s-1108 and pivalic-acid

S-1108, the prodrug of S-1006, was given to healthy volunteers three times a day (TID) for 8 days in a dose of 200 mg in a crossover placebo-controlled study. The safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated from pivaloyloxymethyl ester of S-1108 were investigated. There were no abnormal symptoms or signs, as observed by physical and laboratory tests. The half-life and area under the concentration-time curve of S-1006 was reduced from 1.11 +/- 0.17 h at the first dose to 0.87 +/- 0.18 h at the last dose and from 7.30 +/- 1.10 to 5.20 +/- 0.85 micrograms.h/ml, respectively. However, there was no significant difference in the peak concentration between the two doses. Pivalic acid was found to be completely detoxified by conjugation with carnitine. The total urinary recovery of pivalic acid as pivaloylcarnitine was 98.7 +/- 3.6%, resulting in an increase of daily carnitine urinary excretion two- to threefold the predose value. During the multiple administration of S-1108, the plasma carnitine concentration was reduced to and maintained at 50 to 70% of the control value, suggesting that there might be enough carnitine store in the body to detoxify the pivalic acid in a dose of 200 mg TID. Moreover, the reduced plasma carnitine was rapidly returned to the control value within a few days after the cessation of the administration of 200 mg TID.

Topics: Adult; Carnitine; Cephalosporins; Drug Administration Schedule; Drug Evaluation; Humans; Male; Pentanoic Acids; Tablets

Acute bacterial infectious diseases are major causes for outpatient visits for young children. Pivalate-conjugated antibiotics (PCAs) are frequently prescribed for these situations in Japan, while several literatures have shown a potential risk of hypoglycemia associated with PCAs. This study aimed to evaluate the incidence of PCA-induced hypoglycemia in children, compared with other oral beta-lactam antibiotics.. This retrospective cohort study using a Japanese medical and pharmacy claims database was performed on children aged 1 month to 5 years old with at least once prescription of PCAs or other oral beta-lactam antibiotics from January 2011 to December 2013. Hypoglycemia was defined based on diagnostic codes or the prescription of 10% or 20% glucose injection. We examined the prevalence of hypoglycemic events and performed multivariate analysis to investigate the risk of hypoglycemia with PCAs compared with the control oral beta-lactam antibiotics.. We identified 179,594 eligible patients in this population. In the PCA and control groups, there were 454,153 and 417,287 prescriptions and 3356 (0.74%, 95% confidence intervals [CI] 0.71-0.76) and 2605 (0.62%, 95% CI 0.60-0.65) hypoglycemic events, respectively. Multivariate analysis revealed that PCAs were associated with hypoglycemia (adjusted odds ratios [OR] 1.18, 95% CI 1.12-1.24), and even a shorter duration of PCAs prescribing (≤7 days) was significantly associated with hypoglycemia (adjusted OR 1.17, 95% CI 1.11-1.24).. These results suggest that in young children PCA use, even for a short period, is a risk factor of hypoglycemia.

Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; Cephalosporins; Child, Preschool; Comorbidity; Databases, Factual; Female; Humans; Hypoglycemia; Infant; Japan; Male; Pentanoic Acids; Retrospective Studies

[pivaloyl-14C]S-1108, which is 14C labeled at the pivalic acid moiety of the pivaloyloxymethyl side chain of S-1108, was administered orally to rats and dogs, and the disposition of pivalic acid cleft from S-1108 was examined. Besides pivaloylcarnitine and pivaloylglucuronide, pivaloylglycine was identified in dog urine as a metabolite of pivalic acid by thin-layer chromatography and high-performance liquid chromatography analysis. The concentrations in the plasma of rats to which doses of 6.65, 26.6, and 532 mg/kg of body weight were administered showed dose-proportionate levels. The radioactivity was eliminated rapidly, with a half-life of approximately 3 h until 24 h at both the 6.65- and 26.6-mg/kg doses. Free pivalic acid in plasma accounted for more than 80% of the concentration of radioactivity. Radioactivity was distributed throughout the body and was eliminated quickly at a rate similar to that of radioactivity from plasma. Most of the absorbed radioactivity was excreted in the urine, and it was completed within 24 h after administration. In dogs, the half-life of radioactivity in plasma was longer than that in the rats. The ratio of free pivalic acid in plasma was 60 to 70% of the radioactivity in plasma. The concentration of radioactivity in the liver, cortex of the kidney, and skeletal muscle 144 h after oral dosing was more than 10 times higher than the concentration in plasma for all doses. Urinary excretion in dogs was slower than that in rats. The differences in the disposition of pivalic acid between dogs and rats may account for differences in the degree of skeletal muscle disorders. The safety in humans of S-1108 given at 200 mg three times a day is discussed in relation to the metabolic formation of the carnitine conjugate of pivalic acid and the reduction of the carnitine concentration in plasma.

