Development of a Physiologically Based Model to Describe the Pharmacokinetics of Methylphenidate in Juvenile and Adult Humans and Nonhuman Primates

Abstract

The widespread usage of methylphenidate (MPH) in the pediatric population has received considerable attention due to its potential effect on child development. For the first time a physiologically based pharmacokinetic (PBPK) model has been developed in juvenile and adult humans and nonhuman primates to quantitatively evaluate species- and age-dependent enantiomer specific pharmacokinetics of MPH and its primary metabolite ritalinic acid. The PBPK model was first calibrated in adult humans using in vitro enzyme kinetic data of MPH enantiomers, together with plasma and urine pharmacokinetic data with MPH in adult humans. Metabolism of MPH in the small intestine was assumed to account for the low oral bioavailability of MPH. Due to lack of information, model development for children and juvenile and adult nonhuman primates primarily relied on intra- and interspecies extrapolation using allometric scaling. The juvenile monkeys appear to metabolize MPH more rapidly than adult monkeys and humans, both adults and children. Model prediction performance is comparable between juvenile monkeys and children, with average root mean squared error values of 4.1 and 2.1, providing scientific basis for interspecies extrapolation of toxicity findings. Model estimated human equivalent doses in children that achieve similar internal dose metrics to those associated with pubertal delays in juvenile monkeys were found to be close to the therapeutic doses of MPH used in pediatric patients. This computational analysis suggests that continued pharmacovigilance assessment is prudent for the safe use of MPH.

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

“…biological basis, performance, and reliability) were addressed to a greater or lesser extent by these non-regulatory assessments (Supplemental Table B). Among these examples, those noted to address most, if not all, of the recommended elements included acrylamide (Sweeney et al 2010), methylphenidate (Yang et al 2014), 2-phenoxyethanol (Troutman et al 2015), and 1,1,1-trichoroethane (Lu et al 2008), although terminology varied (e.g. "validation" versus "verification").…”

“…With the exception of 1,3-butadiene in mice (Kirman & Grant 2012) and methylphenidate in monkeys (Yang et al 2014), CSAF estimated from PBPK-based extrapolations were all based on data in rats and ranged from 0.6 for acrylonitrile ingestion to 2.5 for acrylonitrile inhalation (Kirman et al 2008) (Supplemental Table B). For 1,3-butadiene (Kirman & Grant 2012), the calculated CSAF of 0.03, thereby increasing the HED by $30-fold relative to the POD in mice, was based on a model incorporating TK data from both rats and mice; that for methylphenidate was based on juvenile or adult rhesus monkeys (where the calculated CSAF ranged from 0.03 to 0.1 depending on AUC or Cmax and age (juvenile or adult).…”

Physiologically based pharmacokinetic modeling of human exposure to perfluorooctanoic acid suggests historical non drinking-water exposures are important for predicting current serum concentrations

“…Uptake in the stomach and small intestine was described using first-order rate constants k0c (/h/kg −0.25 ) and kabsc (/h/kg −0.25 ), respectively. A gastric emptying rate ( GEc , /h/kg −0.25 ) reported in the literature (Yang et al, 2014) was used to describe the rate at which PFOA was transferred from the stomach into the small intestine. Elimination occurred in the urine, feces, and bile.…”

Mathematical modeling and simulation in animal health – Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

“…For most environmental chemicals, the measured maximum metabolic rate (V max ) and/ or Michaelis constant (K m ) using in vitro human or rodent hepatic microsomes, hepatocytes, or individual cytochrome P450s in human-expressed recombinant systems are usually available. Exposure doses to environmental toxicants could be very high (i.e., in animal toxicity studies), allowing their metabolism to reach saturation in the body, and hence, their metabolism is usually described with the Michaelis-Menten equation to simulate saturable metabolism (Crowell et al, 2011;Lin et al, 2011;Yang et al, 2014c). As for veterinary drugs, metabolic rate parameters derived from hepatocytes and liver microsomal preparations are also available in preclinical species (i.e., rodents and dogs) and target food animal species, including pigs, chickens, cattle, and goats (Dalvi et al, 1987;van 't Klooster et al, 1993;Nebbia et al, 2001;Szotakova et al, 2004).…”

“…Representative equations describing key pharmacokinetic processes can be found from the references cited above. Complete model codes are also available for several recently published models (Yoon et al, 2009;Loccisano et al, 2012;Weijs et al, 2014;Yang et al, 2014c;Lin et al, 2015aLin et al, , 2016b. Readers are encouraged to refer to these references for further explanations of model equations and codes.…”