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K Stoeckel

Publications and source records attributed to K Stoeckel.

At least 19 recordsLinked to original sources
PubMed2005

[Relative bioavailability of an optimised galenical formulation of mefloquine].

The bioequivalence of an optimised formulation of a generic mefloquine (Mephaquin Lactabs/Test) compared to the reference product under fed conditions was assessed in a GCP/ICH conformable study. A standard two-way randomised crossover design with a 9 week washout period between treatments was used. Blood samples for determination of mefloquine concentrations for calculation of Cmax and AUC were collected at pre-dose and at predefined intervals up to 2016 hours after administration of a single oral dose of 750 mg. A standard bioequivalence analysis was performed on the two one-sided t-test procedure for log-transformed Cmax and AUC. 90% confidence intervals were calculated for both parameters and evaluated against regulatory standards of 80-125% (T/R). Analysis of plasma for mefloquine concentration was performed using a validated LC/MS method with MS detection. The ratio of mean AUC and Cmax (T/R) was 1.015 and 1.044, respectively. The 90% confidence intervals were 95.8-109.3% for AUC and 98.2-110.5% for Cmax. Mephaquin produces plasma concentrations comparable to those after administration of the reference product. The 90% confidence intervals for AUC and Cmax are within the acceptable ranges for bioequivalence of 80-125%. Thus, the optimised galenical formulation of Mephaquin Lactabs is bioequivalent to the reference product.

Administration, Oral↗
PubMed1999

High-dose omeprazole: use of a multiple-dose study design to assess bioequivalence and accuracy of CYP2C19 phenotyping.

The objectives of this multiple-dose study were to compare the performance of a new formulation of omeprazole (40 mg) with that of an established formulation and to assess the accuracy of CYP2C19 phenotyping during high-dose chronic administration. Twenty-eight healthy subjects were randomized (1:1) to receive 40 mg of either Gasec-40 Gastrocaps (Mepha) or Antra 40 (Astra) daily for 5 days. The pharmacokinetics of omeprazole and the omeprazole/5'-hydroxyomeprazole ratio 3 hours postdose were assessed on day 5. Subjects switched formulations starting on day 6, and all measurements were repeated on day 8. Subjects with metabolic ratios greater than 6 were genotyped for CYP2C19. Gasec-40 was found to be bioequivalent to Antra based on the 90% confidence interval for AUC (102.4-111.7) and Cmax (100.6-120.7). Formulation had no effect on the ratio of omeprazole to 5'-hydroxyomeprazole, which was higher than previously reported with single 20 mg doses of omeprazole. The mean ratio did not differ between day 5 and day 8 but was highly variable: 7 of 28 subjects had more than a 2-fold difference between assessments. In four individuals identified by genotype as extensive metabolizers (EMs), phenotype could not be clearly assigned. The relative bioavailability of omeprazole can be accurately assessed using this multiple-dose study design. Chronic administration of 40 mg doses of omeprazole shifts the metabolic ratio in EMs toward that in poor metabolizers (PMs), apparently because of the nonlinear metabolic clearance of the drug. The assignment of phenotype in patients receiving chronic high-dose omeprazole treatment should be interpreted with caution.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Stability of cephalosporin prodrug esters in human intestinal juice: implications for oral bioavailability.

