Serum Pharmacokinetic Profiles Research Articles

POS-144 A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE-DOSE, PARALLEL GROUP SAFETY AND BIOAVAILABILITY STUDY OF BION-1301 ADMINISTERED BY INTRAVENOUS (IV) AND SUBCUTANEOUS (SC) ROUTES

IgAN (IgA nephropathy) is the most common primary glomerulonephritis in the world. There are currently no approved treatments and limited off-label treatment options consist largely of supportive measures which do not directly address the underlying immunologic pathogenesis of disease. APRIL (A proliferation-inducing ligand) is critical for IgA class switching, maturation and survival of IgA secreting plasma cells, and production of gd-IgA1 (galactose—deficient IgA1) which is recognized as an auto-antigen leading to the formation of pathogenic IgA immune complexes. BION-1301 is a novel humanized monoclonal antibody that neutralizes APRIL and is currently in Phase 1 development in healthy volunteers and patients with IgAN. In prior Phase 1 studies, BION-1301 was well-tolerated in healthy volunteers and reduced serum levels of free APRIL, IgA, IgM, and to a lesser extent IgG at single doses up to 1350 mg IV and multiple doses up to 450 mg IV every 2 weeks. This study compares pharmacokinetic (PK) and pharmacodynamic (PD) profiles following the administration of BION-1301 300 mg by IV and SC routes in healthy volunteers. Up to 34 healthy volunteers were randomized 1:1 to receive BION-1301 300mg either by IV or SC administration. The primary endpoint was an estimate of the bioavailability of BION-1301 with secondary endpoints of safety, tolerability, PK, PD, and immunogenicity. Subjects were closely monitored during the in-clinic stay through day 8, with in-clinic follow-up visits occurring through the end of study at day 57. PK, PD, and immunogenicity samples were collected periodically throughout the course of the study. BION-1301 continues to be well tolerated with no Grade 3 treatment emergent adverse events or serious adverse event to date. Serum PK profiles; PD profiles including free APRIL, IgA, IgG, and IgM levels; and anti-drug antibody levels will be presented and compared between IV and SC routes. Blockade of APRIL by BION-1301 remains a promising therapeutic approach for the treatment of IgAN. PK and PD data comparing IV and SC administration of BION-1301 will be used to refine the SC dose selection for future global clinical studies of BION-1301 in IgAN.

Clinical pharmacokinetics of tramadol and main metabolites in horses undergoing orchiectomy

Background: Tramadol is a synthetic codeine analogue used as an analgesic in human and veterinary medicine. It is not approved for use in horses, but could represent a valid tool for pain treatment in this species.Objectives: The serum pharmacokinetic profile and urinary excretion of tramadol and its metabolites (O-desmethyltramadol [M1], N-desmethyltramadol [M2] and N,O-desmethyltramadol [M5]) was investigated in a multidrug anaesthetic and analgesic approach for orchiectomy in horses. The evaluation of the degree of cardiovascular stability, the intraoperative effect and postoperative analgesia obtained by the visual analogue scale are also reported.Animal and methods: Tramadol (4 mg/kg BW) was administered intravenously to eight male yearlings as a bolus over 60 seconds, 5 min after intubation and 15 min prior to surgery. Drug quantification was performed in serum and urine for tramadol, M1, M2 and M5 by high-performance liquid chromatography with fluorimetric detection.Results: Mean tramadol concentration was 14.87 ± 11.14 μg/mL at 0.08 h, and 0.05 ± 0.06 μg/mL at 10 h. Serum concentrations of M1 and M2 metabolites were quite limited. For M1 and M2, median maximum concentration (Cmax) and time to achieve maximum concentration (Tmax) were 0.05 μg/mL and 0.75 h, and 0.08 μg/mL and 2 h, respectively; M5 was never detected. In urine, tramadol was the most recovered compound, followed by M1, M2 and M5.Conclusions and clinical relevance: Showing no adverse events and based on the kinetic behaviour, pre-operative tramadol IV at a dose of 4 mg/kg BW might be useful and safe as analgesic in horses undergoing surgery.

