Harmonic Mean Elimination Half-life Research Articles

Pharmacokinetics, Safety, and Tolerability of Cedirogant in Healthy Japanese and Chinese Adults.

Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma, thymus (RORγt) developed for treatment of psoriasis. This study aimed to characterize pharmacokinetics, pharmacodynamics, safety, and tolerability of cedirogant following a single oral dose in Japanese participants and multiple oral doses in Japanese and Chinese participants. The single doses evaluated in healthy Japanese participants were 75, 225, and 395mg. The multiple doses evaluated in both healthy Japanese and Chinese participants was 375mg once daily for 14 days. Cedirogant plasma exposure increased dose proportionally with administration of single doses. Maximum cedirogant plasma concentration was reached within a median time of 4-5 hours after dosing. The harmonic mean elimination half-life ranged from 19 to 25 hours. Cedirogant pharmacokinetics were similar between Japanese and Chinese participants. Compared with healthy Western participants in a cross-study analysis, steady-state cedirogant plasma exposure was 38%-73% higher in Japanese or Chinese participants. Ex vivo interleukin-17 inhibition increased in a dose-dependent manner and was maximized by 375mg once-daily doses. The cedirogant regimens tested were generally well tolerated, and no new safety issues were identified. The results supported enrollment of Japanese and Chinese subjects in subsequent clinical trials for cedirogant.

Pharmacokinetics of detomidine following intravenous or oral-transmucosal administration and sedative effects of the oral-transmucosal treatment in dogs.

To determine the pharmacokinetics of detomidine hydrochloride administered IV (as an injectable formulation) or by the oral-transmucosal (OTM) route (as a gel) and assess sedative effects of the OTM treatment in healthy dogs. 12 healthy adult dogs. In phase 1, detomidine was administered by IV (0.5 mg/m(2)) or OTM (1 mg/m(2)) routes to 6 dogs. After a 24-hour washout period, each dog received the alternate treatment. Blood samples were collected for quantification via liquid chromatography with mass spectrometry and pharmacokinetic analysis. In phase 2, 6 dogs received dexmedetomidine IV (0.125 mg/m(2)) or detomidine gel by OTM administration (0.5 mg/m(2)), and sedation was measured by a blinded observer using 2 standardized sedation scales while dogs underwent jugular catheter placement. After a l-week washout period, each dog received the alternate treatment. Median maximum concentration, time to maximum concentration, and bioavailability for detomidine gel following OTM administration were 7.03 ng/mL, 1.00 hour, and 34.52%, respectively; harmonic mean elimination half-life was 0.63 hours. All dogs were sedated and became laterally recumbent with phase 1 treatments. In phase 2, median global sedation score following OTM administration of detomidine gel was significantly lower (indicating a lesser degree of sedation) than that following IV dexmedetomidine treatment; however, total sedation score during jugular vein catheterization did not differ between treatments. The gel was subjectively easy to administer, and systemic absorption was sufficient for sedation. Detomidine gel administered by the OTM route provided sedation suitable for a short, minimally invasive procedure in healthy dogs.

Effect of sub-anesthetic xylazine and ketamine (’ketamine stun’) administered to calves immediately prior to castration

ObjectiveTo describe the pharmacokinetics, cortisol response and behavioral changes associated with administration of sub-anesthetic xylazine and ketamine prior to castration. Study designProspective, randomized experiment. AnimalsTwenty-two male beef calves (260-310 kg). MethodsCalves were randomly assigned to receive the following treatment immediately prior to surgical or simulated castration; 1) uncastrated, placebo-treated control (CONT) (n = 4), 2) Castrated, placebo treated control (CAST) (n = 6), 3) castrated with intravenous xylazine (X) (0.05 mg kg−1) (n = 6), and 4) castrated with IV xylazine (X) (0.05 mg kg−1) combined with ketamine (K) (0.1 mg kg−1) (n = 6). Blood samples collected over 10 hours post-castration were analyzed by LC-MS-MS for drug concentrations and chemiluminescent immunoassay for cortisol determination. ResultsDrug concentrations during the first 60 minutes post-castration fit a one-compartment open model with first-order elimination. The harmonic mean elimination half-lives (± pseudo SD) for X, X with K and K were 12.9 ± 1.2, 11.2 ± 3.1 and 10.6 ± 2.8 minutes, respectively. The proportion of the total area under the effect curve (AUEC) for cortisol during this period was significantly lower in the X group (13 ± 3%; p = 0.006) and the X+K group (14 ± 2%; p = 0.016) compared with the CAST calves (21 ± 2%). However, after 300 minutes the AUEC in the X group was higher than CAST. Significantly more calves demonstrated attitude that was unchanged from pre-manipulation behavior in the CONT (p = 0.021) and X+K treated calves (p = 0.0051) compared with the CAST calves. ConclusionsBehavioral changes and lower serum cortisol concentrations during the first 60 minutes post-castration were associated with quantifiable xylazine and ketamine concentrations. Clinical relevanceLow doses of xylazine and ketamine administered immediately prior to castration may offer a safe, efficacious and cost-effective systemically administered alternative or adjunct to local anesthesia.

