Pharmacokinetic profile of cefixime in man.

Cefixime is an orally absorbed third generation cephalosporin with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and is highly resistant to beta-lactamase degradation. In general serum and urinary concentrations of cefixime achieved after recommended daily doses are well above the minimal inhibitory concentrations at 90% for indicated microorganisms. The pharmacokinetics of cefixime were determined in adult and pediatric subjects. In general the half-life of the drug is about 3 to 4 hours and is not dependent on dose. The drug is not extensively bound to serum proteins; the free fraction is about 31% and is concentration-independent. The absolute bioavailability, based on comparisons of area under the serum concentration-time curve values after 200-mg intravenous, 200-mg oral solution, and 200- and 400-mg capsule doses, ranged from 40 to 52%, showing a comparable bioavailability for cefixime at single 200- and 400-mg oral doses. In a dose proportionality study, over an oral dose range of 200 to 2000 mg, peak serum concentration (Cmax) and area under the concentration-time values increased linearly but were not directly proportional with dose. Upon multiple dosing for 2 weeks on a 400-mg daily or 200-mg twice a day regimen, serum concentrations and urinary recovery of unchanged drug were similar for each group, and there was no drug accumulation. Peak serum concentration and area under the concentration-time curve values after a 400-mg dose were almost double those after a 200-mg dose. All formulations of cefixime were bioequivalent to an oral reference solution at doses of 200 and 400 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Absolute bioavailability of cefixime in man.

In a four-way cross-over study, the absolute bioavailability of cefixime was determined in 16 healthy volunteers. Each subject received a single 200-mg dose as an intravenous (IV) and oral solution, and 200-mg and 400-mg capsule doses of the drug. Blood and urine samples were collected for 24 hours after each dose. Cefixime was well tolerated after IV and oral doses of the drug and no serious drug-related adverse effects were observed. The maximal serum concentration (Cmax) of cefixime following the 200-mg oral solution and 200-mg and 400-mg capsule doses were 3.22, 2.92, and 4.84 micrograms/mL, respectively. Mean area under the serum concentration time curves (AUC) following the IV, 200-mg oral solution, and 200-mg and 400-mg capsule doses were 47.0, 26.0, 23.6, and 39.4 micrograms.hr/mL, respectively. Mean elimination half-life values of the drug were comparable after oral and IV doses, ranging from 3.2 to 3.5 hours. Based on serum AUC values, the absolute bioavailability of cefixime was 52.3%, 47.9%, and 40.2% after the 200-mg oral solution, 200-mg capsule and 400-mg capsule doses, respectively. Respective ratios based on 24-hour urinary recovery data were 44.7%, 41.7%, and 40.5%. Therefore, the results show that the percent of cefixime adsorbed after 200-mg and 400-mg oral doses was similar.

Importance of oral dosing rate on the hemodynamic and pharmacokinetic profile on nilvadipine.

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three-way randomized crossover study at a dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: -33, -13 and +46%; -17, -14 and +38%; and -24, -14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect-concentration relationships were fit to a modified Emax model. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration-time curve (AUC0----infinity) between dosing regimens 2 (38.7 ng.hr/mL) and 3 (42.1 ng.hr/mL) (P greater than 0.05), the mean AUC0----infinity after regimen 1 (76.3 ng.hr/mL) was significantly greater than after dosing regimens 2 or 3 (P less than 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state.

The pharmacokinetics of cefixime (CL 284,635; FK027), a new orally active broad-spectrum cephalosporin, were determined in 26 healthy volunteers, after multiple 200-mg twice-a-day (group 1; N = 13) or 400-mg once-a-day (group 2; N = 13) dosing for 15 days. On study days 1, 8, and 15, mean peak serum concentrations (Cmax) were 1.67, 1.75, and 1.87 micrograms/mL, respectively, for group 1 and 2.76, 3.04, and 2.67, respectively, for group 2. Over the 15-day period, mean trough serum concentrations were, on average, 0.40 and 0.08 microgram/mL for groups 1 and 2, respectively. Comparison (ANOVA) of serum and urinary excretion pharmacokinetic parameters for cefixime on days 1, 8, and 15 found no significant (P greater than .05) differences for either group except for a small but significantly (P less than .05) earlier time to reach Cmax and higher renal clearance on days 8 and 15 in group 1. These differences, however, are not clinically significant. On study days 1, 8, and 15, mean Cmax and AUC0-tau values for Group 2 were about 1.5 to 2.2 time those for Group 1. Urinary excretion of cefixime accounted for 11.9 to 14.5% and 9.9 to 12.4% of the dose in groups 1 and 2, respectively, over the 15-day study. Overall, there was no accumulation of cefixime in serum or urine nor was there a reduction in serum concentrations of urinary amounts over the 15-day dosing period when the drug was given either as a 200-mg twice-a-day or 400-mg once-a-day dosing regimen.