Pharmacokinetics and Pharmacodynamics of Once-Daily Administration of Intravenous Tobramycin in Adult Patients with Cystic Fibrosis Hospitalized for an Acute Pulmonary Exacerbation

The serum pharmacokinetic profile of intravenous (i.v.) tobramycin administration was characterized for a sample of nine adult patients with cystic fibrosis (CF) who were hospitalized for an acute pulmonary exacerbation. Current recommended i.v. tobramycin dosing protocols are predicted through modeling and simulation to be suboptimal. Empirical tobramycin regimens of ≥15 mg/kg of body weight administered i.v. once daily should be evaluated for adult patients with CF to optimize outcomes.

Clinical Pharmacokinetics of Oral Controlled-Release 5-Fluorocytosine

5-Fluorocytosine (5FC) is an oral antifungal that is currently used in combination with amphotericin B to treat Cryptococcus neoformans meningoencephalitis. The oral dosing of 5FC could be optimized by the use of a controlled-release (CR) formulation. The objective of the current study was to develop two prototype 5FC-CR formulations and evaluate the single-dose (1,500-mg) serum pharmacokinetic profiles of those formulations relative to the profile of the commercially available, immediate-release 5FC product (Ancobon) by the use of a phase 1, open-label, randomized, three-phase, crossover pharmacokinetic study design. Hydroxypropyl methylcellulose was utilized as the rate-controlling matrix to compound the 5FC-CR tablets. The two prototype 5FC-CR formulations demonstrated 80% release at 13.0 and 18.4 h, respectively, whereas the immediate-release product demonstrated 80% release at 0.28 h, as determined in vitro by the United States Pharmacopeia apparatus 2 dissolution method. Five subjects completed all three phases of the study without any adverse events. The mean maximum concentration, the area under the curve from time zero to 24 h, and the area under the curve from time zero to infinity were approximately 50% lower (P < 0.01) with the 5FC-CR formulations than with the immediate-release 5FC product. However, no statistically significant differences in the minimum concentrations at 24 h were noted between the formulations. The gastric absorption profile of 5FC-CR was well predicted by in vitro dissolution. Future exploration of a gastroretentive 5FC-CR formulation could overcome the marked lack of bioequivalence observed in the present study.

A randomized study of the serum pharmacokinetics of lower thoracic extended-release epidural morphine (DepoDur®) after lidocaine-epinephrine test dose administration in patients undergoing upper abdominal surgery

The primary objective was to evaluate the serum pharmacokinetic profile of a single 15-mg dose of extended-release epidural morphine (EREM) administered at the lower thoracic epidural space alone or following a lidocaine-epinephrine test dose in patients undergoing major upper abdominal surgery. This randomized, open-label study recruited men and women > or = 18 years of age scheduled for major upper abdominal surgery. Patients were randomly assigned to 1 of 5 treatment groups and were administered a single 15-mg dose of EREM or EREM preceded by a 3 ml lidocaine (1.5%)/epinephrine (1 : 200,000) test dose with or without a saline flush: EREM alone; test dose + flush + 3-minute wait + EREM; test dose + flush + 10-minute wait + EREM; test dose + flush + 15-minute wait + EREM; or test dose + 3-minute wait + EREM. EREM was administered at the lower thoracic epidural intervertebral space (T8 - T12) approximately 30 minutes before the surgical incision. Noncompartmental pharmacokinetic parameters were determined based on the serum concentration-time profiles of morphine and morphine metabolites. Effectiveness and safety were also assessed. The intent-to-treat and safety populations included 39 patients; the pharmacokinetic population included 37 patients. Administration of EREM 3 minutes after a lidocaine-epinephrine test dose, with or without a flush, resulted in an increased mean maximum serum concentration of morphine (Cmax; flush, 30.2 +/- 8.5 ng/ml; no flush, 25.6 +/- 10.1 ng/ml; EREM alone, 11.5 +/- 7.3 ng/ml) and a decreased median time to Cmax (tmax; flush, 0.2 h; no flush, 0.2 h; EREM alone, 2.0 h) compared with administration of EREM alone, without affecting relative morphine bioavailability. Flushing the catheter and waiting 15 minutes normalized the Cmax (11.4 +/- 6.4 ng/ml) but not the median tmax (0.5 h). There were no significant group differences in safety, tolerability, or analgesic effectiveness. The interaction between EREM and a lidocaine-epinephrine test dose administered at T8 - T12 can be minimized by waiting 15 minutes after test dose administration. The overall safety and effectiveness of 15 mg EREM administered at the lower thoracic epidural intervertebral space in patients undergoing major upper abdominal surgery appears similar to that observed in previous studies assessing lumbar administration. ClinicalTrials.gov Identifier: NCT00728832.