The levels of degradation of cefetamet pivoxil (CAT), cefuroxime axetil (CAE), and cefpodoxime proxetil (CPD) in 0.6 M phosphate buffer (pH 7.4) and human intestinal juice (pH 7.4) at 37 degreesC over 24 h were compared. Significant differences in the time courses of degradation and in the patterns of degradation products were observed. (i) The relative proportions of the Delta2- and Delta3-cephalosporins were roughly reversed in the two incubation media. In phosphate buffer, the major degradation product was the Delta2-cephalosporin (CAT = 61%; CAE = 74%; CPD = 85%), while in intestinal juice it was the Delta3-cephalosporin (CAT = 86%; CAE = 75%; CPD = 87%). (ii) Generally, the degradation of the prodrug esters progressed faster in intestinal juice than in phosphate buffer (e.g., for CAT the half-lives [t1/2s] were 0.78 and 4.3 h, respectively). (iii) The two diastereoisomers of CAE and CPD were degraded at different rates in intestinal juice (for the CAE diasteroisomers, t1/2s = 0.37 and 0.93 h; for the CPD diastereoisomers, t1/2s = 0.18 and 0.98 h) but were degraded at similar rates in phosphate buffer (for the CAE diastereoisomers, t1/2 = 1.6 h; for the CPD t1/2 diastereoisomers, = 2.2 h). It is concluded that (i) the Delta2 isomerization does not significantly affect the bioavailability of prodrug esters since enzymatic hydrolysis in the intestinal fluid proceeds mainly to the active Delta3-cephalosporin and (ii) the high degree of stereoselectivity of the enzymatic ester hydrolysis should make it possible to increase the bioavailabilities of certain prodrug esters (CAE, CPD) by using the more stable diasterioisomer.

Administration, Oral↗
PubMed1996

Pharmacokinetics of ceftriaxone in patients undergoing continuous veno-venous hemofiltration.

Continuous hemofiltration is used widely in the management of patients with acute renal failure, but administration guidelines for many drugs have yet to be established. In this study, the pharmacokinetics of ceftriaxone were compared in patients with normal renal function (n = 9), mild renal insufficiency (n = 5), and acute renal failure receiving continuous veno-venous hemofiltration (n = 6). Pharmacokinetic parameters were determined under steady state conditions. Patients with mild renal insufficiency had a significantly lower renal clearance and longer half-life of ceftriaxone; however, drug recovery in the ultrafiltrate with continuous veno-venous hemofiltration was similar to that in the urine of patients with normal renal function. Pharmacokinetic parameters for renal, nonrenal, and systemic clearance and for volume of distribution and half-life were also similar between patients receiving continuous veno-venous hemofiltration and those with normal renal function. The sieving coefficient (S) of ceftriaxone (0.69) significantly exceeded the expected free fraction in plasma, confirming previous reports that protein binding does not limit the sieving of this compound. The results suggest that a reduction in the usual daily dose of ceftriaxone is not required in patients with acute renal failure receiving continuous veno-venous hemofiltration.

Acute Kidney Injury↗
PubMed1996

Influence of maturation and growth on cefetamet pivoxil pharmacokinetics: rational dosing for infants.

The pharmacokinetics of intravenous (i.v.) cefetamet and the bioavailability of oral cefetamet pivoxil in infants aged 3.5 to 17.3 months who were hospitalized for urological surgery were characterized. The absorption of cefetamet pivoxil administered in a syrup formulation was 38 +/- 19% (n = 5) for infants, which was comparable to values observed for children and adults. The plasma half-life of i.v. cefetamet was 3.03 +/- 0.96 h (mean +/- standard deviation; n = 20) in the infants. This was not different from the value observed for normal adult subjects but was longer than that reported for children aged 3 to 12 years. Urinary recovery of cefetamet after i.v. administration to infants was 63.4 +/- 17.7% (n = 16), which was less than the 80% recovery found in older children and adults. The steady-state volume of distribution was 399 +/- 116 ml/kg of body weight. It was comparable in size and showed the same dependence on body weight as it did in children and adults. The mean systemic clearance per kilogram of body weight in the infants was lower than that in children and adults, apparently because of immaturity of clearance processes. A model that accounted for maturation and growth with increasing age was developed for the clearance. On the basis of this model, the clearance capacity increased from birth to 5 years by a factor of 4.5 because of maturation. Maturation progressed exponentially, with a half-life of 14 months. This model was used to develop dosing regimen guidelines for pediatric patients aged 3.5 months and older.

Administration, Oral↗
PubMed1996

Penetration of cefetamet pivoxil and cefuroxime axetil into the maxillary sinus mucosa at steady state.

