Population pharmacokinetic modeling and simulation to support qualification of pyridoxic acid as endogenous biomarker of OAT1/3 renal transporters.

Renal clearance of many drugs is mediated by renal organic anion transporters OAT1/3 and inhibition of these transporters may lead to drug-drug interactions (DDIs). Pyridoxic acid (PDA) and homovanillic acid (HVA) were indicated as potential biomarkers of OAT1/3. The objective of this study was to develop a population pharmacokinetic model for PDA and HVA to support biomarker qualification. Simultaneous fitting of biomarker plasma and urine data in the presence and absence of potent OAT1/3 inhibitor (probenecid, 500 mg every 6 h) was performed. The impact of study design (multiple vs. single dose of OAT1/3 inhibitor) and ability to detect interactions in the presence of weak/moderate OAT1/3 inhibitors was investigated, together with corresponding power calculations. The population models developed successfully described biomarker baseline and PDA/HVA OAT1/3-mediated interaction data. No prominent effect of circadian rhythm on PDA and HVA individual baseline levels was evident. Renal elimination contributed greater than 80% to total clearance of both endogenous biomarkers investigated. Estimated probenecid unbound in vivo OAT inhibitory constant was up to 6.4-fold lower than in vitro values obtained with PDA as a probe. The PDA model was successfully verified against independent literature reported datasets. No significant difference in power of DDI detection was found between multiple and single dose study design when using the same total daily dose of 2000 mg probenecid. Model-based simulations and power calculations confirmed sensitivity and robustness of plasma PDA data to identify weak, moderate, and strong OAT1/3 inhibitors in an adequately powered clinical study to support optimal design of prospective clinical OAT1/3 interaction studies.

Gastric emptying rate of drug preparations. III. Effects of size of enteric micro-capsules with mean diameters ranging from 0.1 to 1.1 mm in man.

The gastric emptying rates of three enteric micro-capsule preparations with mean diameters of 1.1 mm and less (1.1, 0.5 and 0.1 mm) were compared. The gastric emptying rate was evaluated by determining the pharmacokinetic parameters of pyridoxic acid, including Vmax (peak excretion rate) and Tmax (time to reach peak excretion rate) after oral administration of micro-capsules containing pyridoxal phosphate as a marker drug to five healthy subjects. When given under fasting conditions, the gastric emptying rates of these preparations, according to Tmax, differed significantly; the preparations with smaller particle sizes were emptied from the stomach at a faster rate than those with larger particle sizes. However, under non-fasting conditions the gastric emptying rates were virtually the same, regardless of particle size, and all the preparations were emptied from the stomach at a much slower rate than when administered under fasting conditions.