Extended-Release Epidural Morphine (DepoDur) Following Epidural Bupivacaine in Patients Undergoing Lower Abdominal Surgery

The primary objective was to compare the serum pharmacokinetic profile of a single dose of extended-release epidural morphine (EREM) administered alone versus 15 to 60 mins after an analgesic epidural dose of bupivacaine. This multicenter study enrolled 144 patients, 18 years or older, with scheduled lower abdominal surgery under general anesthesia. Patients were randomly assigned to a single 15-mg dose of EREM; the same dose administered 15, 30, or 60 mins after epidural bupivacaine (20 mL 0.25%); or epidural placebo (normal saline) administered 15, 30, or 60 mins after bupivacaine. Postoperatively, fentanyl patient-controlled analgesia was offered for breakthrough pain. Multiple serum samples were analyzed for morphine and morphine metabolites. Safety and efficacy were assessed. The mean maximum serum concentration and area under the concentration-time curve for morphine and metabolites were not significantly different when EREM was administered alone versus 15, 30, or 60 mins after bupivacaine. Median time to maximum serum concentration and median apparent terminal elimination half-life were also comparable. Total fentanyl patient-controlled analgesia consumption was comparable among all EREM groups (with/without prior bupivacaine) but significantly (P < 0.05) lower compared with the bupivacaine + placebo group. Nausea, vomiting, and dizziness were consistently more frequent in groups receiving EREM after bupivacaine versus EREM alone. The pharmacokinetic and efficacy profiles of a single 15-mg dose of EREM were not significantly altered when administered 15, 30, or 60 mins after an analgesic epidural dose of bupivacaine.

Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis

Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.

Intestinal absorption of p-coumaric and gallic acids in rats after oral administration.

Ferulic acid (FA) and p-coumaric acid (CA) are absorbed by the monocarboxylic acid transporter (MCT) in Caco-2 cells, although gallic acid (GA) is not. Therefore, the MCT is selective for certain phenolic acids. Absorption of orally administered CA and GA in rats was studied to obtain serum pharmacokinetic profiles and to investigate their intestinal absorption characteristics in vivo. Rats were administered 100 micromol/kg body weight of CA and GA, and blood was collected from the portal vein and abdominal artery after administration. CA, GA, and their metabolites were quantified with a highly selective and sensitive coulometric detection method using high-performance liquid chromatography-electrochemical detection. Ingested CA was rapidly absorbed in the gastrointestinal tract in an intact form. The serum concentration of intact CA in the portal vein peaked 10 min after dosing (C(max) was 165.7 micromol/L). In contrast, GA was slowly absorbed, with a t(max) for intact GA of 60 min and a C(max) of 0.71 micromol/L. The area under the curve for intact CA and GA was calculated from the serum concentration profile in the portal vein to be 2991.3 and 42.6 micromol min L(-)(1), respectively. The relative bioavailability of CA against GA was about 70. This is the first demonstration that absorption efficiency of CA is much higher than that of GA in vivo. The absorption characteristics of CA are clearly different from those of GA. These findings are in good agreement with the results obtained in vitro using a Caco-2 cell system.