Age-Dependent Pharmacokinetics of Lansoprazole in Neonates and Infants

Evidence suggests that age may affect the pharmacokinetics of lansoprazole in pediatric patients, but little information is available in neonates and infants. To determine the pharmacokinetics of lansoprazole in neonates and infants <1 year of age with gastroesophageal reflux disease (GERD)-associated symptoms. Two single- and repeated-dose, randomized, open-label, multicenter studies were conducted. Studies involved a pretreatment period of 7 or 14 days, a dose administration period of 5 days, and a follow-up period of 30 days for adverse events collection. The studies were conducted in both hospital and private clinic settings. The studies were performed in 24 neonates (aged <or=28 days) and 24 infants (aged >28 days, but <1 year) with GERD-associated symptoms diagnosed by medical history and the clinical judgment of the treating physician. Participants received lansoprazole 0.5 or 1.0 mg/kg/day (neonates) or 1.0 or 2.0 mg/kg/day (infants) for 5 days. Plasma pharmacokinetic parameters on dose administration day 1 were calculated, and plasma concentrations on day 5 were obtained. The pharmacokinetics of lansoprazole were approximately dose proportional. After a single dose in neonates, the mean maximum plasma concentrations (C(max)) were 831 and 1672 ng/mL, and the mean area under the plasma concentration-time curve (AUC) values were 5086 and 9372 ng . h/mL for lansoprazole doses of 0.5 and 1.0 mg/kg, respectively. The time to C(max) (t(max)) [3.1 hours] and harmonic mean terminal elimination half-life (t((1/2))) [2.8 hours] were slightly longer in neonates receiving 0.5 mg/kg than the t(max) (2.6 hours) and t((1/2)) (2.0 hours) values observed in neonates receiving 1.0 mg/kg. Mean oral clearance (CL/F) was identical for the two doses (0.16 L/h/kg). After a single 1.0 or 2.0 mg/kg dose in infants, the lansoprazole C(max) values were 959 and 2087 ng/mL and the mean AUC values were approximately 2203 and 5794 ng . h/mL, respectively. The mean t(max) and mean t((1/2)) were 1.8 hours and 0.8 hours, respectively, for both doses (1.0 or 2.0 mg/kg), while mean CL/F was 0.71 and 0.61 L/h/kg, respectively. In both patient groups, mean plasma concentrations on day 5 were similar to day 1 concentrations. No clinically meaningful accumulation was observed following 5 days' dose administration. Plots of lansoprazole pharmacokinetics against chronologic age showed that dose-normalized C(max), t((1/2)), and AUC were two, three, and five times higher, respectively, in study participants aged <or=10 weeks than in study participants aged >10 weeks-1 year. Lansoprazole was well tolerated in all patients. The pharmacokinetics of lansoprazole in pediatric patients are age dependent, with those aged <or=10 weeks showing higher plasma exposure and lower plasma clearance than those aged >10 weeks-1 year. Thus, pediatric patients aged <or=10 weeks require a lower dose of lansoprazole than pediatric patients aged >10 weeks to achieve similar plasma exposure.

Pharmacokinetics, Pharmacodynamics and Safety of Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase, in a Dose Escalation Study in Healthy Subjects

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase currently being developed for the management of hyperuricemia in patients with gout. To investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects. In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240 mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3-14. During the course of the study, blood and urine samples were collected to assess the pharmacokinetics of febuxostat and its metabolites, and its pharmacodynamic effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study. Orally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5-1.3 hours. The pharmacokinetics of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10-120 mg dose range, with a mean apparent total clearance of 10-12 L/h and an apparent volume of distribution at steady state of 33-64 L. The harmonic mean elimination half-life of febuxostat ranged from 1.3 to 15.8 hours. The increase in the area under the plasma concentration-time curve of febuxostat at doses >120 mg appeared to be greater than dose proportional, while the febuxostat maximum plasma drug concentration was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22-44% of the dose) and oxidation (2-8%) with only 1-6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% (net change: 1.34-3.88 mg/dL) for all doses and was dose linear for the 10-120 mg/day dosage range. The majority of adverse events were mild-to-moderate in intensity. Febuxostat was well tolerated at once-daily doses of 10-240 mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10-120 mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.

