to adult levels after puberty . CYP3A4 undergoes a slower maturation with considerable increases in the first 6 months but does not reach adult levels until after 2 years of age [40, 41]. CYP3A4 activity also exceeds the adult in early childhood and returns to adult levels after puberty. Their developmental maturation suggests bioavailability is likely to be higher in neonates and infants until these enzymes reach adult expression levels. The xenobiotic transporters also contribute to first-pass effects. THC is a substrate of efflux transporters including p-glycoprotein (MDR1) and BCRP, while CBD only inhibits these efflux transporters. These transporters undergo rapid ontogeny in the first 6 months of life to reach adult values by 2 years of age, but may not contribute to age-related differences in bioavailability beyond 6 months of age . The immaturity of these transporters can further enhance THC bioavailability relative to the adult.
Bacterial activity within the gastrointestinal tract lumen may influence first pass metabolism. Whether cannabinoids undergo bacterial metabolism is unknown, but glucuronide metabolites may undergo deconjugation in the gut lumen. Children from 3 to 15 years of age showed no differences in activity of bacterial enzymes such as beta-glucuronidase, beta-glucosidase, and other enzymes and intestinal bacterial colonies approach adult characteristics by 1–4 years of age . The gastrointestinal microbiome also influences the regulation of drug metabolizing enzymes and transporters, but information in the pediatric patient is lacking. A multitude of factors can influence the microbiome including age, disease, diet, and drug exposure, and our understanding of their impact during development is limited.
Overall, postnatal development of pH, gastrointestinal motility, and first-pass mechanisms should reach maturity by 5 years of age  at which time the rate and extent of oral absorption should have similarity to adult estimates. The variable rate and pattern of maturation, though, will lead to large ranges in Tmax, Cmax, and bioavailability estimates between the different pediatric age classes. Since variability in blood concentrations is principally inversely proportional to oral bioavailability, we may expect important differences in the oral dose requirements needed to attain equivalent plasma concentrations and therapeutic responses. Variable bioavailability will challenge treating caregivers on advising doses indicated by age, and individualization of dosage regimens will remain necessary. This expectation, though, creates opportunity for development of pediatric dosage formulations that considers both the potential age influences on cannabinoid liberation from the dosage formulation and the need to provide higher and more consistent oral bioavailability. Effective oral formulations promise more consistent dosage recommendations and reductions in the risk of under- or overdosing.
Age-related differences in the extent of tissue distribution (i.e., volume of distribution, Vd) will impact intensity and duration of cannabinoid activity. In adults, the high plasma protein binding characteristics (>97% bound in the adult)  of the cannabinoids result in a small central Vd (2.5–3 L). The cannabinoids undergo rapid and extensive distribution into lipophilic tissues (e.g., brain and adipose) and the highly perfused tissues (e.g., heart, lung, and liver) resulting in a large steady state Vd with reports ranging from 2.5–3 to 10 L/kg [27, 45]. The slow redistribution of cannabinoids from tissues, in particular adipose, as well as enterohepatic recirculation lead to long half-lives ranging from 1.5 to 5 days or longer for THC and 1–2 days for CBD, and even longer for the metabolites [27, 45]. Since the Vd is an important determinant of half-life, which, in turn, is used to guide the dosing interval, the expected age-related differences in cannabinoid Vd are likely to lead to differences in half-lives between the pediatric age strata and a possible need to consider such differences in the dosing interval.
Body composition, plasma and tissue protein binding, and physicochemical characteristics of the cannabinoids will influence the extent of their distribution (i.e., Vd). For many compounds, Vd demonstrates a linear relationship with body size. In the pediatric population, body size can change from less than 1 kg to up to 100 kg or more with development. Consequently, Vd expressed on a per body weight basis will show tremendous variability in the pediatric population. Ratio of fat, muscle, and intracellular and extracellular water also changes with maturation. At birth, total body water is 75%, and total body water-to-fat ratio is the highest in neonates and young infants with total body water reaching adult values by 6 months . However, older infants and toddlers tend to have the highest fat-to-body water ratio only to reach adult ratios in later childhood . Although higher body fat to water ratio may suggest higher Vd for the hydrophobic cannabinoids in these age groups, studies with other highly lipophilic drugs suggest that the Vd was not different between adults and infants . Past infancy, then, the Vd might be similar between children and adults for the cannabinoids . The lipophilic nature of the cannabinoids, though, raise concerns with childhood obesity and whether obese children should be dosed based on actual or ideal body weights .
Plasma protein binding is an important physiological determinant of Vd and the unbound fraction in the blood. In adults, cannabinoids bind extensively to lipoproteins and albumin where the unbound fraction can range from 1 to 5% [44, 45]. In the pediatric population, the plasma levels of albumin and alpha1-acid glycoprotein, the two major plasma binding proteins, are lower at birth and increase gradually to reach adult values by 1–3 years of age . Lipoprotein and triglyceride levels also rise gradually during the first year of life, with further increases in childhood and adolescence . Consequently, neonates and infants might exhibit lower bound fractions of the cannabinoids due to lower lipoprotein and albumin concentrations. These age dependent increases in plasma proteins might also mean higher distribution volumes in the neonate and infant and a lower Cmax.