Pharmacokinetic principles in the design of immediate-release components in sustained-release formulations with zero-order release characteristics.

The potential advantages and disadvantages of incorporating an immediate-release (IR) component in sustained-release formulations with zero-order release characteristics (SR) are discussed. The dose of the IR component for SR doses other than the first one (DIS) should be less than that for the first SR dose (DI). Multiple dosing of an SR formulation with an IR component of dose DI may lead to unnecessary accumulation and fluctuation of plasma drug concentrations. An innovative and practical method for estimating the DI and DIS doses of this IR component is also presented.

Pharmacokinetic evaluation of a sustained-release formulation of trihexyphenidyl in healthy volunteers.

Twenty-four male subjects were randomized to receive two oral dosage forms of trihexyphenidyl HCl (alpha-cyclohexyl-alpha-phenyl-1-piperidinepropanol HCl). The dosage regimens were (1) a 5-mg immediate release (IR) tablet given twice daily at time zero and 12 h later, and (2) two 5-mg sustained-release (SR) capsule formulations given daily. The number of adverse experiences following the SR formulation were approximately 50% of those for the IR formulation, the peak concentration (Cmax) after the SR formulation was significantly lower (p less than 0.05) than that after the first dose of the IR formulation, and the time to reach Cmax (tmax) was significantly longer after the SR formulation (p less than 0.05). The SR formulation maintained serum concentrations above 50, 60, and 70% of Cmax values for average time periods of 11.7, 9.4, and 5.9 h, respectively, compared with values of 1.8, 1.2, and 0.9 h after the IR formulation; the differences were all significant (p less than 0.05). The mean elimination half-life (t1/2) was similar (p greater than 0.05) after the SR (10.1 h) and IR (8.7 h) formulations. The statistical power of the study was 98.1% to detect a 20% difference in the area under the curve from time zero to time infinity (AUC0----infinity) between formulations. Although the AUC0----infinity after the SR formulation was statistically smaller (p less than 0.05) than after the IR tablet, the difference was less than 20%. Therefore, the SR formulation was bioequivalent to the IR tablet formulation of trihexyphenidyl.

Pharmacokinetics of tiqueside (beta-tigogenin cellobioside) in dogs, rats, rabbits, and monkeys.

Tiqueside (CP-88,818, beta-tigogenin cellobioside) is an effective cholesterol absorption inhibitor that may be useful in the treatment of hypercholesteremia. We have investigated the pharmacokinetics of tiqueside in dogs, rats, rabbits, and monkeys. In dogs, the volume of distribution (Vdss) was 2.11 L/kg, clearance was 0.58 mL/min-kg, and half-life was 45 h following a 1.4 mg/kg intravenous dose. Absolute bioavailability in fed dogs decreased from 6.7% for a 30 mg/kg dose to 1.7% for a 375 mg/kg dose. The oral bioavailability at a dose of 375 mg/kg was approximately 4-fold lower in fasted dogs than fed dogs. AUC-(0-24) for doses up to 2000 mg/kg were only slightly greater than AUC-(0-24) for a 375 mg/kg dose. In rats dosed intravenously at 8.0 mg/kg, Vdss was 3.52 L/kg, clearance was 14.6 mL/min-kg, and half-life was 3.6 h. Estimated bioavailability for rats dosed in feed at 250-2000 mg/kg/day was less than 0.5%. In rabbits dosed at 4.0 mg/kg i.v., Vdss was 2.95 L/kg, clearance was 0.59 mL/min-kg, and half-life was 61 h. Bioavailability for rabbits dosed in feed at 62.5 or 125 mg/kg/day was approximately 7%. Systemic exposure in rhesus monkeys after oral dosing was lower than that for dogs and rabbits. Thus, low systemic exposure to tiqueside following oral administration has been demonstrated in several animal species.

