Metabolism, pharmacokinetics and excretion of [14C]dimethyl fumarate in healthy volunteers: an example of xenobiotic biotransformation following endogenous metabolic pathways.

Delayed-release dimethyl fumarate (DMF), Tecfidera®, is approved globally for treating relapsing-remitting multiple sclerosis. The disposition of DMF was determined in humans after administration of a single oral dose of [14C]DMF, and the total recovery was estimated to be between 58.4% to 75.0%, primarily through expired air.The absorption of [14C]DMF-derived radioactivity was rapid, with Tmax at 1h postdose. Glucose was the predominant circulating metabolite, accounting for ∼60% of the total extractable radioactivity. Cysteine and N-acetylcysteine conjugates of mono- or di-methyl succinate were found to be the major urinary metabolites.In vitro studies showed that [14C]DMF was mainly metabolised to MMF, and fumarase exclusively converted fumaric acid to malic acid and did not catalyse the conversion of fumaric acid esters to malic acid. DMF was observed to bind with human serum albumin through Michael addition to the Cys-34 residue when exposed to human plasma.These findings indicate that DMF undergoes metabolism via hydrolysis, GSH conjugation, and the TCA cycle, leading to the formation of citric acid, CO2, and water. These ubiquitous and well-conserved metabolism pathways minimise the risk of drug-drug interactions and reduce variability related to pharmacogenetics and ethnicity.

Pharmacokinetics, pharmacodynamics, and safety of peginterferon beta-1a in subjects with normal or impaired renal function.

Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) of peginterferon beta-1a following a single subcutaneous dose at 63 µg (n = 5) or 125 µg (n = 30). The results showed a fractional increase in area-under-the-concentration-time curve (AUC [30-53%]) and peak serum concentration (Cmax [26-42%]) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and Cmax were similar for healthy subjects and end-stage-renal-disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta-1a was well tolerated in all groups. These results do not warrant peginterferon beta-1a dose adjustment in subjects with renal impairment.

Chiral liquid chromatography-tandem mass spectrometry assay to determine that dexpramipexole is not converted to pramipexole in vivo after administered in humans.

Dexpramipexole (DEX) was being investigated in clinical studies for the treatment of amyotrophic lateral sclerosis (ALS). To monitor the potential chiral interconversion of dexpramipexole to pramipexole (PPX) in vivo, a highly sensitive and selective chiral LC-MS/MS assay was developed and qualified for the detection of pramipexole in the presence of dexpramipexole in human plasma. In this assay, plasma samples were extracted by protein precipitation coupled with solid phase extraction (SPE). The analyte PPX was separated from its enantiomer DEX using a chiral HPLC method. The assay was qualified with a dynamic range of 0.150-1.00ng/mL. The lower limit of quantitation (LLOQ) for PPX was 0.150ng/mL in the presence of up to 1000ng/mL of DEX. The qualified method was used to analyze plasma samples from a DEX clinical study. No PPX was detected in humans at pharmacologically significant levels after administration of dexpramipexole at single doses up to 600mg per day.

Pharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function.

This phase I, open-label, single-dose study evaluated the pharmacokinetics, safety, and tolerability of renally excreted drug dexpramipexole in subjects with normal and impaired renal function, i.e. mild, moderate, severe renal impairment, or end-stage renal disease (ESRD) requiring hemodialysis when matched by age and sex. Dexpramipexole area under the curves (AUCs), but not Cmax , were significantly increased with the severity of renal impairment after a single dose administration. The geometric mean ratio of dose-normalized AUC(0-72) was 1.4, 1.7, 2.7, and 4.5, respectively, in mild, moderate, severe renal impairment, and ESRD subjects when compared to healthy subjects. There was a strong association between renal function (eGFR) and dexpramipexole CLr. The slope (90% confidence interval(CI)) of eGFR and renal clearance (CLr) in the regression model was 3.1 (2.4, 3.7). Dexpramipexole elimination in ESRD subjects during both dialysis and non-dialysis (i.e., interval between dialysis) was insignificant. Single 75 mg and 150 mg doses of dexpramipexole were well tolerated, and the safety profile was comparable across renal function groups. Extensive drug accumulation may occur with repeated dosing in patients with significant renal impairment. It is recommended that dexpramipexole not to be given to patients with severe renal impairment or in those with ESRD.

Pharmacokinetics of oral tonapofylline and its acyl-glucuronide metabolite in patients with mild and moderate hepatic impairment.

The objective of the study was to evaluate the effect of hepatic impairment on the pharmacokinetics of tonapofylline. Patients with mild or moderate hepatic impairment were enrolled in parallel with demographically matched healthy subjects. All study participants received a single 75-mg oral tonapofylline capsule. The pharmacokinetic parameters for both tonapofylline and its active metabolite, acyl-glucuronide (tonapofylline-AG), were affected by hepatic impairment significantly (P < .1) except for time to peak plasma concentration (t(max)), terminal half-life (t(½)), and apparent volume of distribution based on the terminal phase (Vdz/F). In the mild group, peak plasma concentration (C(max)), area under the time-concentration curve from time 0 to 48 hours postdose (AUC(48 h)), and from time 0 to infinity (AU(Cinf)) of tonapofylline modestly increased as compared with the control healthy subjects (GMR 1.62, 1.57, and 1.53, respectively). The extent of increase of these parameters for tonapofylline-AG was more profound than tonapofylline with geometric mean ratio (GMR) ranging from 2.02 to 2.08. Moderate hepatic impairment was also associated with modest increases of C(max), AUC(48 h), and AUC(inf) of tonapofylline (GMR 1.41, 1.98, and 2.08, respectively). Similar to the mild group, the increase of these parameters were higher for tonapofylline-AG with GMR ranging from 2.80 to 3.86. Single oral 75-mg tonapofylline was safe and well tolerated in patients with mild or moderate hepatic impairment.