Plasma concentrations of methylphenidate enantiomers in adults with ADHD and substance use disorder, with focus on high doses and relationship to carboxylesterase activity.

Scarce data are available on methylphenidate (MPH) plasma concentrations reached after doses higher than 180 mg. The interindividual and intraindividual variability in the exposure of MPH and ritalinic acid (RA) enantiomers was examined in 28 patients with ADHD and substance use disorders, with MPH daily doses between 30 and 600 mg (median 160 mg). MPH and RA plasma concentrations were analysed with an enantioselective LC-MS/MS method. d-MPH plasma concentration/dose varied 25-fold between subjects but was reasonably stable within an individual. Twelve subjects had quantifiable l-MPH plasma concentrations, which accounted for up to 48% of the total MPH plasma concentration. The less active l-MPH enantiomer could, in individuals with low carboxylesterase 1 (CES1) activity, contribute significantly to the total MPH plasma drug concentration and hamper the estimation of the exposure to the more active d-MPH enantiomer. However, the high correlation between the total (d + l) RA/MPH metabolic ratio and the d-RA/d-MPH metabolic ratio (rs  = 0.94) indicates that the ratio based on non-enantioselective analysis could be used as a marker of CES1 activity. Whether this holds true for subjects with aberrant metabolism due to genetic variants or during concomitant treatment with inhibitors or inducers of the enzyme remains to be studied.

Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles.

AIMS: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. METHODS: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. RESULTS: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate-to-severe side effects were reported in a concentration-dependent manner. CONCLUSION: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers.

PURPOSE: The primary aim of this study was to explore the potential of alternative sampling matrices for methylphenidate by assessing the correlations between dl-threo-methylphenidate and dl-threo-ritalinic acid concentrations in exhaled breath and oral fluid with those in plasma, in repeated samples collected after a single oral dose of methylphenidate. The secondary aim was to study the enantioselective pharmacokinetics of methylphenidate in plasma, with a focus on interindividual variability in the metabolism of methylphenidate to ritalinic acid. METHODS: Twelve healthy volunteers received a single oral dose of dl-threo-methylphenidate (Ritalin® capsules, 20 mg). Venous blood samples were collected for 24 h, and plasma analyzed for threo-enantiomers of methylphenidate and ritalinic acid with LC-MS/MS. Repeated sampling of exhaled breath, using a particle filter device, and of non-stimulated oral fluid, using a felt pad device, was also performed. Exhaled breath and oral fluid were analyzed with a non-enantioselective LC-MS/MS method for dl-threo-methylphenidate and dl-threo-ritalinic acid. RESULTS: In all subjects, d-threo-methylphenidate was detectable in plasma for at least 15 h after the dose with a biphasic profile. l-threo-Methylphenidate was measurable in only five subjects and in most cases in low concentrations. However, one female subject displayed a biphasic concentration-time profile for l-threo-methylphenidate. This subject also had the highest d-threo-methylphenidate AUC (191 ng*h/mL versus 32-119 ng*h/mL in the other subjects). d-threo-Ritalinic acid concentrations were on average 25-fold higher (range 6-126) than the corresponding d-threo-methylphenidate concentrations. Single-time point plasma concentration ratios between d-threo-ritalinic acid and d-threo-methylphenidate 1.5-12 h after dose correlated highly (r = 0.88-0.98) with the d-threo-ritalinic acid AUC/d-threo-methylphenidate AUC ratio. In eleven subjects, dl-threo-methylphenidate in oral fluid mirrored the biphasic profile of methylphenidate (sum of d- and l-threo-enantiomers) in plasma, but the concentrations in oral fluid were on average 1.8 times higher than in plasma. dl-threo-Methylphenidate was detected in exhaled breath in all subjects, but there was no consistent concentration-time pattern. CONCLUSIONS: In some subjects, the pharmacologically less active l-threo-enantiomer may contribute to the total plasma methylphenidate concentrations. Monitoring methylphenidate concentrations without enantiomeric determination carries the risk of missing such subjects, which might affect how the plasma concentrations of methylphenidate are interpreted and used for clinical decision making. The use of exhaled breath and oral fluid to assess medication adherence to MPH in patients with ADHD warrants further studies.