The penetration of cefetamet and cefuroxime into the maxillary sinus mucosa after the administration of cefetamet pivoxil and cefuroxime axetil was investigated in patients undergoing elective surgery of the maxillary sinus. A total of 27 patients, 13 for cefetamet pivoxil and 14 for cefuroxime axetil, ranging from 15 to 70 years of age participated in this study. Each patient received three oral doses of either one tablet of cefetamet pivoxil (500 mg of GLOBOCEF) or two film tablets of cefuroxime axetil (125 and 250 mg of ZINAT) every 12 h. Sinus mucosa tissue samples were removed during surgery at times ranging from 2 to 4.5 h after the last oral administration. Blood samples were collected before drug administration, 2 h after the first and third doses, and concomitantly with tissue sample collection during surgery. All samples were analyzed by high-performance liquid chromatography. The concentrations of cefetamet and cefuroxime in plasma samples measured concomitantly with those in tissue samples ranged between 0.83 and 4.5 micrograms/ml for cefetamet and 0.59 and 3 micrograms/ml for cefuroxime. The mean tissue-to-plasma ratios calculated with reference to total (bound plus unbound) plasma drug concentrations were 0.60 (range, 0.52 to 0.77) for cefetamet (n = 4) and 0.38 (range, 0.28 to 0.44) for cefuroxime (n = 6). Both drugs seem to penetrate freely and easily into the sinus mucosa. The antibacterial activities of cefetamet pivoxil and cefuroxime axetil in cases of sinusitis therefore depend mainly on their achieved active plasma drug concentrations and their intrinsic activities in inhibiting the causative organism(s).

Adolescent↗
PubMed1994

Accumulation kinetics of propranolol in the rat: comparison of Michaelis-Menten-mediated clearance and clearance changes consistent with the "altered enzyme hypothesis".

(+)-Propranolol was infused at two rates into the pyloric vein (a portal vein tributary) of 15 male Sprague Dawley rats until apparent steady-state conditions were established (i.e., 8 hr at each rate). One group (n = 7) received the high dose (40 micrograms/min/kg) first, and in the other group (n = 8) the low dose (20 micrograms/kg/min) was used to initiate treatment. Free and total serum concentrations of propranolol were measured. When the low dose was given first, the apparent steady-state concentrations achieved during low- and high-rate infusion steps were 166 +/- 37 and 774 +/- 235 ng/mL, respectively. These data are consistent with a simple Michaelis-Menten kinetic model and the key parameters of such a model (Vmax and Km) were estimated. However, a crucial test of such a model (and one which should give insight regarding the relevance of an "altered enzyme hypothesis") is to reverse the order of infusion steps since, in a system controlled by Michaelis-Menten kinetics, the same steady-state concentrations should be achieved regardless of the order in which infusion steps are given. When the sequence of infusion rates was reversed, steady-state concentrations were 492 +/- 142 and 298 +/- 79 ng/mL for the high and low infusion rates, respectively. Clearly, a history of high-dose exposure reduces the intrinsic clearance of total drug (CLss) during a subsequent low-dose exposure (i.e., the apparent steady-state levels during the low-dose pyloric vein infusions were significantly different; P < 0.001). When these data were corrected for plasma protein binding, the same trends emerged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Pharmacokinetics of ceftriaxone in patients with typhoid fever.

Ceftriaxone in short courses has emerged as an effective alternative to chloramphenicol for the treatment of typhoid fever. To study the pharmacokinetics of ceftriaxone in acute typhoid fever, 10 febrile Nepalese adolescents and young adults with blood culture-positive illness were treated with 3 g of ceftriaxone (intravenous infusion for 30 min) daily for 3 days. On the 1st and 3rd day of treatment, blood and urine samples were collected at defined intervals for measurements of drug concentrations. Kinetic parameters including concentrations at the end of infusion (Cmax) and 24 h after the end of infusion (Cmin), elimination half-life (t1/2), area under the plasma concentration-time curve (AUC), total plasma clearance, renal clearance, percentage excreted in urine, and volume of distribution were estimated. On day 1, mean values were as follows: Cmax, 291 micrograms/ml; Cmin, 21.7 micrograms/ml; plasma t1/2, 5.2 h; AUC, 1,428 micrograms.h/ml; total plasma clearance, 37 ml/min; renal clearance, 19 ml/min; percentage excreted in urine, 49.7%; and volume of distribution, 16.1 liters. Mean values on day 3 were not significantly different from those on day 1. Compared with published values for healthy volunteers who received the same dose, our mean t1/2s and AUCs were lower and our mean total plasma clearances, renal clearances, and volumes of distribution were higher. The good clinical responses of these patients to therapy and the adequate Cmins support the use of ceftriaxone once daily for the treatment of typhoid fever.

