Pharmacokinetics and pharmacodynamics of a novel nizatidine controlled-release formulation in healthy subjects

The pharmacokinetics and intragastric pH effects of a novel nizatidine controlled-release (CR) formulation were compared to a currently marketed immediate-release (IR) nizatidine formulation (Axid). The bimodal pulsatile release characteristics of nizatidine CR decreased its Cmax by approximately 42% compared to nizatidine IR while maintaining 90% relative bioavailability; tmax was approximately 1.6 times longer with the CR formulation. These characteristics enabled controlled-release nizatidine to sustain effective plasma drug concentrations for a greater duration than immediate-release nizatidine over the dosing intervals. In multiple doses, the 24-hour AUC ratio for all comparisons of nizatidine CR 150 mg bid, nizatidine CR 300 mg daily, and nizatidine IR 150 mg bid was between 97% and 99%. Mean pH AUC values for nizatidine CR 150 mg bid and nizatidine IR 150 mg bid were similar overall during the 0- to 14-hour and 14- to 24-hour dosing intervals. For the 14- to 24-hour dosing interval, nizatidine CR 150 mg maintained gastric pH over 3.0 and 4.0 for 42% and 27% of the time compared to 39% and 23% for nizatidine IR, respectively. Nizatidine CR 300 mg, compared to the 150-mg CR and IR regimens, had a greater effect on increasing evening intragastric pH, thus providing support for the potential utility of nizatidine CR 300 mg dosed at night in alleviating nocturnal symptoms of gastroesophageal reflux disease.     

Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients

This study was done to determine if the pharmacokinetics and gastric pH response of intravenous cimetidine are superior to oral dosing in seriously ill patients. A paired study of intravenous followed by oral liquid cimetidine was given to eight men and two women who were inpatients in a VA Hospital. Treatment was prescribed for either upper gastrointestinal (GI) bleeding or prophylaxis against GI bleeding. All patients received cimetidine 300 mg every 6 hours intravenously on day 1 and orally on day 2. After the fourth dose each day, venous blood samples and gastric pH measurements were taken serially for 6 hours. Peak serum cimetidine concentration was 2.0 +/- 0.5 mg/L for the intravenous dose and 1.5 +/- 0.3 mg/L for the oral dose (P = .001). Area under the curve (AUC) of cimetidine concentration was 3.81 +/- 1.1 mg/hr/L for the intravenous dose and 4.19 +/- 1.22 mg/hr/L for the oral dose (P greater than .30). Bioavailability (AUCpo/AUCiv) was 1.13 +/- 0.25, demonstrating complete oral absorption. The time during a 6-hour dosing interval that the gastric pH remained above 3.0 was 3.3 +/- 2.1 hours for the intravenous dose and 2.5 +/- 2.3 hours for the oral dose, P = .171). The time that the serum cimetidine concentration remained above 0.5 mg/L was 2.0 +/- 0.9 hours for the intravenous dose and 2.7 +/- 1.0 hours for the oral dose (P = .055). We concluded that bioavailability, time that gastric pH is maintained greater 3.0, and time that the serum cimetidine concentration is greater than 0.5 mg/L for intravenous cimetidine are not significantly different from oral cimetidine in seriously ill patients.     

Steady-state disposition of diflunisal: once- versus twice-daily administration

To evaluate the steady-state bioequivalence of the nonsteroidal antiinflammatory analgesic agent, diflunisal, administered once versus twice daily, 13 healthy volunteers received diflunisal as follows: 1000 mg at 8:00 AM and 500 mg at 8:00 AM and 8:00 PM, each for 14 days in a randomized crossover study. The mean (+/- SD) steady-state peak plasma concentrations were significantly greater after once-daily dosing (186 +/- 25 micrograms/ml vs 150 +/- 37 micrograms/ml; p less than 0.01). The time to peak concentration was also longer after the single-dose regimen (2.5 +/- 0.8 vs 1.9 +/- 0.9 hr; p less than 0.05). The regimens were similar with respect to the mean 24-hour area under the plasma concentration-time curve at steady state (2839 +/- 612 vs 2782 +/- 778 micrograms.hr.ml-1), steady-state plasma concentrations (118 +/- 25 vs 116 +/- 32 micrograms/ml), trough plasma concentration (85 +/- 27 vs 92 +/- 28 micrograms/ml) as well as 24-hour urinary excretion (776 +/- 79 vs 771 +/- 89 mg) of diflunisal. Based on urinary recoveries, the bioequivalence ratio (once vs twice daily) was 1.01 +/- 0.08. These results indicate that diflunisal administered once daily might offer comparable therapeutic effects but be more convenient than a twice-daily regimen.     

