Optimal Dosing Recommendations of Clonidine in Pediatrics Using Physiologically Based Pharmacokinetic Modeling

Clonidine is a centrally acting α-2 adrenergic receptor agonist used to treat hypertension¹  and substance withdrawal from alcohol, opioids, and smoking in adults.²  It is also prescribed “off-label” to treat anxiety and insomnia.³  In pediatrics, it is widely used to treat attention deficit hyperactivity disorder (ADHD), Tourette’s syndrome, sedation, neonatal abstinence syndrome (NAS), and neonatal opioid withdrawal syndrome (NOWS).^4–8  Clonidine causes a noticeable improvement in ADHD symptoms but is used less frequently due to adverse effects such as sedation, hypotension, rebound hypertension, and cardiac conduction abnormalities.⁹  While not as effective as methylphenidate in treating ADHD, conjunctive use of clonidine is beneficial.¹⁰  The mechanism of action of clonidine in ADHD involves the inhibition of norepinephrine secretion in the brain’s prefrontal cortex.¹¹  This is thought to prevent attention to irrelevant stimuli and improve focused attention. In Tourette’s syndrome, extended-release clonidine helps with behavioral and tic symptoms.¹²  Though less effective than aripiprazole in clinical trials, it has fewer adverse effects and demonstrates better performance when compared with placebo.¹³ 

In NAS, clonidine reduces duration of hospital admission with a lower risk of oversedation than ­phenobarbital.¹⁴  Since clonidine works at the sympathetic nervous system (SNS) relay point, it can be effective for both NAS and NOWS. However, dosing in these vulnerable patients can be challenging. The required dose relates to the stimulus and the central α-2 adrenergic receptor activation. In NOWS, the SNS traffic may be quite high at the locus coeruleus and require an extremely high α-2 input from clonidine to control it. Using the broader term of NAS, this now includes non-narcotics such as selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs). In addition, NAS may respond differently based on pharmacologic agents.

Clonidine is rapidly absorbed in the blood following oral administration with a bioavailability of ∼75.2%. Two hours after oral administration, clonidine reaches its highest concentration in the plasma (C_max).¹⁵  It is reasonably soluble in lipids, with a lipophilicity (as represented by log P) of 1.59.¹³  The liver metabolizes less than fifty percent of clonidine via CYP2D6, CYP1A2, and CYP3A4 into inactive metabolites. The other 50% of clonidine is excreted in the urine as the unchanged drug and 20% is excreted in the feces.¹⁶  Clonidine’s half-life greatly depends on renal function, ranging from between 6 and 23 hours.¹⁶ 

Despite wide use of clonidine in pediatrics, its PK across the pediatric age continuum is not well characterized and there is no standardized optimal dosing regimen recommended for clonidine use in pediatrics. This lack of information on optimal clonidine in dosing in pediatrics may be attributed to challenges in conduction traditional PK studies in children.¹⁷  Physiologically based pharmacokinetic (PBPK) modeling is a mathematic modeling technique that integrates drug properties (log P, solubility, protein binding, etc.) and population information (organ size, CYP ontogeny, etc.) to predict the body’s response to drugs at various concentrations.^18,19  The ontogeny of CYP enzyme maturation involved in clonidine’s metabolism can be incorporated into the PBPK model. When the PBPK model's ability to predict is verified using clinical PK data, several dosing recommendations can be evaluated to elucidate the optimal dosing.

In this study, we initially developed a PBPK model of clonidine in adults and extrapolated it to pediatrics by incorporating CYP enzyme ontogeny equations. The pediatric model was evaluated with clinical data from published clinical studies. The verified pediatric clonidine PBPK model was used to predict the optimal dosing of children across the pediatric age spectrum.

Software. The PBPK models were developed with the PK-Sim modeling software (version 9.1), Open Systems Pharmacology Suite (https://www.open-systems-pharmacology.org/). Model input parameter optimization was accomplished using the algorithm implemented into PK-Sim. Clinical data in the scientific literature were digitized using Plot Digitizer (version 2.6.9, https://plotdigitizer.sourceforge.net/).