With high binding characteristics, seemingly small differences in binding, though, may result in large differences in the availability of cannabinoids to bind to their therapeutic targets. The unbound concentration is known to better reflect the pharmacodynamics of highly bound drugs , and a greater unbound fraction coupled with a lower elimination capacity for the cannabinoids (see section below) would enhance the availability of cannabinoids at their pharmacological sites of action. This can result in more intense pharmacological or toxicological responses and possibly a need to adjust doses to ensure equivalent PD responses. In addition to the amount of protein available for binding, binding affinity shows age-related changes. The presence of endogenous competitors for plasma protein binding sites, such as bilirubin and free fatty acids, is higher in the neonate , and along with exogenous competitors (e.g., co-administered drugs) may further increase the unbound cannabinoid concentration with subsequent enhancements in their pharmacological or adverse effects. Either way this might necessitate a dose reduction.
Relevant to the cannabinoids is the possible influence of age-related differences in the volume of the brain and the permeability of the blood-brain-barrier. Brain volume is larger in younger children and approaches adult values at 4–6 years of age . THC but not CBD is a substrate for P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) , while both cannabinoids inhibit P-gp and BCRP activity [55, 56]. These transporters function to limit permeation of THC and other drug substrates across the blood-brain-barrier and expedite their elimination from the brain, while CBD brain uptake and removal is not influenced by these transporters . This might suggest a longer residence time of CBD in brain tissue relative to THC and a potential disconnect between plasma levels and the psychoactive effects of these compounds. As an inhibitor of efflux transporters, CBD might also modulate brain disposition of THC, which could explain, in part, its known ability to modulate THC psychoactive effects . Important cannabinoid-drug interactions might ensue with co-administration of other efflux transporter substrates with a concomitant risk for brain accumulation of these drugs and potential adverse effects. Finally, known pharmacogenetic polymorphisms in these transporters result in reduced activity, which may enhance brain penetration and residence, increase the psychoactive effects, and, in turn, risk
The lipophilic cannabinoids are eliminated primarily through hepatic metabolic clearance. Hepatic clearance depends on three physiological determinants, plasma protein binding, hepatic blood flow, and intrinsic clearance (the overall ability of the liver to metabolize a compound). The cannabinoids appear to fall within the class of intermediate to high extraction ratio compounds (systemic clearance ranging from 600 to 1190 mL/min for THC and 960 to 1560 mL/min for CBD) [59, 60], suggesting that hepatic clearance is influenced variably by hepatic blood flow, intrinsic clearance, and plasma protein binding or predominantly by the hepatic blood flow at the highest hepatic clearance values. All determinants undergo developmental maturation. Hepatic metabolic clearance of the cannabinoids principally involves cytochrome P450 enzyme-mediated metabolism. The metabolites generated from P450 enzyme reactions may undergo further phase II enzyme conjugation reactions for their subsequent renal or biliary excretion. An understanding of the contribution of Phase I and II enzymes is important as the rate and pattern of their maturation tend to follow different developmental trajectories.
Cannabinoids are principally metabolized by CYP3A4, CYP2C9, and CYP2C19 [45, 61]. As a superfamily of enzymes, the developmental trajectories of P450 enzymes are grouped into three characteristic classes . CYP3A4 and CYP2C enzymes are class II enzymes, where enzymes are expressed at low levels at birth and gradually increase postnatally to achieve adult values within a year or two of age . For instance, CYP2C19 activity is less than one-third adult values at birth, surges to 50% of adult activity in the first month of postnatal life, and reaches adult values at 1 year of age . After 1 year, the hepatic clearance of CYP2C19 substrates show similarity to adult values . Although CYP3A4 is the most abundant hepatic P450 enzyme in the adult, the predominant CYP3A isoform at birth is CYP3A7, while CYP3A4 expression is only 10% of adult levels [62, 63]. A developmental switch is observed such that CYP3A4 activity increases concomitantly with reductions in CYP3A7 activity. By 1 year of age, CYP3A4 activity is 75% adult levels, while CYP3A7 activity is considerably reduced [62, 63]. Although the two isoforms share 95% identity in their nucleotide sequence, differences in substrate specificities are noted for the two isoforms as well as a lower metabolism rate by CYP3A7 . No study has evaluated the metabolic activity of CYP3A7 against CBD and THC, but CBD was identified as an inhibitor of this CYP3A isoform .
CBD, THC, and their respective metabolites also undergo phase II metabolism principally by the UDP-glucuronosyltransferase (UGT) enzymes. UGT1 and UGT2 families are involved in drug metabolism and typically more than one isoform contributes to the metabolism of a single compound . Generally, the UGT enzymes have 25% activity in young infants relative to adult levels with adult levels achieved within 6–30 months of birth . However, individual UGT enzymes undergo different maturation patterns leading to considerable variability reported in the glucuronidation capacity of newborns and infants.