Effects of ranitidine, given t.d.s., on intragastric and oesophageal pH in patients with gastrooesophageal reflux

The purpose of this study was to determine the effects of 150 mg ranitidine, 300 mg ranitidine or placebo, administered every 8 h, on gastro-oesophageal pH and heartburn parameters in reflux patients. Twelve symptomatic reflux patients received each of the three treatments in a randomized, double-blind, crossover fashion. Intragastric and oesophageal pH were monitored continuously for a 24 h period. Meals were standardized, consumed at set times and patients were allowed to recline and sleep from 23.00 hours until 06.00 hours only. The gastric record was analysed for the percentage of time that the pH was greater than or equal to 4. The oesophageal record was analysed for acid contact time (percentage time (%) pH less than or equal to 4.0) and reflux episode frequency. Finally, patients recorded each new episode of heartburn and graded daytime heartburn severity at the end of each hour. Ranitidine increased the median (%) time that the intragastric pH remained at or above 4, from 4.5 (placebo) to 33.9% (150 mg dose) and 33.3% (300 mg dose). Ranitidine dose-dependently reduced the median 24-hour oesophageal acid contact time from 13.3% (placebo) to 6.8% (150 mg dose) and 2.5% (300 mg dose). The 300 mg dose significantly reduced daytime heartburn episode frequency and severity while the 150 mg dose reduced heartburn severity only. We conclude that 150 and 300 mg doses of ranitidine administered every 8 h have major, sometimes dose-dependent effects on the objective parameters and symptoms of gastro-oesophageal reflux.     

Comparative in vitro activity and pharmacodynamics of five fluoroquinolones against clinical isolates of Streptococcus pneumoniae

STUDY OBJECTIVE: To compare in vitro activity and pharmacodynamics of five fluoroquinolones against clinical isolates of Streptococcus pneumoniae. DESIGN: In vitro analysis. SETTING: University research laboratory. INTERVENTION: Minimum inhibitory concentrations (MICs) were determined for penicillin and five fluoroquinolones by E test for 201 S. pneumoniae isolates. Serum concentration-time profiles were simulated for the following regimens: ciprofloxacin 750 mg orally every 12 hours and 400 mg intravenously every 8 hours; levofloxacin 500 mg orally and intravenously every 24 hours; trovafloxacin 200 mg orally and intravenously every 24 hours; gatifloxacin 400 mg orally and intravenously every 24 hours; and clinafloxacin 200 mg orally and intravenously every 12 hours. MEASUREMENTS AND MAIN RESULTS: Free 24-hour areas under the serum concentration-time curves (AUC0-24) were calculated using the trapezoidal rule, and the average AUC0-24:MIC ratio was calculated for each regimen. Differences in ratios among agents were determined by analysis of variance (Scheffe post hoc test, p < 0.05). For intravenous dosing, the average AUC0-24:MIC for gatifloxacin, clinafloxacin, trovafloxacin, ciprofloxacin, and levofloxacin was 146, 142, 122, 71, and 61, respectively. For both oral and intravenous regimens, gatifloxacin and clinafloxacin ratios were significantly greater than those for trovafloxacin, levofloxacin, and ciprofloxacin (p < or = 0.007). Ratios for trovafloxacin were significantly greater than those for levofloxacin and ciprofloxacin (p < 0.0001), and levofloxacin and ciprofloxacin ratios were not significantly different from each other. CONCLUSION: Gatifloxacin and clinafloxacin achieve significantly higher AUC0-24:MIC ratios for S. pneumoniae than trovafloxacin, levofloxacin, and ciprofloxacin. Large comparative studies are necessary to determine the clinical significance of these findings.     