Topics: Animals; Carbon Radioisotopes; Cephalosporins; Chromatography, Thin Layer; Dogs; Male; Pentanoic Acids; Prodrugs; Rats; Rats, Sprague-Dawley; Tissue Distribution

The metabolism and clinical safety of the pivalic acid-containing antibiotic S-1108, an orally active pro-drug cephalosporin, were investigated to assess the clinical effects, with special emphasis on the influence of carnitine consumption in 15 patients with various infectious diseases receiving S-1108 three times a day at a 300- or 600-mg total daily dose for 3 to 7 days. The free carnitine concentrations in plasma were greatly reduced to approximately 65% of pretreatment levels, and the plasma pivaloylcarnitine (the main metabolite of pivaloyloxymethyl ester) concentrations were increased during the 200-mg (three times a day) regimens but returned to the pretreatment levels within 3 to 5 days after the cessation of treatment. In three elderly patients with declining renal function (creatinine clearance rate, 31 to 50 ml/min), the acylcarnitine/free carnitine ratio increased from 0.1 to 0.4 up to 0.7 to 1.5 at day 5 during the 7-day treatment, showed a tendency to decrease, and then returned to the pretreatment ratio 4 days after discontinuation of the drug. The degree of free carnitine reduction and increase of the acylcarnitine/free carnitine ratio depended mostly on the dose and the duration of S-1108 treatment. The increased acylcarnitine/free carnitine ratio in elderly patients was due to reduction of the free carnitine concentration in plasma and mainly to the retardation of nontoxic pivaloylcarnitine excretion. This study indicated that there was a decrease in free carnitine levels in plasma, but there were no clinical symptoms or adverse effects associated with carnitine reduction in patients during the 7-day multiple administration of S-1108.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Bacterial Infections; Carnitine; Cephalosporins; Female; Humans; Kidney Diseases; Male; Middle Aged; Pentanoic Acids; Prodrugs

A high-performance liquid chromatographic (HPLC) method was developed for the determination of pivaloylcarnitine, one of the major metabolites of pivaloyloxymethyl (+)-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2- pentenamido]-3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2- ene-2-carboxylate hydrochloride hydrate (S-1108), an oral cephem antibiotic, in human plasma and urine. Fluorescence detection was done with 3-bromomethyl-6,7-dimethoxy-1-methyl-2(1H)-quinoxalinone as the labeling reagent. Pivaloylcarnitine and cyclopropylacetylcarnitine, the internal standard, were selectively fractionated from plasma or urine on a disposable cation-exchange column. Derivatization was completed in 20 min at 40 degrees C in the presence of N,N'-diisopropylethylamine as the catalyst. A column-switching device was used to remove the excess reagent for HPLC analysis. The recovery of pivaloylcarnitine was greater than 98%, and average within-day and between-day coefficients of variation were less than 5% at concentration ranges of 0.05-2 micrograms/mL for plasma and 5-500 micrograms/mL for urine. Detection limits were 0.02 micrograms/mL for plasma and 1 micrograms/mL for urine. The urinary recovery of pivaloylcarnitine was 94% after the administration of S-1108, a result that suggested that S-1108 was almost quantitatively converted to pivalic acid and then conjugated with carnitine.

Topics: Calibration; Carnitine; Cephalosporins; Chromatography, High Pressure Liquid; Drug Stability; Humans; Pentanoic Acids; Prodrugs; Quinoxalines; Sensitivity and Specificity; Spectrometry, Fluorescence

The metabolism and pharmacokinetics of pivalic acid, a major metabolite of S-1108, were studied with three healthy volunteers. Concentrations of S-1006 (the active compound), pivalic acid, and pivaloylcarnitine in plasma and urine were measured after administration of S-1108. Recoveries in urine at the doses of S-1108 given (100 and 200 mg) were 33 to 41% for S-1006, 93% for total pivalic acid, and 89 to 94% for pivaloylcarnitine in 24 h, and maximum concentrations in plasma were 2 micrograms of S-1006 per ml, 1 micrograms of total pivalic acid per ml, and 2 micrograms of pivaloylcarnitine per ml after a 200-mg oral administration of S-1108. More than 90% of the pivalic acid was excreted as pivaloylcarnitine, and no measurable amount of free pivalic acid was present in urine samples, indicating that the pivalic acid liberated from S-1108 was almost quantitatively conjugated with carnitine in the human body. The level of free carnitine in plasma was unaffected by a single 200-mg administration of S-1108, whereas urinary excretion of free carnitine decreased as levels of acylcarnitine increased. The acylcarnitines were excreted primarily in the form of pivaloylcarnitine. This study clearly showed how the pivalic acid was metabolized and excreted in humans. The importance of monitoring carnitine, an essential cofactor in fatty acid metabolism, was also discussed in terms of its utilization by pivalic acid.

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Carnitine; Cephalosporins; Humans; Male; Pentanoic Acids