The developmental pattern of the major cannabinoid metabolizing enzymes suggests that systemic clearance and oral bioavailability may change throughout the pediatric period. Neonates and infants may demonstrate lower systemic clearance and higher oral bioavailability due to reductions in hepatic metabolism, but adolescents may have similar values to the adult. Interesting children ages 2–12 may require larger weight adjusted doses. In a mechanistic-based analysis, for drugs almost solely eliminated by CYP3A4 children required higher (~2 times) doses corrected for body weight relative to the younger child and adult, although similar weight-corrected doses between children and adults were required for drugs eliminated solely by CYP2C19 or UGT isoforms to achieve equivalent plasma concentrations . Given the contribution of both P450 enzymes to the elimination of cannabinoids, higher weight adjusted doses may be required in children relative to the adult due to higher systemic clearance or first-pass metabolism.
Quantitatively and qualitatively P450 and UGT enzymes show considerable variation in their developmental maturation both within and between the age strata. A consequence of this variation may be altered cannabinoid metabolite profiles relative to the adult. After oral administration in the adult, extensive first-pass metabolism results in the production of high circulating levels of bioactive hydroxylated metabolites of CBD and THC . These active metabolites contribute to the pharmacology of
Renal and biliary excretion mediates the elimination of the cannabinoid phase I and II enzyme metabolites. Elimination by the kidney occurs by glomerular filtration and tubular secretion. Neonates are born with reduced glomerular and tubular function, which is further compromised in the preterm neonate due to incomplete nephrogenesis . Profound anatomical and functional changes in the kidney occur following birth that include enhancements in renal blood flow, redistribution of blood flow in the kidney, improvements in glomerular filtration efficiency, and the growth and maturation of renal tubules and tubular processes. These changes result in rapid attainment of renal elimination function within the first year of age . Maturation of glomerular filtration processes precedes tubular processes, such that glomerular filtration rate reaches adult levels by 6 months of age and tubular reabsorption and excretion processes mature to adult levels by 1 year of age . The excretion rate in toddlers and preschool children, though, can exceed adult levels but subsequently returns to adult levels in childhood . The anatomical and functional immaturity of the kidney and the discordance in the maturation of glomerular and tubule function can contribute to considerable interindividual variability in renal elimination in pediatric patients.
Transporters are categorized into ATP-Binding Cassette (ABC) and Solute Carrier (SLC) families. ABC proteins are efflux transporters expressed apically at tissue-blood interfaces and function to limit penetration of compounds into these tissues. Maturation of ABC transporters can result in a developmental vulnerability to THC use. ABC transporter ontogeny as well as genetic variation (polymorphisms) is known to influence treatment response to drugs and increase risk for psychiatric disorders in pediatric populations as a result of altered disposition to the brain . For example, the common P-glycoprotein (ABCB1) genetic variant C3435T, which results in altered p-glycoprotein expression, was associated with increased risk of
5. Ontogeny of pharmacodynamic processes
Dosing considerations of the pediatric patient not only need to acknowledge the impact of age-related changes in PK processes, but also the maturation of the endocannabinoid system and how this will influence PD and the relationship between exposure and response. Very little data, though, are available from human clinical studies on the developmental maturation of the endocannabinoid system and how these may influence cannabinoid pharmacology. What is known is that the endocannabinoid system is expressed early in fetal life and plays a critical role in normal neurological development. Cannabinoid receptor populations and levels of the enzyme systems and endocannabinoids are dynamic in pediatric development particularly during adolescence . Some data suggest daily high dose exposure to THC may pose a risk to normal neurological development, although the data are not available for CBD .
The lack of data on PD ontogeny and age-specific exposure-response relationships risks development of inappropriate therapeutic ranges. In the absence of any data, the treating caregiver may apply therapeutic ranges in adults or older pediatric age groups to younger pediatric age classes on the assumption of a similar exposure-response relationship to help inform dose selection . Yet drawing from examples with other drugs, changes in receptor density expression with maturation have altered the efficacy and safety of drugs in children, such as reduced PD sensitivity to propofol resulting in overdosing and subsequently myocardial failure, metabolic acidosis, multiorgan failure, and death . Given that the endocannabinoid system undergoes continued development, therapeutic windows are likely to be different among the different pediatric age strata.
6. Other factors
6.1. Safety and adverse effects
The toxicity of cannabinoids is generally considered quite low. In adults, cannabinoids have a number of central nervous system effects that include intoxication, appetite stimulation, disruption of psychomotor behavior, short-term memory impairment, antinociceptive actions, and anti-emesis. Lethal doses are unknown, but the size of a single lethal dose is likely to be very high. The apparent low toxicity in adults, though, cannot necessarily translate to a low adverse effect potential in pediatric patients. Very little information exists on the pediatric specific adverse effects of
6.2. Pharmacokinetic and pharmacodynamic interactions
In pediatric patients, medical
Other PK and PD interactions of concern include interactions at efflux transporters and impact of disease. The exposure-response relationship can be affected by clinically relevant interactions at the efflux transporters expressed at the blood brain barrier. Such interactions can alter the brain distribution of the pharmacologically active cannabinoid fraction to enhance cannabinoid response at a given
6.3. Perspectives on the use of medical cannabis in pediatric populations
We face a clinical and ethical dilemma in the use of medical