Validation of a Sensor-Based Gait Analysis System with a Gold-Standard Motion Capture System in Patients with Parkinson's Disease.

Digital technologies provide the opportunity to analyze gait patterns in patients with Parkinson's Disease using wearable sensors in clinical settings and a home environment. Confirming the technical validity of inertial sensors with a 3D motion capture system is a necessary step for the clinical application of sensor-based gait analysis. Therefore, the objective of this study was to compare gait parameters measured by a mobile sensor-based gait analysis system and a motion capture system as the gold standard. Gait parameters of 37 patients were compared between both systems after performing a standardized 5 × 10 m walking test by reliability analysis using intra-class correlation and Bland-Altman plots. Additionally, gait parameters of an age-matched healthy control group (n = 14) were compared to the Parkinson cohort. Gait parameters representing bradykinesia and short steps showed excellent reliability (ICC > 0.96). Shuffling gait parameters reached ICC > 0.82. In a stridewise synchronization, no differences were observed for gait speed, stride length, stride time, relative stance and swing time (p > 0.05). In contrast, heel strike, toe off and toe clearance significantly differed between both systems (p < 0.01). Both gait analysis systems distinguish Parkinson patients from controls. Our results indicate that wearable sensors generate valid gait parameters compared to the motion capture system and can consequently be used for clinically relevant gait recordings in flexible environments.

Nonlinear pharmacokinetics of piperacillin in healthy volunteers--implications for optimal dosage regimens.

AIMS: (i) To describe the first-order and mixed-order elimination pathways of piperacillin, (ii) to determine the between occasion variability (BOV) of pharmacokinetic parameters and (iii) to propose optimized dosage regimens. METHODS: We performed a five-period replicate dose study in four healthy volunteers. Each subject received 4g piperacillin as a single 5min intravenous infusion in each study period. Drug analysis was performed by HPLC. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and Monte Carlo simulation to predict the probability of target attainment (PTA) with a target time of non-protein bound concentration above MIC >50% of the dosing interval. RESULTS: A model with first-order nonrenal elimination and parallel first-order and mixed-order renal elimination had the best predictive performance. For a 70kg subject we estimated 4.40lh(-1) for nonrenal clearance, 5.70lh(-1) for first-order renal clearance, 170mgh(-1) for V(max) , and 49.7mgl(-1) for K(m) for the mixed-order renal elimination. The BOV was 39% for V(max) , 117% for K(m) , and 8.5% for total clearance. A 30min infusion of 4g every 6h achieved robust (≥90%) PTAs for MICs ≤12mgl(-1) . As an alternative mode of administration, a 5h infusion of 6g every 8h achieved robust PTAs for MICs ≤48mgl(-1) . CONCLUSIONS: Part of the renal elimination of piperacillin is saturable at clinically used doses. The BOV of total clearance and volume of distribution were low. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 12 and 48mgl(-1) .

Toxicokinetics of acrylamide in humans after ingestion of a defined dose in a test meal to improve risk assessment for acrylamide carcinogenicity.

High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 microg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral exposure. However, only sparse human toxicokinetic data is available for acrylamide, which is needed for the extrapolation of human cancer risk from animal data. We evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. Unchanged acrylamide, its mercapturic acid metabolite N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), its epoxy derivative glycidamide, and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 60.3 +/- 11.2% of the dose was recovered in the urine. Although no glycidamide was found, unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of (mean +/- SD) 4.4 +/- 1.5%, 50.0 +/- 9.4%, and 5.9 +/- 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 +/- 0.4, 17.4 +/- 3.9, and 25.1 +/- 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 +/- 0.02. In conclusion, most of the acrylamide ingested with food is absorbed in humans. Conjugation with glutathione exceeds the formation of the reactive metabolite glycidamide. The data suggests an at least 2-fold and 4-fold lower relative internal exposure for glycidamide from dietary acrylamide in humans compared with rats or mice, respectively. This should be considered for quantitative cancer risk assessment.

Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?

Isoniazid is metabolized by the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). A greater number of high-activity alleles are related to increased acetylation capacity and in some reports to low efficacy and toxicity of isoniazid. The objective of this study was to assess individual isoniazid exposure based on NAT2 genotype to predict a personalized therapeutic dose. Isoniazid was administered to 18 healthy Caucasians (age 30 +/- 6 years, body weight 74 +/- 10 kg, five women) in random order as a 200-mg infusion, a 100-mg oral, and a 300-mg oral single dose. For the assessment of NAT2 genotype, common single nucleotide polymorphisms identifying 99.9% of variant alleles were characterized. Noncompartmental pharmacokinetics and compartmental population pharmacokinetics were estimated from isoniazid plasma concentrations until 24 h postdose by high-pressure liquid chromatography. The influence of NAT2 genotype, drug formulation, body weight, and sex on dose-normalized isoniazid pharmacokinetics was assessed by analysis of variance from noncompartmental data and confirmed by population pharmacokinetics. Eight high-activity NAT2*4 alleles were identified. Sex had no effect; the other factors explained 93% of the variability in apparent isoniazid clearance (analysis of variance). NAT2 genotype alone accounted for 88% of variability. Individual isoniazid clearance could be predicted as clearance (liters/hour) = 10 + 9 x (number of NAT2*4 alleles). To achieve similar isoniazid exposure, current standard doses presumably appropriate for patients with one high-activity NAT2 allele may be decreased or increased by approximately 50% for patients with no or two such alleles, respectively. Prospective clinical trials are required to assess the merits of this approach.

Cytochrome P450 2C9 phenotyping using low-dose tolbutamide.

OBJECTIVES: The hypoglycaemic drug tolbutamide is used for assessment of CYP2C9 activity in vivo. However, therapeutically active doses of 500 mg bear the risk of hypoglycaemia, and a tolbutamide-derived parameter based on a single plasma or urine concentration reflecting CYP2C9 activity accurately is lacking. METHODS: We examined tolbutamide and its metabolites 4'-hydroxy-tolbutamide and carboxytolbutamide in plasma and urine of 26 healthy, male volunteers up to 24 h after intake of 125 mg tolbutamide using liquid chromatography-tandem mass spectrometry. CYP2C9 genotypes were determined by sequencing of exons 3 and 7. Raw plasma and urine data were compared with pharmacokinetic parameters, CYP2C9 genotypes, and data from a study in 23 volunteers with all six CYP2C9*1-*3 combinations who received 500 mg tolbutamide. RESULTS: Plasma clearance and tolbutamide plasma concentrations 24 h after drug intake reflected the genotypes: 0.85 l/h and 1.70 microg/ml (95% confidence interval, CI, 0.80-0.89 l/h and 1.50-1.90 microg/ml) for CYP2C9*1 homozygotes (n=15), 0.77 l/h and 2.14 microg/ml (95%CI, 0.67-0.88 l/h and 1.64-2.63 microg/ml) for *1/*2 genotypes (n=7), 0.60 l/h and 3.13 microg/ml (95%CI, 0.58-0.62 l/h and 2.68-3.58 microg/ml) for *1/*3 genotypes (n=3), and 0.57 l/h and 3.27 microg/ml in the single *2/*2 carrier. Natural logarithms of tolbutamide plasma concentrations 24 h after intake correlated to plasma clearance (r(2)=0.84, P<0.0000001). This correlation was confirmed in the comparison data set (r(2)=0.97, P<0.0000001). CONCLUSIONS: A low dose of 125 mg tolbutamide can safely and accurately be used for CYP2C9 phenotyping. As a simple metric for CYP2C9 activity, we propose to determine tolbutamide in plasma 24 h after drug intake.