PHARMACOKINETICS OF ENROFLOXACIN AFTER SINGLE-DOSE ORAL AND INTRAVENOUS ADMINISTRATION IN THE AMERICAN ALLIGATOR (ALLIGATOR MISSISSIPPIENSIS)

The pharmacokinetics of enrofloxacin administered orally and i.v. to American alligators (Alligator mississippiensis) at 5 mg/kg was determined. Plasma levels of enrofloxacin and its metabolite ciprofloxacin were measured using high-performance liquid chromatography and the resulting concentration versus time curve analyzed using compartmental modeling techniques for the i.v. data and noncompartmental modeling techniques for the oral data. A two-compartment model best represented the i.v. data. Intravenous administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 4.19 +/- 4.23 microg/ml at time zero, with average plasma drug levels remaining above 1.0 microg/ml for an average of 36 hr. Plasma volume of distribution for i.v. enrofloxacin was 1.88 +/- 0.96 L/kg, with a harmonic mean elimination half-life of 21.05 hr and mean total body clearance rate of 0.047 +/- 0.021 L/hr/kg. Plasma levels of p.o. enrofloxacin remained below 1.0 microg/ml in all test animals, and average concentrations ranged from 0.08 to 0.50 microg/ml throughout the sampling period. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of 0.50 +/- 0.27 microg/ml at 55 +/- 29 hr after administration, with a harmonic mean terminal elimination half-life of 77.73 hr. Minimal levels of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration, with concentrations below minimum inhibitory concentrations for most susceptible organisms. On the basis of the results of this study, enrofloxacin administered to American alligators at 5 mg/kg i.v. q 36 hr is expected to maintain plasma concentrations that approximate the minimum inhibitory concentration for susceptible organisms (0.5 microg/ml). Enrofloxacin administered to American alligators at 5 mg/kg p.o. is not expected to achieve minimum inhibitory values for susceptible organisms.

PHARMACOKINETIC DISPOSITION OF A LONG-ACTING OXYTETRACYCLINE FORMULATION AFTER SINGLE-DOSE INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATIONS IN THE AMERICAN ALLIGATOR (ALLIGATOR MISSISSIPPIENSIS)

The pharmacokinetics of a long-acting oxytetracycline preparation administered i.v. and i.m. to American alligators (Alligator mississippiensis) at 10 mg/kg was determined. Plasma levels of oxytetracycline were measured using high-performance liquid chromatography, and the resulting concentration versus time curve was analyzed using compartmental modeling and noncompartmental modeling techniques for i.v. and i.m. samples, respectively. A two-compartment model best represented the i.v. data. Intravenous administration of oxytetracycline resulted in an extrapolated mean plasma concentration at time zero of 60.63 +/- 28.26 microg/ml, with average plasma drug levels of 2.82 +/- 0.71 microg/ml at the end of the 192-hr sampling period. Plasma volume of distribution for i.v. oxytetracycline was 0.20 +/- 0.09 L/kg, with a harmonic mean elimination half-life of 15.15 hr and mean total body clearance rate of 0.007 +/- 0.002 L/hr/kg. Intramuscular administration of oxytetracycline achieved a mean peak plasma concentration of 6.85 +/- 1.96 microg/ml at 1 hr after administration, with average plasma drug levels of 4.96 +/- 1.97 microg/ml at the end of the 192-hr sampling period. The harmonic mean terminal elimination half-life for i.m. oxytetracycline was 131.23 hr. Based on the results of this study, long-acting preparations of oxytetracycline administered parenterally to American alligators at 10 mg/kg q 5 days is expected to maintain plasma concentrations above the minimum inhibitory concentration of 4.0 microg/ml for susceptible organisms.