A comparison of esomeprazole and lansoprazole for control of intragastric pH in patients with symptoms of gastro-oesophageal reflux disease

BACKGROUND: Intragastric acid suppression is the most direct measure of the pharmacodynamic efficacy of proton pump inhibitors, which are the most effective drugs for acid-related diseases. AIM: To compare the effectiveness of once and twice daily dosing of lansoprazole and esomeprazole in controlling intragastric acidity (target gastric pH > 4.0) over a 24-hour period. METHODS: In an open-label, two-way crossover study, 45 Helicobacter pylori-negative patients with gastro-oesophageal reflux disease were randomized to receive one of two regimens: 30 mg lansoprazole or esomeprazole 40 mg once daily. Intragastric pH was assessed by 24-hour pH monitoring on day 5 of each regimen. Dosing was increased to twice daily and pH was reassessed on day 10. Following a 14-day washout, patients were crossed over to the other medication and the dosage regimens and pH assessments were repeated. RESULTS: Data were analysed from 35 patients who completed all scheduled assessments and had 24-hour monitoring for each end-point. Mean time pH > 4.0 and mean 24-hour pH were highest for esomeprazole 40 mg twice daily, followed by lansoprazole 30 mg twice daily, esomeprazole 40 mg once daily and lansoprazole 30 mg once daily. Esomeprazole 40 mg twice daily provided superior control of intragastric pH compared with either once or twice daily dosing of lansoprazole and once daily dosing of esomeprazole (P < 0.01). Esomeprazole 40 mg once daily was comparable with lansoprazole 30 mg twice daily and both were superior to lansoprazole 30 mg once daily (P < 0.01). CONCLUSIONS: Response to acid suppression treatment depends on the treatment selected. Esomeprazole 40 mg twice daily provided better control of intragastric pH than all other regimens evaluated. Esomeprazole 40 mg daily, however, was comparable with lansoprazole 30 mg twice daily and superior to lansoprazole 30 mg once daily.     

Early evening nizatidine intake with a meal optimizes the antisecretory effect

The importance of the temporal relationship between meal and nizatidine intake was studied in a six-armed, double-blind, placebo-controlled trial. Eleven healthy volunteers received early (18.00 hours) or late (21.00 hours) supper, with either placebo, early (18.00 hours) nizatidine, or late (21.00 hours) 300 mg nizatidine. Ambulatory 21-hour gastric pH-metry was performed and plasma nizatidine concentrations were determined by high pressure liquid chromatography. Early-nizatidine/early-supper (median pH 2.50), but not late-nizatidine/late supper (median pH 2.30), produced significantly higher median 21-hour pH values than did early-nizatidine/late-supper (median pH 1.90). Concomitant food delayed the absorption of nizatidine but did not change the drug's bioavailability. Oral nizatidine should be taken with food, preferably early in the evening, to optimize its anti-secretory effect.     

