Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (<i>CES1</i>) Variants

Lyauk, Yassine Kamal; Stage, Claus; Bergmann, Troels K.; Ferrero-Milliani, L; Bjerre, Ditte; Thomsen, Ragnar; Dalhoff, Kim; Rasmussen, Henrik Berg; Jürgens, Gesche

doi:10.1111/cts.12423

Cited by 13 publications

(20 citation statements)

References 43 publications

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“…Given that chemical structures differ significantly among enalapril, clopidogrel, and sacubitril, we speculate that the involvement of amino acid residues in catalyzing the cleavage of the ester bonds of these compounds may vary, which may have resulted in the observed substrate-dependent effect of the three nsSNPs. A recent healthy volunteer study reported that the area under the curve of D-methylphenidate plasma concentrations was increased by 68% in A269S carriers compared with noncarriers after subjects were administered a single dose of 10 mg methylphenidate (Lyauk et al, 2016). However, our in vitro studies of transfected cells and human livers showed that A269S was not associated with CES1 expression or activity.…”

Section: Discussioncontrasting

confidence: 62%

A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms

et al. 2017

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Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In this study, we comprehensively examined the functions of nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include nsSNPs with a minor allele frequency >0.5% in a given population or located in close proximity to the CES1 active site. Five nsSNPs, including L40Ter (rs151291296), G142E (rs121912777), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), were loss-of-function variants for metabolizing the CES1 substrates clopidogrel, enalapril, and sacubitril. In addition, A158V (rs202121317), R199H (rs2307243), E220G (rs200707504), and T290M (rs202001817) decreased CES1 activity to a lesser extent in a substrate-dependent manner. Several nsSNPs, includingL40Ter (rs151291296), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), significantly reduced CES1 protein and/or mRNA expression levels in the transfected cells. Functions of the common nonsynonymous haplotypes D203E-A269S and S75N-D203E-A269S were evaluated using cells stably expressing the haplotypes and a large set of the human liver. Neither CES1 expression nor activity was affected by the two haplotypes. In summary, this study revealed several functional nsSNPs with impaired activity on the metabolism of CES1 substrate drugs. Clinical investigations are warranted to determine whether these nsSNPs can serve as biomarkers for the prediction of therapeutic outcomes of drugs metabolized by CES1.

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Section: Discussioncontrasting

confidence: 62%

A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms

et al. 2017

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“…Thus, one may hypothesise that one of these SNPs, or the combination of them, affects the metabolism of MPH. Of importance, two of the three individuals harbouring the intron 5 SNPs also harboured the rs115629050 (TG) SNP in exon 7, which, in a previous simulation‐based population pharmacokinetic study, was reported to increase the d ‐MPH AUC by 68% . Whether the observed effect was influenced or exerted by this exon 7 SNP or was due to the combination is unknown.…”

Section: Discussionmentioning

confidence: 98%

“…Of importance, two of the three individuals harbouring the intron 5 SNPs also harboured the rs115629050 (TG) SNP in exon 7, which, in a previous simulation-based population pharmacokinetic study, was reported to increase the d-MPH AUC by 68%. 21 Whether the observed effect was influenced or exerted by this exon 7 SNP or was due to the combination is unknown. In a previous study, Yamada et al reported a minor allele frequency of 41.2% for these intron 5 SNPs in a mixed Canadian population, 22 which is considerably higher than the frequency of 4% in our study.…”

Section: Discussionmentioning

confidence: 99%

The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios

Stage

Dalhoff

Rasmussen

et al. 2019

Basic Clin Pharma Tox

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The present clinical trial investigated the impact of selected SNPs in CES1 on the metabolic activity of the enzyme. For this purpose, we used methylphenidate (MPH) as a pharmacological probe and the d‐RA/d‐MPH (metabolite/parent drug) ratios as a measure of enzymatic activity. This metabolic ratio (MR) was validated against the AUC ratios (AUCd‐RA/AUCd‐MPH). CES1 SNPs from 120 volunteers were identified, and 12 SNPs fulfilling predefined inclusion criteria were analysed separately, comparing the effect of each genotype on the metabolic ratios. The SNP criteria were as follows: presence of Hardy‐Weinberg equilibrium, a minor allele frequency ≥ 0.01 and a clearly interpretable sequencing result in at least 30% of the individuals. Each participant ingested 10 mg of racemic methylphenidate, and blood samples were drawn prior to and 3 hours after drug administration. The SNP analysis confirmed the considerable impact of rs71647871 (G143E) in exon 4 on drug metabolism. In addition, three volunteers with markedly lower median MR, indicating decreased CES1 activity, harboured the same combination of three SNPs in intron 5. The median MR for these SNPs was 8.2 for the minor allele compared to 16.4 for the major alleles (P = 0.04). Hence, one of these or the combination of these SNPs could be of clinical significance considering that the median MR of the G143E group was 5.4. The precise genetic relationship of this finding is currently unknown, as is the clinical significance.

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“…Another published study investigated the impact of carboxylesterase-1 enzyme and other covariates on the inter-subject variability for dand l-MPH following oral administration of ER Ritalin LA ® . This study used a 3-transit-compartment ER model in NONMEM to estimate population parameters [6]. The study was conducted in adult subjects using sparse and rich sampling.…”

Section: Introductionmentioning

confidence: 99%

“…The major problem with current published PK models is the inability of the mean data to adequately predict peak exposure [5][6][7] and measure true inter-subject variability. The purpose of this paper is to modify this physiological model and apply it to the PK of publicly-available individual subject parameters derived from fitted individual adult subject data [2,8].…”

Section: Introductionmentioning

confidence: 99%

A Semi-physiologically Based Model for Methylphenidate Pharmacokinetics in Adult Humans

Jackson¹

2019

J Bioequiv Availab

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To determine if a literature-sourced physiological model for immediate-release (IR) methylphenidate (MPH), with addition of parameters for extended-release (ER) absorption can be adapted for NONMEM analysis to describe extended-release MPH drug products (i.e., Concerta® ER 54 mg tablets and Ritalin-LA® 40 mg capsules) pharmacokinetics (PK) in adults. This semi-physiological model will provide a platform to allow more accurate determination of C max in the analysis of methylphenidate plasma data from formulations with complex absorption. Adult reference data for total MPH plasma levels (summation of d-and l-enantiomers) were generated using individual subject parameters from a published NONMEM model for ER MPH (individual subject parameter generated data was used because the true experimental data is proprietary with only the previously-published summary parameters available for public use). The IR physiological model required analysis of both d-and l-MPH enantiomers which were estimated at each time point for the data by calculating the d/l enantiomer ratio from total MPH plasma concentration levels, based upon literature ratio estimates. Absorption was characterized by a fast zero-order and a delayed slow first-order release. Consistent with the literature IR model, two duplicate physiological models were used to describe the d-and l-MPH enantiomers. The mean and variability ratios for the individual subject parameter-generated data/true experimental data were very close to 1.0. The predictive performance of the absorption-modified physiological model and its disposition parameters were demonstrated, as they described both the Concerta® and Ritalin LA® PK and C max values very well. The bias was less than 6% for Concerta® peaks while peak 1 for d-Ritalin LA® was 12.9% and peak 2, 7.5%. The IR MPH physiological model, adapted for NONMEM analyses of the ER MPH drug products Concerta® and Ritalin LA® described the individual parameter-generated reference data well for both formulations.

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Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants

Cited by 13 publications

References 43 publications

A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms

A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms

The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios

A Semi-physiologically Based Model for Methylphenidate Pharmacokinetics in Adult Humans

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