Adolescent↗
PubMed1993

Bioavailability of syrup and tablet formulations of cefetamet pivoxil.

Two studies examining the bioavailability of cefetamet pivoxil in healthy male subjects were conducted. In the first, the bioavailabilities of the 250-mg (M250) and M500 tablet formulations of cefetamet pivoxil to be marketed were compared with that of a tablet used in clinical trials. All products were given with food at a dose of 500 mg. In the second study, the bioavailability of the syrup formulation was evaluated under both fasting and nonfasting conditions and compared with that of the M500 tablet formulation given with food. The absolute bioavailabilities of the M500 and M250 tablets (55.0% +/- 8.0% and 55.7% +/- 7.0%, respectively) were not significantly different from that of the clinical-trial formulation (49.8% +/- 8.5%). The newer tablet formulations exhibited faster absorption as evidenced by higher peak concentrations (3.8 [M500] and 3.9 [M250] mg/liter compared with 3.2 mg/liter for the clinical-trial formulation), a shorter time to peak concentration, and a shorter mean absorption time. The syrup formulation was found to have significantly lower absolute bioavailability (37.9% +/- 6.0%) compared with that of the M500 tablet (58.4% +/- 9.0%) when both were given with food. Food had no significant effect on the bioavailability of the syrup, which averaged 34.0% +/- 8.6% under fasting conditions, although absorption was delayed by food (mean absorption time increased from 2.2 to 3.9 h). This contrasts with the results of previous studies documenting significant increases in tablet bioavailability with food. Despite the lower bioavailability of the syrup, unbound-cefetamet concentrations are expected to remain above the MICs for 90% of the strains tested for susceptible organisms for approximately 10 h of the usual 12-h dosing interval with both syrup and tablet formulations of cefetamet pivoxil given with food.

Administration, Oral↗
PubMed1993

Cefetamet pivoxil clinical pharmacokinetics.

Cefetamet pivoxil is an orally absorbed prodrug ester of the microbiologically active cephalosporin, cefetamet. The prodrug ester is completely hydrolysed to the active compound cefetamet on its first pass through the gut wall, the liver or both. Cefetamet is classified as a third generation cephalosporin with excellent activity against streptococci, Enterobacteriaceae, Neisseria and Haemophilus species. It has enhanced stability against beta-lactamases compared with penicillins and first and second generation cephalosporins. The antibacterial spectrum is comparable with that of cefotaxime except for its poor activity against staphylococci. Following a 20-minute zero-order intravenous infusion, cefetamet had a rapid distribution phase followed by a monoexponential decline. The average pharmacokinetic parameters from 152 healthy volunteers were: total body clearance 136 ml/min (8.16 L/h); renal clearance 119 ml/min (7.14 L/h); nonrenal clearance 17 ml/min (1.02 L/h); volume of distribution at steady-state 0.29 L/kg; terminal elimination half-life 2.2 hours; 88% of the dose recovered in the urine. Cefetamet is not extensively bound to plasma proteins. Consequently, these data indicate that cefetamet is predominantly eliminated unchanged by the kidney via glomerular filtration with possibly a minor component of tubular secretion. Cefetamet has a relatively small apparent volume of distribution consistent with that of other beta-lactam antibiotics. Results following ascending intravenous doses of cefetamet in healthy young male volunteers demonstrated that the pharmacokinetics of intravenous cefetamet are independent of the dose. The absolute bioavailability of cefetamet tablets following oral cefetamet pivoxil administration is enhanced by the presence of food. Under fed conditions, 50 to 60% of the final oral dose is absorbed into the systemic circulation. This food effect is observed when cefetamet pivoxil is administered within 1 hour of a meal. Food also produces a slight delay in the time to reach peak plasma concentrations of this drug. Changes in fluid volume intake with cefetamet pivoxil administration have no effect on the bioavailability of this drug. Similar absorption characteristics have been observed for all of the tablet dosage formulations studied during clinical development. The absolute bioavailability of the final syrup dosage formulation was between 38 and 47%. Little improvement in the bioavailability of this preparation has been observed with food. The absorption and disposition of cefetamet in human subpopulations [i.e. children, elderly (< 75 years of age), renal impairment, liver disease and patients taking concomitant drugs] have been studied extensively. Only impaired renal function appears to significantly alter the elimination of this drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption↗
PubMed1992

Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil.

Five absorption rate models have been compared for describing cefetamet data in 34 adults after oral administration of cefetamet pivoxil with food alone or in combination with either an antacid or an H2 antagonist. A sequential zero- then first-order input process provided the most flexible description of the absorption rate of cefetamet. If the first-order rate constant is linked to the zero-order input parameters the model can be interpreted as the consequence of solubility-limited absorption. While a sequential input is theoretically reasonable to assume, the first-order process appeared to be independent of the zero-order input. A population-based approach was applied to estimate the effect of dose and gastric pH increase on absorption and disposition. There appeared to be a dose-associated change in several parameters. The most marked change was an increase in volume of distribution of cefetamet. Treatments expected to increase gastric pH slowed the first-order component of the absorption process. Three models for estimating the extent of bioavailability have been compared using observations from 18 adults and 13 children receiving iv cefetamet and oral cefetamet pivoxil on two separate occasions. The most consistent estimates of the disposition parameters and the extent of bioavailability were achieved with the sequential zero- and first-order model under the assumption that steady state volume of distribution and nonrenal clearance were the same after iv and oral treatment.

Absorption↗
PubMed1992

The pharmacokinetics of new oral cephalosporins in children.

Differences in the pharmacokinetic parameters of cephalosporins between children and adults may be predictable on the basis of the level of maturation of the physiologic processes involved in drug disposition. It appears that the most important of these factors (gastrointestinal, renal and hepatic function) are reasonably mature by the age of 1 year. As a result, the primary difference between adults and children relates to size and body composition. Comparable bioavailability is expected in children and adults. However, absolute values for systemic clearance (ClS) and volume of distribution (VSS) will be lower in children. It has been suggested that ClS in children is reduced in proportion to body surface area. This may also be true for the VSS of the cephalosporins since they distribute primarily into the extracellular fluid space which has been shown to be similar in children and adults when adjusted for surface area. If both ClS and VSS are proportional to surface area, half-life will be similar in adults and children. Data with cefetamet generally support these principles. Clearance normalized for body surface area averaged 69.3 ml/min/m2 in children aged 3-7 years, 64.9 ml/min/m2 in children of 8-12 years and 68.9 ml/min/m2 in adults. The VSS remained somewhat smaller in children than adults even after correction for surface area. Bioavailability and elimination half-life in children were similar to values in adults. Data with other new cephalosporins are limited, but differences between children and adults in bioavailability and half-life appear to be insignificant.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children.

The pharmacokinetics of cefetamet were determined after intravenous (i.v.) administration of cefetamet and oral administration of cefetamet pivoxil syrup to patients between the ages of 3 and 12 years. The patients were hospitalized for reconstructive urological surgery; to prevent infection, prophylactic i.v. cefetamet was administered on the day of surgery and oral cefetamet pivoxil was administered 2 days later. After i.v. administration, the mean (+/- standard deviation) half-life of cefetamet was 1.97 +/- 0.60 h (n = 18), which was different from the 2.46 +/- 0.33 h reported for nine adults (22 to 68 years old) in a previous study. The average values for the mean residence times were 2.35 +/- 0.94 and 2.83 +/- 0.34 h and the average values for the fraction of the dose eliminated unchanged in the urine were 79.9% +/- 8.99% and 80% +/- 11% in children and adults, respectively. Plots of mean systemic clearance and steady-state volume of distribution versus body weight for the children and comparative adults were linear on log-log coordinates, and the slopes of the plots were 0.661 and 0.880, respectively. These slope values suggested that mean systemic clearance values per unit of body surface area were similar in children and adults and that maintenance doses for children should be the adult maintenance dose multiplied by the child's surface area divided by 1.73 m2. The mean (+/- standard deviation) oral bioavailabilities of cefetamet pivoxil were 49.3% +/- 15.7% in 3- to 7-year-old children who received a 500-mg dose and 37.9% +/- 10.0% in 8- to 12-year-old children who received a 1,000-mg dose. These values were not different from that observed in the adult group after two 500-mg tablets. Likewise, the peak concentration of cefetamet in plasma and its time of occurrence in children were in line with the values which have been observed for adults.