Pharmacokinetics and pharmacodynamics of oral nizatidine

Nizatidine was studied in six high-acid-secretor (basal secretion, greater than or equal to 5 mEq/hr) male volunteers in a randomized, double-blind, nonbalanced, cross-over, placebo and standard drug-controlled study. Doses of 75 mg, 150 mg, and 300 mg bid were compared with placebo and cimetidine 300 mg qid. Nocturnal acid output was significantly reduced (P less than .01) by all doses of nizatidine (36 +/- 22, 36 +/- 31, and 26 +/- 20 mEq) with 75 mg, 150 mg and 300 mg, respectively, and also by cimetidine (43 +/- 39 mEq) as compared with placebo (101 +/- 61 mEq). Nizatidine also significantly reduced meal-stimulated acid secretion at breakfast (14 +/- 9, 9 +/- 7, and 5 +/- 6 mEq/2 hours with 75 mg, 150 mg, and 300 mg, respectively, P less than .01), at lunch (50 +/- 22, 57 +/- 22 and 50 +/- 35 mEq/2 hours, P less than .05) but did not have any effect at dinner (65 +/- 16, 78 +/- 24, and 71 +/- 17 mEq/2 hours) whereas cimetidine, given every 6 hours, significantly (P less than .01) reduced meal-stimulated acid secretion (25 +/- 16, 27 +/- 20 and 31 +/- 15 mEq/2 hours, breakfast, lunch, and dinner, respectively) as compared with placebo (81 +/- 30, 76 +/- 25, and 66 +/- 16 mEq/2 hours, breakfast, lunch, and dinner, respectively). Both drugs have a similar pharmacokinetic profile. Nizatidine seems to be a promising H2 antagonist, more potent than cimetidine (on an mg/mg basis), and efficacy studies on gastric acid disorders should be performed.     

Greater immediate gastric acid suppression with lansoprazole 30 mg administered as a 2-minute intravenous bolus injection versus a 30-minute infusion

STUDY OBJECTIVE: To compare the pharmacokinetics, pharmacodynamics, and safety of lansoprazole administered as a 2-minute intravenous bolus injection versus a 30-minute continuous infusion. DESIGN: Phase I, open-label, randomized, crossover, single-center trial. SETTING: Clinical research facility. SUBJECTS: Thirty-eight healthy volunteers aged 18-55 years. INTERVENTION: Each subject received one of three regimens. Each regimen contained the same three treatments but in a different sequence: an intravenous injection of lansoprazole 30 mg/10 ml of normal saline over 2 minutes, an infusion of lansoprazole 30 mg/60 ml of normal saline over 30 minutes, and an intravenous injection of 10 ml of normal saline (placebo) over 2 minutes. Each treatment was administered once/day for 7 days, with a washout period of at least 5 days separating each one. MEASUREMENTS AND MAIN RESULTS: Blood samples were assayed for lansoprazole concentrations by using liquid chromatography with tandem mass spectrometry. After the 2-minute administration, mean peak lansoprazole concentrations were about 2-fold higher than those after the 30-minute administration on days 1 and 7. Lansoprazole area under the concentration versus time curve met criteria for bioequivalence on both days. Two-minute administration resulted in a greater percentage of time that the 24-hour pH was above 4 compared with the 30-minute administration (53% vs 47%, p=0.045), with comparable 24-hour integrated gastric acidity (114.4 vs 91.6 mmol*hr/L for 2-min vs 30-min, p=0.335). Significantly greater acid suppression occurred during the first hour after the 2-minute administration compared with that after the 30-minute administration (p < or = 0.001). Safety profiles were similar among the regimens. CONCLUSION: Greater immediate gastric acid suppression occurred after administration of lansoprazole 30 mg over 2 minutes than over 30 minutes, with other pharmacokinetic, pharmacodynamic, and safety profiles being similar.     

应用蒙特卡罗模拟优化哌拉西林/他唑巴坦的给药方案

目的：评价哌拉西林/他唑巴坦的延长输注和持续输注给药方案对革兰阴性杆菌的药效学。方法：测定本院2008年1月至2008年6月4种革兰阴性杆菌（大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌及铜绿假单胞菌）的MIC,应用10000例蒙特卡罗模拟（MCS）分析比较哌拉西林/他唑巴坦的延长输注（PI）、持续输注（CI）与传统给药方案的药效学目标到达。结果：对于大肠埃希菌和肺炎克雷伯菌,只有4.5gq6h（PI）的给药方案能达到90%以上的累积反应分数（CFR）,分别为98.4%、91.0%。对于鲍曼不动杆菌和铜绿假单胞菌,没有一种给药方案能达到最佳的CFR。持续输注给药方案9.0gCI与传统给药方案4.5gq8h相比,获得更高的CFR。4.5gq8h（PI）、4.5gq6h（PI）与传统给药方案相比,对4种革兰阴性杆菌获得更高的CFR。结论：哌拉西林/他唑巴坦延长输注及持续输注方案较常规方案更优,可作为临床的经验给药方案。     

