Maternal-Neonatal Raltegravir Population Pharmacokinetics Modeling: Implications for Initial Neonatal Dosing.

Raltegravir readily crosses the placenta to the fetus with maternal use during pregnancy. After birth, neonatal raltegravir elimination is highly variable and often extremely prolonged, with some neonates demonstrating rising profiles after birth despite removal from the source of extrinsic raltegravir. To establish an appropriate dosing regimen, an integrated maternal-neonatal pharmacokinetics model was built to predict raltegravir plasma concentrations in neonates with in utero raltegravir exposure. Postnatal age and body weight were used as structural covariates. The model predicted rising or decreasing neonatal elimination profiles based on the time of maternal drug administration relative to time of birth and degree of in utero drug disposition into the central and peripheral compartments. Based on this model, it is recommended to delay the first oral dose of raltegravir until 1-2 days of age in those neonates born to mothers who received raltegravir during pregnancy, labor, and delivery.

Nicotine Population Pharmacokinetics in Healthy Adult Smokers: A Retrospective Analysis.

BACKGROUND AND OBJECTIVE: Characterizing nicotine pharmacokinetics is challenging in the presence of background exposure. We performed a combined retrospective population pharmacokinetic analysis of 8 trials, including exposure to Tobacco Heating System and cigarettes (both inhaled), nicotine nasal spray and oral nicotine gum. METHOD: Data from 4 single product use trials were used to develop a population pharmacokinetic model with Phoenix® NLME™ and to derive exposure parameters. Data from 4 separate ad libitum use studies were used for external validation. A total of 702 healthy adult smokers (54% males; 21-66 years of age; smoking ≥10 cigarettes/day; from US, Europe and Japan) were eligible for participation. RESULTS: Two-compartment linear disposition combined with zero-order absorption model was adequate to describe nicotine pharmacokinetics, and a mono-exponentially decreasing background component was utilized to account for nicotine carry-over effects. Apparent nicotine clearance was typically 0.407 L/min in males and 26% higher in females (68% inter-individual variability). Bioavailability was product-specific, decreased with increasing nicotine ISO yield, and increased with increasing body weight. Absorption duration was apparently prolonged with nicotine gum. The typical initial and terminal half-lives were 1.35 and 17 h, respectively. The presence of menthol did not impact the determinants of the area under the curve. The model adequately described the external validation data. CONCLUSIONS: The population model was able to describe in different populations the nicotine pharmacokinetics after single product use and after 4 days of ad libitum use of Tobacco Heating System, cigarettes, and of different nicotine replacement therapies with various routes of administration.

Phase 1 Study Assessing the Pharmacokinetic Profile and Safety of Avibactam in Patients With Renal Impairment.

Avibactam is a non-ß-lactam ß-lactamase inhibitor intended for use as a fixed-dose combination with ceftazidime for the treatment of certain serious Gram-negative infections. As avibactam is primarily excreted unchanged in the urine, renal impairment may affect its pharmacokinetics. This phase 1 study investigated the effect of renal impairment and hemodialysis on avibactam pharmacokinetics and safety. Healthy controls and subjects with increasing degrees of renal impairment received a single 30-minute intravenous (IV) infusion of avibactam (100 mg). Anuric subjects requiring hemodialysis received the same infusion pre- and posthemodialysis, separated by a 7- to 14-day washout. Blood and urine samples were collected, and pharmacokinetics were analyzed using noncompartmental methods. The relationships between avibactam total plasma clearance (CL) or renal clearance (CLR ) and creatinine clearance (CrCL) were evaluated by linear correlation analysis. Safety was also monitored. Increasing severity of renal impairment was associated with decreasing CL and CLR and increasing exposure and terminal half-life (t1/2 ). Avibactam CL and CLR demonstrated an approximately linear relationship with CrCL comparable to that previously observed for ceftazidime. In patients requiring hemodialysis, >50% of the administered avibactam was removed during a 4-hour hemodialysis session, demonstrating that avibactam should be administered after hemodialysis. No new safety findings were reported. To conclude, avibactam dose adjustment is warranted in patients with renal impairment based on the severity of impairment. Because the slope of the linear relationship between avibactam total plasma CL and CrCL is similar to that of ceftazidime, renal impairment dose adjustments should maintain the currently advised 4:1 ratio of ceftazidime:avibactam.

Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies.

BACKGROUND AND OBJECTIVE: Avibactam is a novel non-ß-lactam ß-lactamase inhibitor effective against Ambler class A, C and some class D ß-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of ß-lactams, including ceftazidime, against extended-spectrum ß-lactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime. METHODS: The first study (NXL104-1001) was a placebo-controlled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-1002) was performed in two parts. Part 1 assessed multiple-ascending doses of avibactam. Subjects were randomized to receive avibactam 500, 750 or 1000 mg every 8 h (q8 h) over 5 days, or ceftazidime-avibactam 2000-500 mg q8 h over 10 days. Part 2 assessed bioavailability of avibactam after a single oral dose (500 mg) relative to a single 30-min intravenous infusion (500 mg). RESULTS: No serious or severe adverse events were reported in either study. Avibactam exposure generally increased proportionally to dose and there was no trend for accumulation after multiple doses. Almost all avibactam was excreted largely unchanged in the urine within the first 6 h. Concomitant ceftazidime did not affect avibactam's safety and pharmacokinetic profile. Avibactam exposure after oral dosing was very low at 6.2 % of that observed after intravenous infusion. CONCLUSION: Avibactam was generally well tolerated across all dosing regimens, when given alone or with ceftazidime. Avibactam exposure was dose related in both studies, and avibactam pharmacokinetics were linear and not affected by ceftazidime.

Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers.

PURPOSE: Avibactam is a novel non-ß-lactam ß-lactamase inhibitor currently being assessed in combination with ceftazidime, ceftaroline fosamil, and aztreonam. The objectives of this study were to investigate the pharmacokinetics, safety, and tolerability of avibactam in healthy young (aged 18-45 years) and elderly (aged ≥65 years) volunteers of both sexes. METHODS: This was a Phase I, open-label study in which healthy volunteers aged ≥18 years were enrolled into 4 cohorts: young male, young female, elderly male, and elderly female (n = 8 in each group). Subjects were excluded if they had any condition requiring regular medication or any other relevant conditions. All subjects received a single dose of avibactam 500 mg/100 mL given intravenously over 30 minutes. Pharmacokinetic measurements included Cmax, Tmax, AUC0-∞, plasma clearance, and t½. FINDINGS: Within the two age categories the mean age across male and female subjects was well matched. The majority of subjects in the young cohort were black (≥62.5%), whilst the majority of those in the elderly cohorts were white (≥75%). Mean avibactam plasma clearance was similar between the young male, young female, and elderly male cohorts (10.16, 10.34, and 9.82 L/h, respectively), and slightly lower in elderly women (7.98 L/h). Mean Cmax was similar in young male, young female, and elderly female subjects (33.8, 36.9, and 38.4 µg/mL) but lower in elderly male subjects (26.5 µg/mL). Point estimates comparing the ratio of Cmax in male and female subjects over all age groups suggested that Cmax values were 18% lower (90% CI, 30%-5% lower) in male subjects compared with female subjects. Mean AUC0-∞ data were similar between the young male, young female, and elderly male cohorts (49.86, 49.75, and 52.40 µg·h/mL) but higher in elderly women (66.23 µg·h/mL). Point estimates comparing the ratio of AUC0-∞ in elderly and young subjects across both sexes suggested that AUC0-∞ values were 17% higher (90% CI, 5%-31%) in elderly subjects compared with young subjects. The t½ was slightly longer for elderly subjects compared with younger subjects. The most common adverse event was administration/venipuncture site bruising (6 events); all adverse events were mild. IMPLICATIONS: No notable differences in pharmacokinetics were observed between the male and female cohorts. The generalizability of the study is limited due to its small sample size. However, the small differences observed between the young and elderly cohorts are not sufficient to warrant dosing adjustments based on age.

Activities of ceftazidime and avibactam against ß-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model.

Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that is currently undergoing phase 3 clinical trials in combination with ceftazidime. Ceftazidime is hydrolyzed by a broad range of ß-lactamases, but avibactam is able to inhibit the majority of these enzymes. The studies described here attempt to provide insight into the amount of avibactam required to suppress bacterial growth in an environment where the concentrations of both agents are varying as they would when administered to humans. Following the simulation of a single intravenous dose of the drug, ceftazidime alone had no effect on any test organism, but a ceftazidime-avibactam combination resulted in rapid killing of all of the strains, with growth suppressed for the 8 h of the study. For seven of eight strains, this was achieved with a 1-g-250-mg profile, but a 2-g-500-mg profile was necessary to completely suppress a high-level-AmpC-producing isolate. When ceftazidime was infused continuously for 24 h with a single bolus dose of avibactam, rapid killing of all of the strains was again observed, with growth suppressed for 10 to >24 h. Regrowth appeared to commence once the avibactam concentration dropped below a critical concentration of approximately 0.3 µg/ml. In a third series of studies, ceftazidime was administered every 8 h for 24 h with avibactam administered at fixed concentrations for short periods during each ceftazidime dose profile. Simulating a 1-g dose of ceftazidime, an avibactam pulse of >0.25 and <0.5 µg/ml was required to suppress growth for 24 h.

Liquid chromatography-tandem mass spectrometric determination of a new antibacterial agent (AVE6971) in human white blood cells.

An LC-MS/MS assay for the quantitative determination of a new antibacterial agent (AVE6971) has been developed and validated in human white blood cells (WBC). The assay involved a lysing procedure of white blood cells and ultra centrifugation of the extracts. Chromatography was performed on a Supelcosil ABZ+ C(18) (2.1 mm x 50 mm, 5 microm) column using a mobile phase consisting of methanol/acetonitrile/10mM ammonium formate mixture (10:30:60, v/v/v) at a flow rate of 0.2 ml/min. The linearity was within the range of 10-10000 ng/ml of extracts, corresponding to 0.5-500 ng of AVE6971 in WBC pellets tubes. The validated lower limit of quantification was 10 ng/ml. The inter- and intra-run coefficients of variation (CV) for the assay were <12.9% and the accuracy were from -9.0 to -1.2%. AVE6971 was stable in WBC for at least 1 month at -75 degrees C. This assay proved to be suitable for the determination of AVE6971 in WBC from clinical studies.