CYP2D6 genotyping as an alternative to phenotyping for determination of metabolic status in a clinical trial setting.

The emerging application of pharmacogenomics in the clinical trial setting requires careful comparison with more traditional phenotyping methodologies, particularly in the drug metabolism area where phenotyping is used extensively. The research objectives of this study were 1) to assess the utility of cytochrome P450 2D6 (CYP2D6) genotyping as an alternative to traditional phenotyping as a predictor of poor metabolizer status; 2) to identify issues for consideration when implementing CYP2D6 genotyping in clinical trials; and 3) to outline the advantages and disadvantages of CYP2D6 genotyping compared with phenotyping. DNA samples obtained from 558 previously phenotyped individuals were blindly genotyped at the CYP2D6 locus, and the genotype-phenotype correlation was then determined. The CYP2D6 genotyping methodology successfully predicted all but 1 of the 46 poor metabolizer subjects, and it was determined that this 1 individual had a novel (presumably inactive) mutation within the coding region. In addition, we identified 2 subjects with CYP2D6 genotypes indicative of poor metabolizers who had extensive metabolizer phenotypes as determined by dextromethorphan/dextrorphan ratios. This finding suggests that traditional phenotyping methods do not always offer 100% specificity. Our results suggest that CYP2D6 genotyping is a valid alternative to traditional phenotyping in a clinical trial setting, and in some cases may be better. We also discuss some of the issues and considerations related to the use of genotyping in clinical trials and medical practice.

Pharmacokinetics of nilvadipine after single oral doses in healthy volunteers.

Forty healthy male Caucasian volunteers were randomly assigned to five treatment groups to receive a placebo or a 4, 8, 12, 16 or 20 mg dose of nilvadipine. The drug was well tolerated by the subjects at all dose levels. Pharmacokinetic parameters for nilvadipine were determined using model-independent methods. There were no significant differences (p greater than 0.05) in the time to the maximum plasma concentration (Cmax) (tmax), the elimination half-life or the mean residence time among the five treatment groups. Up to doses of about 12 mg, there was a linear relationship between dose and Cmax or area under the plasma concentration-time curve (AUCO----infinity). At doses of 16 and 20 mg, the relationship between dose and Cmax or AUCO----infinity was no longer linear, suggesting that the pharmacokinetics of the drug after single oral doses greater than about 12 mg may be dose-dependent, probably due to concentration-dependent first-pass hepatic elimination of the drug.

Liquid-chromatographic determination of five orally active cephalosporins--cefixime, cefaclor, cefadroxil, cephalexin, and cephradine--in human serum.

We report an isocratic "high-performance" liquid-chromatographic (HPLC) procedure for measurement of five orally administered cephalosporins (cefixime, cefaclor, cefadroxil, cephalexin, and cephradine) in 0.1 mL of human serum. Serum protein is precipitated with acetonitrile, the sample is centrifuged, and the supernate is evaporated under nitrogen. The residue is reconstituted in 0.1 mL of mobile phase, and 50 to 80 microL of this is injected onto a reversed-phase Altex Ultrasphere Octyl (C8) column. The five cephalosporins are resolved by elution with a pH 2.6 mobile phase of methanol/monobasic phosphate buffer (20/80) by vol), flow rate 2 mL/min. The column effluent is monitored at 240 nm. Cefixime serves as the internal standard for the analysis of the four other compounds, cephalexin as the internal standard for cefixime. We used two standard curves for all compounds: a low-range curve for concentrations commonly observed clinically and a higher-range curve for higher concentrations. The former were linear from 1.0 to 10 mg/L for cefaclor, cefadroxil, cephalexin, and cephradine and from 0.1 to 1 mg/L for cefixime. The high-concentration curves were linear from 1 to 10 mg/L for cefixime and from 10 to 100 mg/L for the other compounds. The detection limits were 0.1 mg/L for cefixime, 1 mg/L for the other cephalosporins. Mean within-run and day-to-day CVs were always less than 15% for all compounds studied.

