1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.
The metabolism of the anti-inflammatory drug Celecoxib in rabbits was characterized using liquid chromatography (LC)/tandem mass spectrometry (MS/MS) with precursor ion and constant neutral loss scans followed by product ion scans. After separation by on-line liquid chromatography, the crude urine samples and plasma and fecal extracts were analyzed with turbo-ionspray ionization in negative ion mode using a precursor ion scan of m/z 69 (CF(3)) and a neutral loss scan of 176 (dehydroglucuronic acid). The subsequent product ion scans of the [M - H] ions of these metabolites yielded the identification of three phase I and four phase II metabolites. The phase I metabolites had hydroxylations at the methyl group or on the phenyl ring of Celecoxib, and the subsequent oxidation product of the hydroxymethyl metabolite formed the carboxylic acid metabolite. The phase II metabolites included four positional isomers of acyl glucuronide conjugates of the carboxylic acid metabolite. These positional isomers were caused by the alkaline pH of the rabbit urine and were not found in rabbit plasma. The chemical structures of the metabolites were characterized by interpretation of their product ion spectra and comparison of their LC retention times and the product ion spectra with those of the authentic synthesized standards.
The metabolism of the anti-inflammatory drug Celecoxib in rabbits was characterized using liquid chromatography (LC)/tandem mass spectrometry (MS/MS) with precursor ion and constant neutral loss scans followed by product ion scans. After separation by on-line liquid chromatography, the crude urine samples and plasma and fecal extracts were analyzed with turbo-ionspray ionization in negative ion mode using a precursor ion scan of m/z 69 (CF 3 ) and a neutral loss scan of 176 (dehydroglucuronic acid). The subsequent product ion scans of the [M − H] ions of these metabolites yielded the identification of three phase I and four phase II metabolites. The phase I metabolites had hydroxylations at the methyl group or on the phenyl ring of Celecoxib, and the subsequent oxidation product of the hydroxymethyl metabolite formed the carboxylic acid metabolite. The phase II metabolites included four positional isomers of acyl glucuronide conjugates of the carboxylic acid metabolite. These positional isomers were caused by the alkaline pH of the rabbit urine and were not found in rabbit plasma. The chemical structures of the metabolites were characterized by interpretation of their product ion spectra and comparison of their LC retention times and the product ion spectra with those of the authentic synthesized standards.
PurposeThe aim of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of a single 12.5- or 25-mg dose of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in pediatric (children and adolescents) and adult subjects with type 2 diabetes mellitus (T2DM).MethodsA randomized, open-label, multicenter study was conducted in pediatric and adult subjects. Subjects in two pediatric groups (children and adolescents) were randomized 1:1 to receive a single oral dose of alogliptin 12.5 or 25 mg, respectively; all gender- and race-matched adult subjects received alogliptin 25 mg. Blood and urine samples were collected at prespecified time points for PK/PD analyses. A PK/PD model was developed using data from the study for steady-state simulations. Safety was also assessed.ResultsIn pediatric subjects receiving the 25-mg dose, the mean alogliptin peak plasma concentrations (Cmax) and AUC0-inf values were 26 and 23% lower, respectively, than in adults receiving the 25-mg dose, but maximum observed DPP-4 inhibition effect (Emax) and AUEC0–24 values were similar to those in adults. In pediatric subjects receiving the 12.5-mg dose, the mean alogliptin Cmax and AUC0-inf values were 58 and 54% lower, respectively, than those in adults, hence Emax and AUEC0–24 values were also lower by 11 and 17%, respectively. The PK/PD model simulated data were consistent with study results. No safety concern was found.ConclusionsA 25-mg dose of alogliptin in pediatric subjects achieved alogliptin exposures and DPP-4 inhibition similar to those in adult T2DM patients without safety concerns; therefore, this dose is recommended for a pediatric phase 3 trial.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-016-2175-1) contains supplementary material, which is available to authorized users.
PurposeThis open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12–16 years [cohort 1a; n = 9]; 6–11 years [cohort 2; n = 8]; 4–5 years [cohort 3; n = 3]).MethodsModel-based simulations were performed to guide dosing, especially in 1–5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20–60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg.ResultsExposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized Cmax and AUC0–∞, was ∼15–30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8–25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25–50-kg subjects require half the adult dose (10–40 mg), whereas 50–100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine).ConclusionsThis dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1987-8) contains supplementary material, which is available to authorized users.
Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with any degree of renal impairment, including end-stage renal disease.
Background and ObjectiveAzilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability.MethodsSixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18–45 vs. 65–85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4–8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1–3 and 8–9 and safety/tolerability was monitored.ResultsAge, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32 %) and placebo (29 %). No discontinuations or serious adverse events occurred.ConclusionsBased on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).
Azilsartan medoxomil (AZL‐M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose‐dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M‐II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single‐center, open‐label, phase 1 parallel‐group study that examined the single‐dose (day 1) and multiple‐dose (days 4–8) — 40 mg — pharmacokinetics of AZL and M‐II in 16 subjects with mild and moderate hepatic impairment by Child‐Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M‐II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M‐II. Single and multiple doses of AZL‐M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL‐M is required for subjects with mild and moderate hepatic impairment.
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