Pharmacokinetics of repaglinide in subjects with renal impairment

To evaluate the effect of renal impairment and renal failure on the pharmacokinetics and safety of repaglinide. We conducted a phase I, multicenter, parallel-group, pharmacokinetic comparison trial with single and multiple doses of repaglinide in subjects with various degrees of renal impairment. Subjects with normal renal function (n = 6) and subjects with renal impairment (mild to moderate, n = 6; severe, n = 6) received treatment with 2 mg repaglinide for 7 days. Subjects in the hemodialysis group (n = 6) received two single doses of 2 mg repaglinide separated by a 7- to 14-day washout period. All subjects had repaglinide serum pharmacokinetic profiles measured for the first and last doses administered. Serum steady-state levels, urine levels, and dialysate levels were also measured. Pharmacokinetic parameters did not show significant changes after single or multiple doses of repaglinide, although the elimination rate constant in the group with severe renal impairment decreased after 1 week of treatment. Subjects with severe impairment had significantly higher area under the curve values after single and multiple doses of repaglinide than subjects with normal renal function. No significant differences in values for maximum serum concentration or time to reach maximum concentration were detected between subjects with renal impairment and those with normal renal function. Hemodialysis did not significantly affect repaglinide clearance. Repaglinide was safe and well tolerated in subjects with varying degrees of renal impairment. Although adjustment of starting doses of repaglinide is not necessary for renal impairment or renal failure, severe impairment may require more care when upward adjustments of dosage are made.

Role for Dual Individualization with Cefmenoxime

Cefmenoxime concentration/effect relationships were retrospectively explored for gram-negative bacteria isolated from 14 critical care patients treated for nosocomial pneumonia. The effects of cefmenoxime concentrations on in vitro growth kinetics of 21 isolated pathogens were studied using the Abbott MS-2 Research System, from which a dynamic response concentration was derived. Serum pharmacokinetic profiles were obtained in each patient. These data were used to calculate the in vivo total area under the curve over dynamic response concentration and the time that cefmenoxime concentrations exceeded the dynamic response concentration for each bacteria. The same determinations were made in 18 patients prospectively treated, except that dosage was optimized on the basis of previous mathematical relations to achieve bacterial eradication in four days. This method of dosage optimization is termed dual individualization. Serial cultures of infected tissues were evaluated to determine the number of days to the eradication of bacteria, and the pharmacokinetic and pharmacodynamic variables were used to describe the bacteriologic response of the original pathogen isolated in pretreatment culture. Bacterial eradication rates could be described from cefmenoxime pharmacokinetics in the patient and from the relation between concentration and bacterial inhibition. Patients who were prospectively treated using these retrospectively derived relationships had a predictable day of bacterial eradication. This, in turn, was associated with a shorter duration of treatment (p less than 0.05). The success of prospective dual individualization is encouraging and suggests that more precise optimization of antibiotic dosage can yield a predictable rate of bacterial eradication from the infection site.

In vitro and in vivo laboratory studies on three hydroxyiminophenylacetyl cephalosporins with particular reference to SK&F 80303, an unusually long-acting cephalosporin.

Three cephalosporins with 7-(2-hydroxyiminophenylacetamido) side chains (SK&F 79433, 80000 and 80303), differing in their 3-substituents, exhibited similar broad-spectrum antibacterial activity in vitro against strains of Staphylococcus aureus, Streptococcus faecalis and various Gram-negative bacilli. All three were active in vivo (s.c., mouse) against S. aureus, Escherichia coli or Klebsiella pneumoniae, but they differed significantly in serum pharmacokinetic profiles. SK&F 80303 produced high and extremely prolonged serum levels and protected mice when administered up to 24 hours prior to challenge with beta-lactamase-producing S. aureus or K. pneumoniae. It was resistant to hydrolysis by beta-lactamases from S. aureus, and variably so to beta-lactamases from E. coli strains. SK&F 80303 was bacteriolytic to logarithmically growing S. aureus, E. coli, Proteus mirabilis, K. pneumoniae and Enterobacter cloacae (partially). SK&F 80303 illustrates further the effect of the 3-sulfoalkyltetrazole substituent on the pharmacokinetic properties of cephalosporins. Its combined biological properties make it a possible candidate for therapeutic and long-term prophylactic use.