Development of an Adult PBPK Model. The adult PBPK model was developed and evaluated with observed plasma profiles to assure the reliability of the PBPK model before the model was extrapolated to pediatric populations. A whole-body 15-organ PBPK model implemented in PK-Sim was used for the adult PBPK model.²⁰  The physicochemical parameters and absorption, distribution, metabolism, and elimination (ADME) data for clonidine were collected from the literature and the DrugBank database.^21,22  The physicochemical and ADME properties used for model development and optimization are provided in Table 1. The physicochemical properties of the drug in the adult PBPK model were optimized using the observed data from clinical studies reporting PK of clonidine after intravenous administration.^23,24  Although clonidine is not usually administered by intravenous route to treat ADHD, Tourette’s, NAS, and NOWS, we utilized the intravenous data for initial model verification as it is a standard practice in pediatric PBPK modeling workflow.²⁵  The model predictions after the optimization of parameters were verified using observed data from clinical studies reporting clonidine PK after oral administration.^26–28  The clinical studies were selected based on the study population, route of administration of clonidine, and the sensitivity of the analytical method used for quantification of clonidine levels in human plasma. The details of the clinical studies from where the observed data sets for model optimization and verification are provided in Table 2. The models were considered acceptable if: 1) at least 80% of observed concentrations were captured within a 90% prediction interval of the predicted concentrations, 2) the average fold error (AFE) values of simulated concentrations were between 0.5 and 2. Clonidine is eliminated approximately 50% by the liver and 50% by the kidneys, so both clearance routes were included in the model. The total hepatic metabolism of clonidine was attributed to the enzymes CYP1A2, CYP2D6, and CYP3A4. The percentage contribution of each CYP enzyme towards the hepatic metabolism of clonidine was: CYP2D6 – 67%, CYP3A4 – 22.2%, and CYP1A2 – 10%. The individual clearances from each enzyme were added to the model to account for the total hepatic metabolism (Table 1).

Pediatric Scaling and Model Applications. The adult clonidine PBPK model, after verification with clinical data, was scaled to pediatrics. The drug-­specific parameters, such as physicochemical and ADME properties, were retained in the pediatric model. The population parameters organ size, organ volumes, blood flow, CYP enzyme activity etc., were extrapolated from adults to pediatrics using default ontogeny functions in PK-Sim.²⁰  The details of the ontogeny functions for the enzymes CYP2D6, CYP3A4, and CYP1A2 are provided in the document PK-Sim Ontogeny Database Version 7.3.²⁹  The final pediatric clonidine PBPK model was verified using the observed data from the published pediatric clinical studies.^30,31  The details of the pediatric clinical studies that were used to generate pediatric PBPK model qualification data sets are provided in Table 3.

Pediatric Dose Optimization Simulations. A virtual pediatric population (N = 1000) of age groups neonates (0 days to 27 days) and ADHD and Tourette’s population (6 years through 17 years) were created in PK-Sim. The ADHD and Tourette’s population was chosen based on the most common ages at which children are diagnosed with ADHD and Tourette’s syndrome. We did not include the population between ages 1 month to 5 years as ADHD and Tourette’s are not usually diagnosed in these age groups. The simulations were performed based on commonly reported maximum clonidine dose used to treat ADHD—0.1 to 0.4 mg orally, Tourette’s—0.1 to 0.4 mg orally, and NAS—6 µg/kg orally.^13,32–36  However, the reported maximum clonidine dose to treat NAS is based on the studies that used clonidine as an adjunct to opioids.

Assessment of Dose-Exposure Relationship. The mechanism of action of clonidine to treat ADHD, ­Tourette’s syndrome, and NAS is related to a ­reduction of norepinephrine turnover in the central nervous system.^35,37,38  This inhibition of norepinephrine turnover is mediated by clonidine’s agonist activity at the α-2A adrenergic receptor, primarily found in the brain’s prefrontal cortex. However, the optimal concentration of clonidine that would elicit maximal agonist activity at the α-2A adrenergic receptor in pediatric population is unknown. Gil et al³⁹  reported that the clonidine is a potent α-2A agonist with an EC₅₀ of 40.5 nM (9.3 ng/mL). Therefore, in this study we used 40.5 nM (9.3 ng/L) as target maximum concentration (C_max) of clonidine to ensure efficacy in ADHD and NAS in ­pediatric population.

