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 ؋ (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.

High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 Mg 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 F 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 F SD) 4.4 F 1.5%, 50.0 F 9.4%, and 5.9 F 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 F 0.4, 17.4 F 3.9, and 25.1 F 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 F 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. (Cancer Epidemiol Biomarkers Prev 2006;15(2):266 -71)

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.

Ertapenem was cleared substantially in these in vitro CRRT models. However, our findings illustrate discordance between our observed SC and SA and the published unbound fraction of ertapenem. This finding has been reported with many other drugs, including carbapenem antibiotics. If in vivo studies corroborate our SA and SC findings, dosage adjustment for patients receiving CRRT will be required.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Despite the clinical use of piperacillin for more than two decades, there are still contradictory reports whether or not the elimination of piperacillin is saturable at clinically relevant concentrations. • Two recent studies that applied population pharmacokinetic (PK) modelling found evidence for a saturable component of piperacillin elimination, whereas other published population PK analyses found non‐saturable elimination of piperacillin. • There is limited information on the between occasion variability of beta‐lactams (including piperacillin) and such data might be important to maximize the effectiveness by individualizing beta‐lactam dosage regimens. WHAT THIS STUDY ADDS • Saturable and non‐saturable components of renal elimination were identified for piperacillin and the unbound non‐saturable renal clearance of piperacillin was similar to the glomerular filtration rate. • Between occasion variability of clearance and volume of distribution at steady‐state of piperacillin was below 20% which indicated that the PK of piperacillin was predictable from one dosing interval to the next. • Monte Carlo simulation predicted 5 h infusions every 8 h and continuous infusion of piperacillin would be able to successfully treat infections by pathogens with a 2 to 4‐fold (5 to 8‐fold) higher MIC compared with 30 min infusions given every 6 h (every 8 h) at the same daily dose. 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 4 g piperacillin as a single 5 min 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 70 kg subject we estimated 4.40 l h−1 for nonrenal clearance, 5.70 l h−1 for first‐order renal clearance, 170 mg h−1 for Vmax, and 49.7 mg l−1 for Km for the mixed‐order renal elimination. The BOV was 39% for Vmax, 117% for Km, and 8.5% for total clearance. A 30 min infusion of 4 g every 6 h achieved robust (≥90%) PTAs for MICs ≤12 mg l−1. As an alternative mode of administration, a 5 h infusion of 6 g every 8 h achieved robust PTAs for MICs ≤48 mg l−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 48 mg l−1.