OBJECTIVE -This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers. RESEARCH DESIGN AND METHODS-In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h. CONCLUSIONS -INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes. RESULTS Diabetes Care 28:1077-1082, 2005T he pulmonary delivery of insulin is currently being studied as an alternative method of insulin administration. Early studies have shown promising results, and it has been demonstrated that the onset of action of inhaled insulin is faster than that of regular human insulin (RHI), resembling that of rapid-acting insulin analogs (1-5). RHI has several disadvantages when its use for controlling prandial glycemia is considered. A relatively slow onset of action and a prolonged duration of action results in a suboptimal time-action profile (6). In addition, subcutaneous insulin injections are often considered inconvenient and cause anxiety for many patients (7).Inhaled insulin may be a viable alternative to prandial insulin administration for patients with diabetes because of its more favorable pharmacokinetic profile and less invasive route of administration. However, a direct comparison of the pharmacodynamic properties of INH and subcutaneously injected rapid-acting insulin analogs has not yet been performed. The purpose of this study was to compare the pharmacokinetic and pharmacodynamic properties of human insulin administered to the lung using a novel drypowder inhaled insulin delivery system with those of subcutaneously injected RHI and the rapid-acting insulin analog insulin lispro (ILP). RESEARCH DESIGN ANDMETHODS -Eighteen healthy, nonsmoking male volunteers (age 28 Ϯ 4 years, BMI 23.6 Ϯ 2.0 kg/m 2 ) participated in this open-label, randomized, three-way, crossover study. Seventeen participants completed the study; one withdrew after receiving his first study treatment (INH) due to an adverse event (sepsis) attributed to the testing procedure and not the study treatment.Subjects gave written informed consent and underwent a physical examinat i o n , 1 2 -l e a d e l e c t r o c a r d i o g r a m recording, and clinical laboratory tests. All subjects had normal lung function (mean forced expiratory volume in 1 s [FEV 1 ] Ͼ80% of predicted normal value; FEV 1 -to-forced vital capacity ratio Ͼ0.80) as measured in a standing position using a Spirovit Baar, Switzerland). Nonsmoking status was verified using a negative urine cotinine excretion test (LCMS method, API 3ϩ; Perkin-Elmer, Weiterstadt, Ger-

Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum ␤-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to Ͻ18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of Ն50 ml/min/1.73 m 2 only): for children Ն12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children Ͻ12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

Fifteen healthy male volunteers (in four groups) received single 1 h i.v. infusions of alatrofloxacin (CP-116,517) equivalent to 30, 100, 200 or 300 mg of its active metabolite, trovafloxacin (CP-99,219). Blood and urine were sampled over 73 and 72 h, respectively, and plasma levels of alatrofloxacin and serum concentrations of trovafloxacin were determined by HPLC with UV detection. Alatrofloxacin was not detectable in plasma samples collected after the end of infusion, indicating rapid conversion to trovafloxacin. Maximum serum concentrations of trovafloxacin were achieved at the end of the infusions. Mean maximum plasma trovafloxacin concentrations for the four alatrofloxacin doses were 0.4, 1.8, 2.3 and 4.3 mg/L. The mean area under the concentration-time curve increased proportionally with the dose. The elimination half-life (T(1/2)) for trovafloxacin was independent of the dose and the mean T(1/2)s for the 100, 200 and 300 mg equivalent doses of alatrofloxacin were 10.4, 12.3 and 10.8 h. Approximately 10% of the equivalent dose was recovered as unchanged trovafloxacin in the urine. No clinical adverse or laboratory reactions were associated with i.v. administration of alatrofloxacin and its conversion to trovafloxacin. These results indicate that alatrofloxacin is rapidly converted to trovafloxacin and that the pharmacokinetic parameters for this new fluoroquinolone after i.v. administration of its parent compound are similar to those reported after oral administration of equivalent trovafloxacin doses.

Aims To determine whether repeated once daily administration of grapefruit juice altered the pharmacokinetics or pharmacodynamics of the calcium antagonist amlodipine. Methods The effects of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral and intravenous amlodipine were assessed in 20 healthy men in a placebo‐controlled, open, randomized, four‐way crossover study using single doses of amlodipine 10 mg. For 9 days beginning with the day of administration of amlodipine, grapefruit juice (or water control) was given once daily, and blood samples, blood pressure and heart rate measures were obtained. Plasma concentrations of amlodipine and its enantiomers were determined in separate assays by GC‐ECD. Results Oral amlodipine had high systemic availability (grapefruit juice: 88%; water: 81%). Pharmacokinetic parameters of racemic amlodipine (AUC, Cmax, tmax, and kel) were not markedly changed with grapefruit juice coadministration. Total plasma clearance and volume of distribution, calculated after intravenous amlodipine, were essentially unchanged by grapefruit juice (CL 6.65 ml min−1 kg−1, juice vs 6.93 ml min−1 kg−1, water; Vdss 22.7 l kg−1, juice vs 21.0 l kg−1, water). Grapefruit juice coadministration did not greatly alter the stereoselectivity in amlodipine oral or intravenous kinetics. The sum of S(–) and R(+) enantiomer concentrations correlated well with total racemic amlodipine concentration (r2 = 0.957; P = 0.0001). Coadministration of grapefruit juice with either route of amlodipine administration did not significantly alter blood pressure changes vs control. Conclusions Grapefruit juice has no appreciable effect on amlodipine pharmacodynamics or pharmacokinetics, including its stereoselective kinetics. Bioavailability enhancement by grapefruit juice, noted with other dihydropyridine calcium antagonists, does not occur with amlodipine. Once daily grapefruit juice administration with usual oral doses of amlodipine is unlikely to alter the profile of response in clinical practice.

To determine the effect of the concurrent administration of Maalox and omeprazole in the bioavailability of trovafloxacin (CP-99,219), an open, placebo-controlled, randomized, four-way crossover study was conducted in 12 healthy male volunteers. Each received treatments of three 100 mg trovafloxacin tablets in the morning 30 min after 30 mL of Maalox (A), 30 min after placebo (B), 2 h before 30 mL of Maalox (C) and 2 h after 40 mg of omeprazole (D). For treatments A and C, Maalox was also given at 22.00 h the night before the study day, 1 and 3 h after meals and at bedtime on the study day. For B and D, placebo and omeprazole, respectively, were also given at 22.00 h the night before the study day. After treatments A and C, mean area under the curve (AUC) was reduced by 66% and 28% (14.2 and 30.2 mg.h/L), respectively, and mean T(1/2) declined by 33% and 31% (8.3 and 8.5 h), respectively, relative to the values after B (42.1 mg.h/L; 12.4 h). The mean Kel-corrected relative bioavailabilities for A and C were 50% and 104%, respectively, suggesting a large reduction in the initial absorption of trovafloxacin with A. Treatment D had no appreciable effect on mean T(1/2) but mean AUC and Cmax were reduced by 18% and 32%, respectively, relative to B. The mean relative bioavailability after D was 82%. We conclude that the concurrent administration of trovafloxacin and aluminium- and magnesium-containing antacids should be avoided but that co-administration with omeprazole is unlikely to have a clinically significant effect on the extent of absorption of the antibiotic.