Tobramycin pharmacokinetics in children with febrile neutropenia undergoing stem cell transplantation: once-daily versus thrice-daily administration

STUDY OBJECTIVE: To describe the pharmacokinetic disposition of tobramycin in children undergoing stem cell transplantation (SCT) after intravenous administration either every 24 hours or every 8 hours, and to use this information to create initial dosing guidelines for administration every 24 hours in this patient population. DESIGN: Pharmacokinetic analysis of a randomized controlled trial. SETTING: The Hospital for Sick Children, Toronto, Ontario, Canada. PATIENTS: Sixty children (< 18 yrs) with febrile neutropenia undergoing stem cell transplantation. INTERVENTION: Patients were randomized to receive intravenous tobramycin either every 24 hours (29 patients) or every 8 hours (31 patients). Initially, they received either 2.5 mg/kg/dose every 8 hours or weight-based doses by age group (< 5 yrs, 9 mg/kg/dose; 5 to < 12 yrs, 8 mg/kg/dose; > or = 12 yrs, 7 mg/kg/dose) every 24 hours. MEASUREMENTS AND MAIN RESULTS: Serum tobramycin concentrations were obtained at 2 and 8 hours after the first dose. Initial guidelines for dosing every 24 hours were derived using the parameters from all patients to achieve a maximum serum concentration (Cmax) of 20-22.5 mg/L and a drug-free interval (time during dosing interval when the tobramycin concentration was < 1 mg/L) of at least 4 hours. After the first tobramycin dose, the elimination rate constant (kel) and volume of distribution (Vd) observed in the every-8-hour group (23 patients) were 0.34 +/- 0.09 hours(-1) and 0.48 +/- 0.21 L/kg, respectively. The kel and Vd in the every-24-hour group (22 patients) were 0.43 +/- 0.12 hr(-1) and 0.43 +/- 0.26 L/kg, respectively. Tobramycin Vd varied with age. Initial doses of tobramycin every 24 hours recommended to achieve the target parameters are 10 mg/kg/dose for patients aged 6 months to less than 9 years, 8 mg/kg/dose for those aged 9 to less than 12 years, and 6 mg/kg/dose for those aged 12 years or older. CONCLUSION: Children undergoing SCT who receive tobramycin every 24 hours should receive an initial dose based on age. Further validation of the proposed dosing guidelines is required.     

Lack of effect of nizatidine-induced elevation of gastric pH on the oral bioavailability of dapsone in healthy volunteers

STUDY OBJECTIVE: To investigate the effect of histamine2 (H2)-receptor antagonist-induced elevation of gastric pH on oral bioavailability of a single dose of dapsone 100 mg. DESIGN: Prospective, randomized, crossover, open-label, single-dose pharmacokinetic study. SETTING: Teaching hospital. PATIENTS: Sixteen men were enrolled in the study; data from 11 subjects were evaluable. INTERVENTIONS: Participants received two treatments separated by at least 14 days. Treatment A consisted of a single dose of dapsone 100 mg. Treatment B consisted of a single dose of dapsone 100 mg plus two doses of oral nizatidine 300 mg administered 3-4 hours apart to maintain gastric pH above 6.0. Plasma samples collected before and up to 120 hours after dapsone administration were analyzed for dapsone and monoacetyldapsone (MADDS) by high-performance liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. MEASUREMENTS AND MAIN RESULTS: Gastric pH in the first 6 hours after dapsone administration was above 6.0 for a mean +/- SD of 1.1% +/- 2.9% of the time in the absence of nizatidine and 69.5% +/- 18.0% of the time during nizatidine therapy. The geometric mean dapsone maximum plasma concentration (Cmax) declined by 13% (p<0.01), and median time to Cmax occurred 2 hours later (p<0.01) with nizatidine coadministration compared with dapsone alone. Inclusion of the 90% confidence interval for the mean Cmax ratio within the equivalence interval of 0.8-1.25 demonstrated the lack of clinical significance for this modest decrease in Cmax. Neither the area under the dapsone plasma concentration-time curve from zero to infinity nor the elimination half-life of dapsone were significantly altered by nizatidine. No clinically significant changes were observed in the pharmacokinetics of MADDS with regard to coadministration of nizatidine. CONCLUSION: Elevation of gastric pH by H2-receptor antagonists, such as nizatidine, does not result in clinically important changes in the rate or extent of oral dapsone absorption.     