The pharmacokinetics of ketamine after a continuous infusion under halothane anaesthesia in horses

The pharmacodynamics and pharmacokinetics of ketamine, when administered by infusion as an adjunct to halothane anaesthesia in horses, were investigated in 5 equine patients presented for routine castration. Anaesthesia was induced with detomidine, 20 μg/kg, followed by ketamine, 2.2 mg/kg bwt, the trachea intubated and the horses allowed to breathe halothane in oxygen. Five minutes later, a constant rate infusion of ketamine, 40 μg/kg min, was commenced and the halothane vaporiser concentration adjusted to maintain a light plane of anaesthesia. The mean infusion duration was 62 min (range 40–103). The ketamine was switched off approximately 15 min before the halothane. Plasma ketamine and norketamine levels, determined by high performance liquid chromatography, ranged from 0.74–2.04 μg/ml and 0.15–0.75 μg/ml, respectively, during the infusion period. The harmonic mean elimination half-life of ketamine was 46.1 min, mean volume of distribution at steady state (Vdss) was 1365 (271) ml/kg, mean body clearance (Cl) was 32.3 (9.1) ml/min.kg, and average mean residence time for the infusion (MRTinf) was 105.9 (20.4) min, respectively. Following termination of halothane, mean times to sternal recumbency and standing were 21.1 (6.9) and 41.6 (17.0) min, respectively. Surgical conditions were considered highly satisfactory, and physiological parameters were well preserved in most animals.

Clinical pharmacokinetic characterization of norfloxacin nicotinate in swine following systemic administration.

Norfloxacin nicotinate (NFN) is a new water-soluble fluoroquinolone antibacterial agent. The in vitro activity of NFN for microorganisms isolated from swine and the pharmacokinetic properties of NFN following single intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration were investigated. The minimal inhibitory concentrations (MIC's) of NFN for a wide range of reference (ATCC-American Type Culture Collection) microbial swine isolates, comprising 21 bacterial and 5 mycoplasmal species, ranged between 0.03 micrograms/ml (for Salmonella cholerasuis and Actinobacillus pleuropneumonia) and 12.5 micrograms/ml (for Streptococcus porcinus). The MIC of NFN for Mycoplasma hyopneumoniae, the causative agent of enzootic pneumonia of pigs, was < 1.0 microgram/ml although M. hyosynoviae was less sensitive, with a MIC value of 3.12 micrograms/ml. The MIC values of the drug for swine field isolates, comprising 8 bacterial species, were in good agreement with the values determined for the corresponding ATCC strains. Pharmacokinetic values for NFN were calculated following i. v. administration at 7.0 mg/kg and i. m. and s. c. administration at 14.0 mg/kg in a 3-way cross over study involving 6 pigs. Plasma concentrations of unchanged drug were determined by HPLC during 24 h post injection. Plasma NFN concentrations measured after i.v. dosing best fitted a 2-compartment open system pharmacokinetic model. The harmonic mean distribution half-life (t1/2 alpha) and elimination half-life (t1/2 beta) were 4.2 minutes and 2.1 h, respectively. The mean residence time (MRT) was 2.9 +/- 0.6 h and the steady state volume of distribution (Vss) was 3.2 +/- 0.1 l/kg. The mean t1/2 beta values after either i. m. or s. c. administration were 4.45 h with very rapid absorption rates (< 15 min to peak plasma drug concentration). Bioavailability was 51-64%. Less than 20% and 25% of the dose were excreted in the urine as parent drug during the first 24 h after i.v. and s.c. dosing, respectively whereas the amount of unchanged drug recovered in the feces was very small (1.3 to 1.6% of the dose). The pharmacokinetic and MIC data generated in the course of the present study suggest that a dose schedule of 14.0 mg/kg injected i. m. or s. c. every 24 h is capable of achieving and maintaining tissue drug concentrations of potential therapeutic value for the treatment of the most common bacterial and mycoplasmal infections in swine.

Pharmacokinetics of metronidazole after rectal administration in horses

Summary Five healthy adult mares and 1 gelding were given a single dose (15 mg/kg of body weight) of metronidazole per rectum. After manual evacuation of feces from the rectum, a suspension of crushed tablets and water (40 ml) was administered via a 28-F catheter advanced 30 cm into the rectum. Blood samples were obtained by jugular venipuncture, and metronidazole concentration was measured serially for the 14 hours after drug administration. Mean serum concentration of metronidazole peaked at 4.5 μg/ml, 0.83 hour after administration, and decreased to 0.38 μg/ml, 14 hours after administration. Mean elimination rate constant was 0.23/h, and the harmonic mean elimination half-life was 3.04 hours. Further study is necessary to determine a therapeutic dose regimen for metronidazole administered per rectum.

