dTherapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (C max ) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUC ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean C max and AUC , respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.

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Omeprazole blocks the gastric H + /K + adenosine triphosphatase, thus inhibiting gastric acid secretion, and is metabolized by cytochrome P450 (CYP) 2C19. Due to the physiological changes in the elderly, there are different pharmacokinetic consequences compared to young people. The aim of this study was to evaluate the pharmacokinetic profiles of omeprazole in 15 elderly participants according to the CYP2C19 genotype. The concentration-time profiles of omeprazole and its metabolites, 5-hydroxy (5-OH) omeprazole and omeprazole sulfone, were similar between the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer groups. In contrast, when comparing the EM group and CYP2C19 poor metabolizer (PM) group, the EM/PM geometric mean ratio (95% confidence interval) of area under the plasma concentration-time curve from time of dosing to the last measurable concentration was 0.52 (0.27-1.01) and that of the IM group was 0.71 (0.32-1.59), indicating that the exposure of omeprazole in the PM group was increased. The exposure of 5-OH omeprazole was significantly decreased in the PM group when compared to the EM group, with an EM/PM geometric mean ratio (95% confidence interval) of 2. 20 (1.50-3.22). In conclusion, the tendency of drug exposure according to the CYP2C19 genotype in the elderly and young adults was similar in that the exposure level was highest in the PM group. However, when compared to young adults, the difference between the genotype groups was smaller in the elderly.

VVZ-149, a dual antagonist of GlyT2 and 5HT 2 A receptors, is an investigational analgesic with a novel mechanism of action that is currently under earlystage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ-149 injections in healthy male volunteers were explored in a randomized, double-blind, single-and multiple-ascending-dose (SAD and MAD, respectively), placebo-controlled clinical study. Subjects randomly received a 4-hour intravenous infusion of 0.25-8 mg/kg VVZ-149 or placebo in the SAD study (n = 46) or a 4-hour intravenous infusion of 4-7 mg/kg VVZ-149 or placebo twice daily for 3 days in the MAD study (n = 20). Serial blood and urine samples were collected for the pharmacokinetic analysis of VVZ-149 and its active metabolite (VVZ-368). Noncompartmental and compartmental pharmacokinetic analyses were performed. Various dosing scenarios were simulated to identify the adequate dosing regimen for the subsequent trials. Plasma exposure to VVZ-149 and VVZ-368 showed a dose-proportional increase. VVZ-149 did not accumulate in the plasma, whereas the plasma concentration of VVZ-368 increased by 1.23-to 2.49-fold after the fifth and sixth doses, respectively, in the MAD trial. Among the simulated dosing regimens, a loading dose followed by a maintenance dose was found to be an optimal dosing regimen, yielding the effective concentration estimated from animal studies in rat models of neuropathic or inflammatory pain. Single-or multiple-dose administration of VVZ-149 was generally well tolerated. These results showed that 0.5-8 mg/kg VVZ-149 exhibited linear pharmacokinetic characteristics and can be safely administered in further clinical studies.

The absorption, metabolism, and excretion (AME) profiles of KD101, currently under clinical development to treat obesity, were assessed in humans using accelerator mass spectrometry (AMS) after a single oral administration of KD101 at 400 mg and a microdose of 14 C‐KD101 at ~ 35.2 μg with a total radioactivity of 6.81 kBq. The mean total recovery of administered radioactivity was 85.2% with predominant excretion in the urine (78.0%). The radio‐chromatographic metabolite profiling showed that most of the total radioactivity in the plasma and the urine was ascribable to metabolites. The UDP‐glucuronosyltransferase (UGT), including UGT1A1, UGT1A3, and UGT2B7, might have contributed to the interindividual variability in the metabolism and excretion of KD101. The microtracing approach using AMS is a useful tool to evaluate the AME of a drug under development without risk for high radiation exposure to humans.