Pharmacokinetics and pharmacodynamics of AR9281, an inhibitor of soluble epoxide hydrolase, in single- and multiple-dose studies in healthy human subjects

AR9281, a potent and selective inhibitor of soluble epoxide hydrolase (s-EH), is in clinical development targeting hypertension and type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamics of AR9281 were evaluated in double-blind, randomized, placebo-controlled, ascending, single oral dose (10-1000 mg) and multiple dose (100-400 mg every 8 hours for 7 days) studies in healthy subjects. AR9281 was well tolerated, and no dose-related adverse events were observed during either study. The drug was rapidly absorbed with a mean terminal half-life ranging from 3 to 5 hours. The area under the plasma concentration-time curve increased in an approximately dose-proportional manner up to the 500-mg dose and exhibited a greater than dose linearity at higher doses. AR9281 directly and dose-dependently inhibited blood s-EH activity with 90% inhibition or greater over an 8-hour period at the 250-mg dose and over a 12-hour period at the 500-mg dose. Multiple doses of AR9281 ranging from 100 to 400 mg every 8 hours resulted in a sustained inhibition of s-EH activity at 90% or greater during the trough. The current studies provide proof of safety and target inhibition of AR9281 in healthy subjects. AR9281 pharmacokinetic and pharmacodynamic characteristics support a twice-daily or thrice-daily dosing regimen in patients.     

Single-dose pharmacokinetics of nizatidine (Axid) in children

The pharmacokinetics of nizatidine following a single 5.0 mg/kg oral dose given as an extemporaneous liquid formulation in apple juice was examined in 12 healthy children (8.0 +/- 2.4 years, 30.7 +/- 8.4 kg). Nizatidine and N-desmethylnizatidine were quantitated by HPLC/MS from five post dose blood samples taken over a 12-hour period. The apparent terminal elimination rate constant for nizatidine in the pediatric subjects (0.58 +/- 0.8h(-1)) was virtually identical to that (0.54 +/- 0.13 h(-1)) previously reported from adult studies. When corrected for an estimated 30% reduction in nizatidine oral bioavailability observed in adults upon coingestion of the drug with other fruit/vegetable juices, nizatidine pharmacokinetic parameter estimates (e.g., Cmax, CL/F, Vss/F) in our pediatric subjects were similar to those previously reported in adults who were administered dimensionally similar (e.g., approximately 4 mg/kg) solid oral doses of the drug. Examination of the mean area under the curve (i.e., AUC0-infinity for nizatidine and N-desmethylnizatidine suggested an approximate 15% metabolic conversion of the parent drug. Finally, nizatidine plasma concentrations in pediatric patients following a single 5.0 mg/kg oral dose exceeded the EC50 value of the drug for gastric acid suppression determined from adult studies for approximately 6 hours.     