Adult PBPK Model Prediction. The adult PBPK model of clonidine adequately predicted the PK of clonidine for all dosing regimens and routes of administration. We optimized our adult model using the adult development data sets (Table 2) by changing the parameters lipophilicity (log P) and fraction unbound. When we compared our optimized model with the development and independent evaluation data sets, the optimized model met our predetermined acceptance criteria (Figure 1; Table 4). We then compared our oral model predictions with the observed data from oral studies, and they met our predetermined acceptance criteria (Figure 2; Table 4). Our model slightly underestimated observed plasma concentrations after ­intravenous administration (Figure 1) and slightly overestimated observed plasma concentrations after oral administration (Figure 2).

Pediatric PBPK Model Prediction. The pediatric PBPK model was evaluated given data from Nielsen et al³⁰  and Larsson et al.³¹  We observed good model predictability when comparing predicted and observed concentration-time data for both data sets, and they met our predetermined criteria (Figure 3; Table 5). The predictions were better with pediatric observed data set with intravenous administration (Nielsen et al³⁰ ) compared with the data set with oral administration (Larsson et al³¹ ).

Dosing Simulations. The simulations showed that the C_max of clonidine after administration of current clinically used dosages of 6 µg/kg for NAS and NOWS, 0.1 mg/day, 0.15 mg/day, and 0.4 mg/day for Tourette’s and ADHD did not achieve the C_max to match the optimal target clonidine concentration of 40.5 nM (9.3 ng/mL). As a result, the typically given doses of 6 µg/kg and 0.1 to 0.4mg/day are not sufficient for achieving maximum α-2 adrenergic agonist activity for treating Tourette’s and ADHD. The exposure matching analysis using the simulations showed that the doses 30 µg/kg for neonates and 0.9 mg per day for ADHD and Tourette’s population are optimal to reach the target concentration of α-2 adrenergic agonist activity. Table 6 provides the average C_max values of clonidine from simulations with various doses of clonidine in different pediatric age groups.

In this study, we utilized the PBPK modeling approach to predict the PK of clonidine at various dosing regimens in the pediatric population across the age spectrum. The pediatric model was scaled from the adult model and was able to predict the pharmacokinetics of clonidine in children. The verified pediatric model was used to simulate the clonidine concentrations and identify the optimal clonidine dosing to achieve maximum central α-2 agonist activity that may result in better therapeutic efficacy to treat NAS, NOWS, ADHD, and Tourette’s syndrome.⁴⁰  Currently, there are no guidelines on clonidine dosing in the pediatric population. Inaccurate clonidine dosing can result in serious adverse events such as hypotension, bradycardia, sedation, and somnolence.⁴¹  In a recently reported incident, clonidine caused severe hypotension and sedation in a 5-year-old boy who accidentally overdosed.⁴² 

Although clonidine is widely used in pediatrics, there is limited understanding of its PK in this population. We are the first to report a pediatric PBPK model of clonidine that can provide dosing recommendations to treat NAS, ADHD, and Tourette’s syndrome. Ke et al,²²  in 2013 reported a PBPK model of clonidine to predict its disposition in pregnant women. Their model incorporated the gestational age-dependent changes in maternal physiology and hepatic CYP2D6, CYP3A5, and CYP1A2 activity. We followed a similar approach for clonidine pediatric PBPK model development, wherein we incorporated age-related physiological changes and ontogeny of CYP2D6, CYP3A5, and CYP1A2 activity in pediatric populations at various age groups.²⁰  Similar to the Ke et al²²  model, our model can also be used in the future to evaluate the drug-drug interactions of clonidine with other drugs used in this population that may inhibit or induce CYP2D6, CYP3A5, and CYP1A2 activity.

