A physiologically-based pharmacokinetic model for prediction of cannabidiol pediatric dose
Nattapon Jaisupa, Sofia Birgersson, Michael Ashton
Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Sweden
Objectives: To develop a PBPK model for CBD to predict age-dependent pediatric dosage regimens by modifying a previously PBPK model validated for adults.
Methods: CBD body disposition was modelled by a formulated set of differential equations under the assumption of perfusion-limited tissue flux (Berkeley Madonna simulator). Tissue-to-plasma partition coefficients (Kt,p) were estimated using the models of Poulin and Theil [1,2]. The physiological parameters of body weight, height, body surface area (BSA), organ volume (V) and organ blood flow (Q) were estimated by age-dependent formulae [3-5]. Hepatic clearance was scaled from in vitro intrinsic clearance (CLint) value from the literature [6]. The hepatic clearance model allowed CBD to inhibit its own metabolism in a time- and concentration-dependent manner by incorporating the inhibitory constant (Ki), half-maximal inactivation concentration (KI) and maximal inactivation rate constant (Kinact) [7]. A first-order absorption rate constant (Ka) of 0.005 min-1 [8], lag time (Tlag) of 30- or 60-minutes dependent on doses and gastric transit time of 60 minutes were used for simulations. Oral bioavailability (F) was allowed to vary between 0.14 to 0.25 dependent on dose. PBPK model output was compared with data in two pediatric PK publications [9, 10], and F and Ka adjusted to fit the observations. CBD concentration-time profiles were then simulated for children of varying age (1 to 15 years) beginning with the recommended dose of 5 mg/kg/day followed by weekly titration to a maintenance dose of 20 mg/kg/day. The resulting average concentrations of unbound CBD at steady state in the brain (Cbrain,ss,u) as well as average concentrations of total CBD at steady state in plasma (Cplasma,ss) from all simulations were calculated and compared to that simulated for adults.
Results: For children aged three years or older, Ka was adjusted to 0.009 min-1 for all doses, whereas bioavailability remained the same as follows: 0.25, 0.18 and 0.14 for the doses 2.5, 5 and 10 mg/kg/dose, respectively. Regarding children between one to two years of age, Ka and bioavailability values were fixed at 0.005 min-1 and 0.05, respectively. Tlag was adjusted to 10 minutes for all ages. Simulation revealed comparable Cbrain,ss,u values in both children (except those younger than three years old) and adults, whereas those belonged to younger children were considerably lower. However, calculated Cbrain,ss,u/Cplasma,ss and AUCbrain,ss,u/AUCplasma,ss were similar in all age groups and comparable to adults (1.3 vs 1.1). Lower fluctuation between Cmax and Ctrough (determined by Cmax/Ctrough) in both brain and plasma was observed in children compared to adults (3.2 to 5.5 vs 10.1 to 11.2). Simulated exposures in children over 12 years old exceeded the values of adults. Maintenance dose of 20 mg/kg/day resulted in very similar Cbrain,ss,u value between children over two years old and adults.
Conclusions: A PBPK model for oral CBD has been developed for pediatric population for the first time. The model was able to predict the average concentrations at steady state both in plasma and brain in pediatrics from neonatal to 12 years of age appropriately. The simulation showed comparable unbound exposures of CBD in the brain between adults and children over three years old, while younger children may require an increased dose. Results also implied slower absorption and lower bioavailability in very young children. This model can potentially be applied for predicting optimal dose regimens resulting in effective brain concentrations.
References:
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