Pharmacokinetics and biliary concentrations of fleroxacin in cholecystectomized patients

Patients with biliary tract infections received 800 mg of fleroxacin orally once daily on five consecutive days; cholecystectomy was on day 3. Starting on the day when dose 5 was administered, serial blood and T-drain bile samples were taken for 72 h and urine was collected for 96 h. The mean (+/- the standard deviation) peak concentration in plasma was 8.2 +/- 4.0 mg/liter at 8.3 h. The harmonic mean elimination half-life was 10.5 h, which is comparable to that reported for healthy volunteers. This increase resulted from reduced renal clearance (mean [+/- standard deviation], 38 +/- 22 ml/min), as the volume of distribution in the patients (1.4 +/- 0.7 liter/kg) did not differ from that reported for healthy subjects. Maximum concentrations in T-drain bile were high (median, 22.1 mg/liter) and exceeded those measured in plasma by a factor of 2 to 3; the individual ratios of the area under the curve for bile divided by that for plasma ranged from 1.3 to 9.9. As observed in healthy volunteers, the major pathway for elimination of fleroxacin was via the kidneys. The fraction of dose 5 eliminated in the 0- to 24-h urine was reduced, however, and the fraction of the dose in the urine as the N-demethyl and N-oxide metabolites was elevated. At the dose regimen used in this study, the MICs for most pathogens that cause biliary tract infections were surpassed in plasma and bile for more than 24 h.

Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals

We determined plasma methocarbamol concentrations over 24 h following a 1.5 g methocarbamol dose (off-dialysis day) to 8 chronic haemodialysis patients and compared these results to those from 17 healthy male volunteers. The harmonic mean elimination half-life was similar between the two groups, 1.24 and 1.14 h, respectively. tmax and the weight-adjusted Cmax were 1.1 h and 27.0 mg.m-1 for haemodialysis patients and 1.1 and 23.1 mg.l-1 for normals. Relative systemic availability was assessed by comparing weight-normalized AUC x k10 products. These results indicate no significant differences with respect to methocarbamol absorption, with the relative systemic availability in patients being 113%. These data suggest that absorption and elimination of methocarbamol is similar between normal subjects and patients undergoing maintenance haemodialysis.

Pharmacokinetics and pharmacodynamics of nifedipine in patients at steady state.

The pharmacokinetics and associated pharmacodynamics of nifedipine were studied at steady state in 12 patients with angina pectoris who were receiving nifedipine 10-40 mg tid. After dosing, serum nifedipine concentrations rose rapidly and decayed in a log-linear fashion. The mean (+/- SEM) maximum serum concentration (Cmax) after dose normalization, and the time to Cmax (tmax) were 115 +/- 7 ng/mL and 0.72 +/- 0.13 hr, respectively. The mean area under the plasma concentration-time curve per 10-mg dose was 304 +/- 34 hr-ng/mL. The average elimination rate constant was 0.205 +/- 0.016 hr, and the harmonic mean elimination half-life was 3.4 hr (range, 2.5-4.9 hr). Heart rate increased (5-6 beats/min, P less than .05) from baseline for up to one hour after dose, while mean diastolic blood pressure decreased (6-15 mm Hg, P less than .05) for up to four hours. Cardiac output was increased (1.1-2.8 L/min, P less than .05), and calculated total systemic resistance (3.8-6.3 mm Hg/L/min, P less than .05) was decreased for the entire dosing interval after nifedipine dosing. Hysteresis plots for heart rate and mean diastolic blood pressure showed a time lag between changes in serum nifedipine concentrations and heart rate, but not between serum nifedipine concentrations and blood pressure. Changes in cardiac output did not correlate with serum nifedipine concentrations. The steady-state kinetic and dynamic parameter values in patients with angina pectoris in this study were similar to those found in healthy volunteers or hypertensive patients after acute nifedipine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Intravenous Bepridil in Patients With Coronary Disease