The recommended optimal dose of clonidine based on our pediatric PBPK model simulations for neonates was 30 µg/kg and 0.9 mg/day for children (6–17 years age, commonly reported age group diagnosed with ADHD and Tourette’s syndrome). The recommended optimal dose in neonates is 5.1 times higher than the currently used dose, whereas in children, the recommended dose is only 2.25 times higher than the currently used dose. This is expected as the ontogeny of CYP2D6 enzyme, which accounts for 67% of clonidine hepatic metabolism, shows a rapid increase during neonatal development, reaching adult levels within 28 days.⁴³  Furthermore, the higher magnitude of dose increase in neonates can also be explained by the excretion of clonidine by kidneys. There is a rapid increase of glomerular filtration rate in neonates, reaching about 50%–60% of the adult values and therefore resulting in a rapid elimination of clonidine in neonates.⁴⁴  Our PBPK model predictions show that in current clinical practice, clonidine may be underdosed in children to treat ADHD, Tourette’s syndrome, NAS, and NOWS. After validating our model predictions with data from prospective clinical studies in children with ADHD, Tourette’s syndrome, NAS, and NOWS, an increase in clonidine dose may be implemented in clinical practice to ensure adequate clonidine concentrations are reached for adequate α-2 agonist activity. The CYP enzymes CYP1A2, CYP3A4, and CYP2D6, responsible for the hepatic metabolism of clonidine, are undetectable during gestation, and therefore we do not expect any change in clonidine hepatic metabolism with gestational age.⁴⁵  However, it is well known that glomerular filtration rate (GFR) in neonates at birth increases with gestational age, and around 50% of clonidine is excreted by renal route, clonidine dosing must be reduced in preterm neonates to avoid any dose-related adverse events.⁴⁶  Based on the availability of clonidine PK data in preterm neonates, our pediatric clonidine PBPK model can be used to predict clonidine PK in preterm neonates and develop optimal dosing regimens in preterm neonates based on their gestational age.

Our clonidine pediatric PBPK model has some limitations. The first is that clonidine is often given in routes other than intravenous and oral, with two other common routes being nasal and transdermal administration. Our model can only accommodate intravenous and oral dosing regimens including oral suspension,. It does not currently extend to other routes of clonidine administration such as transdermal or nasal. There are limited to no clinical pharmacokinetic (PK) data available for those routes in children. However, in the future this PBPK model could easily be modified to accommodate clonidine dosing by other routes such as transdermal and nasal once the clinical PK data are available. The second limitation is that the target concentration of clonidine’s central α-2 agonist activity used to decide optimal dosing was obtained from animal studies. A target concentration of clonidine with α-2 agonist activity derived from human experiments will be more appropriate. Finally, our PBPK model predictions must be verified with data from robust, prospective PK/PD studies of clonidine in children with ADHD, Tourette’s, sedation, NAS, and NOWS before implementation in clinical practice.

In conclusion, the pediatric PBPK model of clonidine scaled from the adult PBPK model and verified using the pediatric PK data provides dosing recommendation for clonidine in different pediatric age groups. The model simulations showed that the current dosing regimen of clonidine used to treat NAS in neonates and ADHD and Tourette’s syndrome in children did not adequately reach target concentrations to achieve maximal α-2 agonist activity. Based on pediatric PBPK model simulations, the doses 30 µg/kg for neonates and 0.4 mg/day for children are recommended to reach a target concentration that are predicted to result in maximal α-2 agonist activity. The pediatric PBPK model described in this study can be extended to other pediatric age groups and route of administration as needed and can also be used to evaluate the drug-drug interactions of clonidine with other medications used in these pediatric populations. However, the model predictions must be tested and confirmed with real-world clinical data to ensure they translate effectively to clinical practice.

ADHD

attention deficit hyperactivity disorder;

ADME

absorption, distribution, metabolism, and elimination;

AFE

absolute fold error;

C_max

maximum plasma concentration;

CYP

cytochrome p450;

EC₅₀

half maximal effective concentration;

NAS

neonatal abstinence syndrome;

NOWS

neonatal opioid withdrawal syndrome;

PBPK

physiologically based pharmacokinetic;

SNS

sympathetic nervous system;

SNRIs

selective norepinephrine reuptake inhibitors;

SSRIs

selective serotonin reuptake inhibitors