The effects of lansoprazole, a new H+,K+-ATPase inhibitor, on gastric pH and serum gastrin

This study examined the effects of dose and time of administration of lansoprazole on gastric pH and serum gastrin in healthy male volunteers. Three groups of six subjects received 10, 20 or 60 mg doses of lansoprazole or placebo. Doses were administered at 22.00 hours daily for 7 days. An additional 18 subjects received once daily 30 mg oral doses of lansoprazole or placebo; these subjects were dosed at either 08.00 hours or 22.00 hours in a randomized, crossover fashion with a 2-week washout period. Gastric pH was monitored for 24 h following the first and final dose, and 1 week following the completion of dosing. Lansoprazole, at all doses except 20 mg/day, significantly increased the median 24-hour gastric pH following 7 days of dosing (P less than 0.05). In addition, morning dosing in the 30-mg crossover group led to a higher 24-h median pH than evening dosing (P = 0.003). There was no difference in night-time median pH between morning and evening dosing. Morning dosing also led to a significant increase in gastric pH on study Day 1 (P less than 0.05). Plasma concentrations of lansoprazole were highly variable between subjects, but there was a significant correlation between AUC and the median 24-h gastric pH. Plasma concentrations and AUCs were higher on Day 7 than on Day 1 for subjects receiving 10 or 20 mg, but not for those receiving 30 or 60 mg doses. Lansoprazole bioavailability demonstrated a circadian effect manifested by higher plasma concentrations following morning dosing. Serum gastrin concentrations were elevated in all active medication groups.     

Lack of unique ciprofloxacin pharmacokinetic characteristics in patients with cystic fibrosis

The single-dose pharmacokinetics of oral ciprofloxacin 750 mg were evaluated in six subjects with cystic fibrosis (CF subjects) and six age, sex and approximate weight-matched control subjects (controls). In addition, the effect of concurrently administered oral pancreatic enzyme replacement on the pharmacokinetics of ciprofloxacin was studied in 12 CF subjects. Ciprofloxacin t1/2, VSSF, CLF, and CLR in the matched CF subjects averaged 4.5 hours, 2.8 L/kg, 2.73 mL/min/kg and 5.7 mL/min/kg, respectively. Forty-two percent of the ciprofloxacin dose was excreted in the urine (0-48 hours) as the parent compound. No statistically significant differences in these ciprofloxacin pharmacokinetic parameter estimates were observed between CF and control subjects. In three CF subjects and two controls, the urinary excretion of ciprofloxacin and four of its metabolities were similar. In contrast, CF subjects demonstrated a prolonged tmax (2.3 versus 1.3 hours P less than .05) though ciprofloxacin Cmax was similar (4.7 versus 3.8 mg/L, NS). The concurrent administration of oral pancreatic enzyme replacement had no effect on the pharmacokinetics of ciprofloxacin. Apparent ciprofloxacin pharmacokinetic parameters in sputum were similar to those observed in serum. Sputum ciprofloxacin concentrations lagged behind serum concentrations but, on average, exceeded serum concentrations for 20 hours of the 24-hour sampling period. These sputum ciprofloxacin concentrations exceeded the reported MIC90 for Pseudomonas aeruginosa for approximately 15 hours. These data suggest an oral ciprofloxacin dose of 750 mg administered q8h to promote accumulation and maintenance of sputum drug concentrations well above pathogen MICs for the majority of a dosing interval in patients with CF.     

Steady-state pharmacokinetics and pharmacodynamics of meropenem in hospitalized patients