Pharmacokinetics of cefixime after oral and intravenous doses in dogs: bioavailability assessment for a drug showing nonlinear serum protein binding.

Cefixime is a new oral cephalosporin which shows dose dependent absorption and concentration dependent serum protein binding in dogs. To study the absolute bioavailability of this drug in dogs, intravenous infusions of 6.25 and 25 mg/kg (each given over 2 hours), approximating the rate of appearance of the drug also given after oral dosing (12.5 and 50 mg/kg) were administered on separate occasions. The mean respective pharmacokinetic parameters obtained after the two intravenous infusions (6.25 and 25 mg/kg) were: total body clearance 4.0 and 5.2 mL/min; volume of distribution 2.2 and 2.8 L; and terminal half-lives of 6.4 hrs. Serum concentrations and area under the serum concentration time curve (AUC) after the low intravenous and oral dose were similar. At the higher doses, serum concentrations and AUC values were significantly higher after the intravenous infusion than after the oral dose. The mean absolute bioavailability (F) values after the 12.5 and 50 mg/kg oral doses using serum AUC comparisons were 52 and 58%, respectively, when calculated against the 6.25 mg/kg intravenous dose and 73 and 38%, respectively, when calculated against the 25 mg/kg intravenous dose. Based on urinary recovery data, F was 49 or 43% for the 12.5 mg/kg oral dose and 34 or 30% for the 50 mg/kg oral dose, depending on the reference intravenous dose used. These results show that because of nonlinearities in the pharmacokinetics of cefixime in the dog, comparison of AUC values obtained after oral doses to AUC values derived following intravenous administration of the drug may result in inaccurate bioavailability estimates if the concentration ranges after the two routes of administration are substantially different. Since the clearance of the drug is concentration-dependent, the absolute bioavailability of the drug must, therefore, be estimated under conditions where serum concentrations obtained after oral and intravenous doses are similar. In summary, for a drug like cefixime which shows nonlinear pharmacokinetics in the dog, estimations of absolute bioavailability, can be more accurately made using urinary excretion data.

A novel quantitative method for determining the biodistribution of radiolabeled xenobiotics using whole-body cryosectioning and autoradioluminography.

A novel method is described for quantitative whole-body autoradioluminography using [14C]-radioactive standards prepared from rat red blood cells. MicroComputer Imaging Device model 2 (MCID) and ImageQuant (IQ) imaging systems were evaluated for imaging performance and autoradioluminography quantitation. Weighted linear regression analysis resulted in linearity over five orders of magnitude with a lower limit of quantitation of 2.7 nCi/g. Using IQ, 16 days were necessary for image analysis and data processing of 30 whole-body cryosections and 1080 standards. MCID reduced the image and data processing of the same cryosections and standards to only 4 days. Embedding a series of radioactive standards with each specimen in the same carboxymethyl cellulose block provided an effective method of assessing intrasection and intersection variations in thickness of whole-body cryosections. These results demonstrated that autoradioluminography provided a sensitive, accurate, precise and reproducible method for the quantitative measurement of the tissue distribution of [14C]-radiolabeled xenobiotics in whole-body cryosections. Evaluating the biodistribution of [14C]-xenobiotics by autoradioluminography, not only provides pharmacokinetic data required for predicting the potential tissue deposition of an absorbed dose of radioactivity in man, but also allows for visual and quantitative evaluation of radioactivity in small anatomical structures that otherwise could not be detected or measured by conventional tissue combustion technology.

Changes in tissue concentrations of 14C-doxorubicin caused by mitoxantrone, mithramycin A and vinblastine in the rat.