Administration, Oral↗
PubMed1990

Ceftriaxone binding to human serum albumin. Indirect displacement by probenecid and diazepam.

In vitro protein binding studies were conducted to examine the interaction between ceftriaxone (CEF), probenecid (PROB) and diazepam (DIAZ). The presence of PROB and DIAZ at concentrations equal to molar albumin concentration caused a decrease in CEF affinity from 3.7 x 10(4) M-1 (control) to 1.1 x 10(4) (PROB) and 2.6 x 10(4) (DIAZ) M-1, but not in binding capacity in pooled human plasma. PROB and DIAZ at five times the molar albumin concentration also caused a decrease in CEF affinity from 4.5 x 10(4) M-1 (control) to 0.45 x 10(4) (PROB) and 3.0 x 10(4) (DIAZ) M-1 in isolated human serum albumin. DIAZ and PROB displaced one another, confirming their common binding site (Site II, the benzodiazepine site) on serum albumin. By contrast, CEF was unable to displace either PROB or DIAZ from defatted albumin. In the presence of elevated free fatty acid concentrations (four times the albumin concentration), CEF decreased the binding of both drugs. CEF free fraction (fp) in isolated human serum albumin (CEF fp = 7.7%) was increased by drugs which bind to Site I: sulfisoxazole (CEF fp = 68.1%), warfarin (CEF fp = 56.0%) and furosemide (CEF fp = 55.0%). At ten times the molar concentration of albumin, CEF displaced both warfarin (warfarin fp from 0.99 to 2.20%) and phenytoin (phenytoin fp from 17.7 to 23.4%) from defatted albumin. CEF appeared to bind to Site I (the warfarin site) on human serum albumin, and was displaced by PROB and DIAZ via a mechanism which did not involve direct competition at a common binding site.

Binding Sites↗
PubMed1990

Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function.

Three different studies were conducted to assess the pharmacokinetics of moclobemide in subjects with conditions complicating dose determination. The first examined the absorption and disposition of moclobemide in an elderly population and compared these with results obtained in a group of normal young subjects. No significant differences were found between the groups in the intravenous (i.v.) parameters of disposition, and no differences with regard to disposition of the metabolite, Ro 12-8095. In addition, the minimum steady-state concentrations of moclobemide and the main plasma metabolite did not differ between the elderly and younger patients. In the second study, clearance tests in patients with cirrhosis of the liver confirmed that hepatic function is drastically reduced in this group of patients; it is therefore possible that moclobemide absorption and distribution might be influenced. In only 3 of the 12 patients investigated, slowly declining plasma concentrations after administration pointed to a severely limited elimination capacity for moclobemide. In the remaining 9 subjects, average values of several parameters changed significantly (t 1/2 beta, MRT and C1), whereas Vss and renal clearance were not significantly altered. In patients with kidney dysfunction, there were no differences in kinetics between patients undergoing hemodialysis and those who were not. Compared with normal healthy volunteers, no differences were found for renal patients, with the exception of the mean absorption time, which was significantly prolonged. From these studies it can be concluded that, pharmacokinetically, neither age nor renal impairment require adjusting the dosage of moclobemide. Patients with liver cirrhosis, however, need to have the usual dose reduced to one half or one third, or else the dosage intervals can be increased to prevent cumulation.

Administration, Oral↗