STUDY OBJECTIVE: To evaluate the steady-state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients. DESIGN: Prospective, open-label, steady-state pharmacokinetic study. SETTING: One tertiary care medical center and one community hospital. PATIENTS: Twenty adult patients (12 men, 8 women) with suspected or documented bacterial infections requiring antimicrobial therapy. INTERVENTION: Patients received 30-minute infusions of meropenem 500 mg every 6 hours (group 1), every 8 hours (group 2), or every 12 hours (group 3) based on estimated creatinine clearances greater than 60, 40-60, or 10-39 ml/minute, respectively. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected after 2 or more days of therapy. Meropenem concentrations were determined by high-performance liquid chromatography, and pharmacokinetic data were analyzed by noncompartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for a percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) of 40% by using pharmacokinetic data for each group and MIC data for seven gram-negative pathogens from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC, 2004-2005) database. Maximum and minimum serum concentrations (mean +/- SD) were 29.2+/-9.8 and 2.4+/-1.1 microg/ml, 33.2+/-8.5 and 3.8+/-2.7 microg/ml, and 33.5+/-4.7 and 4.9+/-1.6 microg/ml for groups 1, 2, and 3, respectively. The half-life values were 2.5+/-0.9, 3.4+/-1.3, and 6.1+/-1.4 hours, and the values for volume of distribution at steady state were 29.3+/-8.7, 23.8+/-8.1, and 28.7+/-8.6 L for groups 1, 2, and 3, respectively. For all three groups, the CFR was greater than 90% for the enteric pathogens and Pseudomonas aeruginosa and 82.4-85.2% for Acinetobacter species. CONCLUSION: Pharmacodynamic analyses suggest that regimens of meropenem 500 mg every 6, 8, or 12 hours, adjusted for renal function, are acceptable for treatment of infections caused by enteric gram-negative pathogens and P. aeruginosa. However, more aggressive dosing or alternative dosing strategies may be necessary for Acinetobacter species.     

Continuous infusion versus intermittent administration of cefepime in patients with Gram-negative bacilli bacteraemia

The objective of this study was to compare the pharmacokinetics of cefepime administered by continuous infusion and intermittent injection regimens. A prospective, randomized, cross-over study of ten patients with Gram-negative bacilli bacteraemia was conducted. All patients were randomized to receive cefepime either as a 4-g continuous infusion over 24 h for 48 h or a 2-g bolus administered intermittently intravenously every 12 h for 48 h. After 48 h the patients received the alternative dose regimen. Cefepime pharmacokinetic studies were carried out during hours 36-48 after the start of both regimens. All of the pathogens isolated from the blood in 7 patients had a minimum inhibitory concentration (MIC) < 1 microg mL(-1). In both regimens, the serum cefepime concentrations at all time points were higher than the MIC for the pathogens isolated from this study. For the continuous infusion arm, the highest steady-state concentration was 49.80+/-18.40 microg mL(-1) and the lowest steady-state concentration was 41.42+/-16.48 microg mL(-1). The steady-state concentrations were greater than 4 times the MIC of 8 microg mL(-1). For the intermittent injection regimen, the mean trough concentration was 4.74+/-3.99 microg mL(-1). The mean serum cefepime concentration was above 8 microg mL(-1) for 81.66% of the dosing interval. Therefore, we conclude that either continuous infusion or intermittent injection can be used as an effective mode of cefepime administration to achieve bactericidal activity.     

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)     

Stability of nizatidine in total nutrient admixtures.

The stability of nizatidine in total nutrient admixtures (TNAs) and the effect of the drug on the stability of lipid emulsions in the TNAs were studied. Duplicate 1476-mL amino acid-dextrose base solutions were prepared; nizatidine 300 mg was added to one. TNAs were prepared by adding to 75-mL samples of the base solutions Intralipid (KabiVitrum) or Liposyn II (Abbott) and sterile water as needed to achieve final lipid concentrations of 3% and 5%. Triplicate 100-mL samples for each lipid product and concentration were prepared; fat-free samples containing nizatidine were also studied. The theoretical final nizatidine concentration was 150 micrograms/mL. Samples were stored at 22 degrees C for 48 hours. Initially and at 12, 24, and 48 hours, the samples were visually inspected, tested for pH and particle-size distribution, and assayed by high-performance liquid chromatography for nizatidine concentration. No color change, precipitation, creaming, or oiling out was noted. For the 12 TNAs containing nizatidine, mean solution pH during the study was 5.88; stability of the lipid products requires pH values greater than or equal to 5.5. Particle-size distribution did not differ appreciably between the nizatidine-containing and drug-free TNAs. Nizatidine concentrations remained greater than 90% of the initial concentration. Nizatidine at a theoretical concentration of 150 micrograms/mL was stable for 48 hours at 22 degrees C in TNA solutions containing 3% and 5% Intralipid or Liposyn II and did not appear to affect lipid emulsion stability.