The purpose of this study was to determine if mitoxantrone (a new antineoplastic drug) and two other anticancer agents (mithramycin A and vinblastine) could result in changes in the tissue distribution and disposition of doxorubicin in rats. Each of 16 male rats received 1 mg/kg of 14C-labeled doxorubicin on day one and received either saline, or doses of 4 mg/kg of mitoxantrone, 1.7 mg/kg of mithramycin A or 2.9 mg/kg of vinblastine on day three. All rats were sacrificed on day eight. Concentrations of radioactivity in the heart, lung, kidney and muscle were higher in the mitoxantrone treated rats than in the controls. Mithramycin A decreased the concentrations of radioactivity in liver, kidney and fatty tissues, while vinblastine increased the concentrations in heart, liver, lung, muscle and skin. In summary, mithramycin A, vinblastine and mitoxantrone caused a change in tissue concentrations of radioactivity of doxorubicin and/or its metabolites following a single I.V. dose of 14C-labeled doxorubicin in rats. This may cause elevated plasma concentrations of doxorubicin. These findings in the rat could theoretically have implications regarding doxorubicin therapy in man.

In vitro protein binding interaction studies involving cefixime.

Cefixime is a new oral cephalosporin currently undergoing clinical trials. Selected agents with the likelihood for coadministration with cefixime in man were examined for their influence on the in vitro binding of cefixime in pooled serum from dog, monkey, and man. Results from these experiments showed no significant change in cerfixime binding in any animal species studied or in man by acetaminophen, heparin, phenytoin, diazepam, ibuprofen or furosemide at their maximum reported therapeutic concentrations. In contrast, both salicylic acid and probenecid resulted in concentration-dependent increases in the free fraction of cefixime (up to 2.5-fold). These findings demonstrate the usefulness of in vitro protein binding screening procedures for studying potential drug interactions that are mediated, at least in part, by changes in the protein binding of a drug.

A technique to study hepatic and intestinal drug metabolism separately in the dog.

A model to study hepatic and intestinal drug metabolism in the dog has been evaluated. The model is made by performing a portacaval transposition, cholecystectomy and inserting a Thomas cannula into the duodenum. The result is a healthy animal in which drugs can be infused either in a normal i.v. (forelimb) fashion, directly into the liver (hindlimb) or given orally. Blood can be sampled from a peripheral vein, peripheral artery or hepatic vein. Bile and urine can be collected continuously. Pharmacokinetics can be studied in awake, unmedicated animals. The model can be used to assess oral, i.v. or hepatic infusion of drugs and their hepatic, intestinal or pulmonary metabolism.

Lack of gastrointestinal metabolism of propranolol in dogs after portacaval transposition.

We studied whether or not propranolol underwent presystemic metabolism in the gastrointestinal wall in five dogs. The dogs were studied before and four weeks after creation of a portacaval transposition. Before surgery, systemic bioavailability of the oral dose was 8 +/- 8% (mean +/- S.D.), whereas after transposition the bioavailability was 102 +/- 9%. The systemic plasma clearance increased from 766 +/- 192 to 976 +/- 280 ml/min. The terminal half life and apparent volume of distribution after transposition were not significantly different from those obtained preoperatively. Our results indicate that there is complete absorption but no metabolism of propranolol by the gastrointestinal wall.

Determination of cefixime in biological samples by reversed-phase high-performance liquid chromatography.

A simple, accurate and precise isocratic reversed-phase high-performance liquid chromatographic method has been developed and validated for the determination of a new cephalosporin in human serum and urine. Human serum samples, calibration standards and quality control samples (250 microliter) were combined with an equal volume of 6% trichloroacetic acid (TCA). Human urine (0.1 ml) was combined with 6% TCA solution containing the internal standard. The compounds were detected by ultraviolet absorbance set to 280 nm for the serum assay and 313 nm for the urine assay. The method for the determination of cefixime in serum was linear from 100 ng/ml to 30.0 micrograms/ml (r = 0.999), and for the urine assay from 5 micrograms/ml to 100 micrograms/ml (r = 0.999). The minimum reportable quantity for the serum assay was 0.05 microgram/ml. The within- and between-day assay variation for both assays were found to be less than 10% in an extensive assay validation scheme. Results of a storage stability study indicated that human serum and urine samples could be safely stored for up to six months at -18 degrees C and three months at -10 degrees C, respectively.