The pharmacokinetics of intravenous bepridil (1-[2-(N-benzylanilino)-1-(isobutoxymethyl)ethyl]pyrrolidine) were studied in 16 patients undergoing cardiac catheterization for evaluation of coronary disease, all with normal base-line hemodynamic and renal functions. Ten patients received 3mg/kg and six patients received 4mg/kg of bepridil infused over a period of 30min. Plasma bepridil concentrations were measured by HPLC and analyzed by model-dependent and model-independent methods. The mean (± SD) maximum plasma bepridil concentrations at the end of the infusion were 2047 ± 820ng/mL (3mg/kg) and 2478 ± 1426ng/mL (4mg/kg). Postinfusion bepridil concentrations were best described by a two-compartment open model. The model-dependent harmonic mean distribution and elimination half-lives were 1.7h (range: 1.1–2.2 h) and 19.7h (range: 8.0–61.9 h), respectively. The harmonic mean elimination half-life from model-independent analysis was 14.9h (range: 7.4–64.0 h). The arithmetic means of other model-independent kinetic parameters were systemic clearance, 0.524 ± 0.215 L·kg−1·h−1; Vd, 15.3 ± 10.9L/kg; and Vdss, 10.1 ± 6.0L/kg. Model-dependent and model-independent estimates of half-life and clearance agreed reasonably well. Bepridil was well tolerated, effecting little or no change in central hemodynamics or EKG intervals. The extensive distribution and relatively slow clearance of bepridil account for its long elimination half-life. Intravenous bepridil appears to be a safe calcium (II) antagonist that is suitable for once-a-day dosing.

Single-dose ceftriaxone pharmacokinetics in pediatric patients with central nervous system infections

Ceftriaxone has greater in vitro and in vivo efficacy against many common bacteria than other third-generation cephalosporins. Single-dose ceftriaxone pharmacokinetics were studied in 17 patients, aged 0.6 to 52 months, with infections of the central nervous system. Patients received a randomized dose of 50 or 75 mg/kg ceftriaxone intravenously over 5 minutes on the second to fifth day of illness. Serial blood samples were collected over 24 hours in all patients, and cerebrospinal fluid (CSF) was obtained 1 to 4.5 hours after injection. Ceftriaxone mean peak plasma concentrations, determined by high-power liquid chromatography, were 267 and 184 microgram/ml for the 75 and 50 mg/kg dosage groups, respectively. The harmonic mean elimination half-life was 4.2 hours, and the mean percent drug penetrance into CSF was 4.8 +/- 3.5%. Of CSF studies evaluated, the glucose concentration was correlated most closely (inversely) with CSF penetration of ceftriaxone. Individual CSF concentrations of ceftriaxone exceeded the minimal inhibitory concentrations of the respective bacteria causing infection by 480 to 5,600 times. Ceftriaxone may be useful in the treatment of serious pediatric infections, including meningitis.

Pharmacokinetics of isotretinoin during repetitive dosing to patients.

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.

Influence of alcohol on the pharmacokinetics of diazepam controlled-release formulation in healthy volunteers.

Twelve normal volunteers were empanelled in an open-label, three-way crossover study to evaluate the influence of alcohol on the pharmacokinetics of controlled-release diazepam capsules. Each volunteer received one 15-mg diazepam controlled-release capsule alone, concomitantly with alcohol or followed by alcohol 2 hours later. The mean plasma concentration-time profiles following both alcohol treatments were superimposable on the profile from the control. The mean plateau concentrations were observed to endure from 2 through 12 hours in all cases. The mean +/- S.D. areas under the plasma concentration-time curves from time zero to infinity were similar indicating no difference in the extent of absorption of diazepam in the presence of alcohol. The harmonic mean elimination half-lives were also similar. Overall, the pharmacokinetics and the release properties of controlled-release diazepam capsule were not influenced by alcohol in normal volunteers.

Pharmacokinetics of isotretinoin following a single oral dose.

A pharmacokinetic profile was developed following oral administration of a single 100-mg oral dose of isotretinoin to 12 normal male volunteers. Concentrations of isotretinoin and its isomer, tretinoin, were measured in blood samples from 12 subjects and in urine and fecal samples from three of the 12 subjects. Blood concentration-time data during a 72-hour sampling interval were variable and, in five of the 12 cases, showed pronounced secondary and tertiary concentration maxima which were consistent with the theory of enterohepatic circulation (EHC) of isotretinoin in man. In five of the 12 subjects, adequate fits of the data could not be obtained using classical bi- or triexponential equations but were successfully fitted using a recently developed recycling model. Maximum blood concentrations of isotretinoin ranged from 74 to 511 ng/ml and occurred between 1 and 4 hours after dosing. Secondary maxima generally occurred between 6 and 24 hours after dosing. The harmonic mean elimination half-life was approximately 20 hours. These findings suggest that steady-state blood concentrations should be observed within one week. Negligible amounts of unchanged isotretinoin were excreted in urine, whereas 53 to 74 per cent of the dose was recovered as intact isotretinoin in the feces. The amount of intact drug in the feces could reflect biliary excretion of the conjugate of isotretinoin that is deconjugated beyond the site where absorption may occur, as well as unabsorbed drug.