Michael Seiberling

Metabolism and disposition of imatinib mesylate in healthy volunteers.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of 14C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (tmax 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 ± 0.095 μg/ml (mean ± S.D., n = 4) for imatinib and 0.115 ± 0.026 μg/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 ± 0.9 h for imatinib, 20.6 ± 1.7 h for CGP74588, and 57.3 ± 12.5 h for 14C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC0-24 h (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

Absolute Bioavailability of Imatinib (Glivec®) Orally versus Intravenous Infusion

The purpose of this study was to investigate the absolute bioavailability of a single oral dose of imatinib (Glivec®), 400 mg (capsules vs. oral solution), compared with imatinib, 100 mg (intravenous [i.v.] infusion), in healthy subjects. Twelve subjects received a single treatment in each treatment period: a 400‐mg oral dose of imatinib in capsule form or as a solution or a 100‐mg i.v. infusion of imatinib. Plasma imatinib concentrations were measured following each treatment; pharmacokinetic parameters and absolute bioavailability were determined. Absolute bioavailability values (compared with i.v. infusion) for the imatinib capsule and oral solution were 98.3% and 97.2%, respectively. Both the rate and extent of imatinib absorption, as measured by Cmax, partial AUC, and total AUC, were similar for the oral solution and the imatinib capsule intended for the market. The 400‐mg oral dose of imatinib, as a capsule or a solution, was completely absorbed and was almost completely bioavailable (> 97%).

Absorption, distribution, metabolism and elimination of the direct renin inhibitor aliskiren in healthy volunteers

Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [14C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose. Peak plasma levels of aliskiren (Cmax) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC0–∞), and indicating very low exposure to metabolites. Terminal half-lives for radioactivity and aliskiren in plasma were 49 h and 44 h, respectively. Dose recovery over 168 h was nearly complete (91.5% of dose); excretion occurred almost completely via the fecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in feces in unchanged form. Based on results from this and from previous studies, the absorbed fraction of aliskiren can be estimated to approximately 5% of dose. The absorbed dose was partly eliminated unchanged via the hepatobiliary route. Oxidized metabolites in excreta accounted for at least 1.3% of the radioactive dose. The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.

Evaluation of an Oral Suspension of VP20621, Spores of Nontoxigenic Clostridium difficile Strain M3, in Healthy Subjects

ABSTRACT VP20621, spores of nontoxigenic Clostridium difficile (NTCD) strain M3, is protective against challenge with toxigenic strains in hamsters. Human administration and colonization may prevent primary C. difficile infection (CDI) or recurrent CDI. Healthy adult subjects 18 to 45 years old or ≥60 years old received single or multiple doses of an oral suspension of VP20621 (104, 106, or 108 spores) or placebo. Group 4 (≥60 years old) received oral vancomycin for 5 days, followed by 14 days of VP20621 or placebo. Subjects were monitored for safety and followed through day 28. Stool was cultured for C. difficile before, during, and after VP20621 administration. Isolates were tested for toxin by enzyme immunoassay, and VP20621 was confirmed by molecular typing. After single escalating doses, no subjects had C. difficile-positive stool cultures. VP20621 was found in the stool of all subjects given 108 spores twice a day. Following vancomycin administration, VP20621 was detected in the stool of all subjects given 104, 106, or 108 spores daily beginning on day 2 to 6. Recovered isolates were toxin negative and confirmed to be VP20621. There were no serious adverse events, and no subjects prematurely discontinued study drugs. Following vancomycin administration, 2 placebo subjects became colonized with toxigenic C. difficile and 3 placebo subjects became colonized with VP20621. Persistent colonization with VP20621 was detected in stools on days 21 to 28 in 44% of subjects. VP20621 was well tolerated and able to colonize the gastrointestinal tracts of subjects pretreated with vancomycin. Further study of VP20621 to prevent CDI in patients is warranted.

Safety and immunogenicity of a pneumococcal histidine triad protein D vaccine candidate in adults.

BACKGROUND Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae. OBJECTIVE To explore safety and immunogenicity of a recombinant protein vaccine candidate against S. pneumoniae composed of adjuvanted pneumococcal histidine triad protein D (PhtD). METHODS This phase I, exploratory, open-label, single-center clinical study enrolled adults (18-50 years). Participants in a pilot safety cohort received a single intramuscular injection of 6 μg. Following safety review, 3 dose cohorts were enrolled (6, 25, and 100 μg); participants received 2 injections administered approximately 30 days apart. Assignment of the second injection and successive dose cohorts were made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events, serious adverse events, and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD antibodies as measured by ELISA. RESULTS Sixty-three participants were enrolled and received the pilot safety dose (n=3) or at least 1 dose of PhtD vaccine candidate at 6 μg (n=20), 25 μg (n=20), or 100 μg (n=20). No safety concerns were identified. No vaccine-related serious adverse event was reported. The most common solicited injection site reaction was pain and most common solicited systemic reactions were myalgia and headache; most reactions were mild and transient. Observed geometric mean concentrations (95% CI) were 200.99 ELISA units (148.46, 272.10), 352.07 (193.49, 640.63), and 699.15 (405.49, 1205.48) post-injection 1 in the 6, 25, and 100 μg dose cohorts, respectively, and 378.25 (275.56, 519.21), 837.32 (539.29, 1300.04), and 1568.62 (1082.92, 2272.16) post-injection 2. CONCLUSIONS All dose levels were safe and immunogenic. The frequency of solicited reactions was highest at the 100 μg dose. Administration of a second injection significantly increased the levels of anti-PhtD antibodies (ClinicalTrials.gov registry no. NCT01444001).

Pharmacokinetics and Safety Profile of the Human Anti-Pseudomonas aeruginosa Serotype O11 Immunoglobulin M Monoclonal Antibody KBPA-101 in Healthy Volunteers

ABSTRACT KBPA-101 is a human monoclonal antibody of the immunoglobulin M isotype, which is directed against the O-polysaccharide moiety of Pseudomonas aeruginosa serotype O11. This double-blind, dose escalation study evaluated the safety and pharmacokinetics of KBPA-101 in 32 healthy volunteers aged 19 to 46 years. Each subject received a single intravenous infusion of KBPA-101 at a dose of 0.1, 0.4, 1.2, or 4 mg/kg of body weight or placebo infused over 2 h. Plasma samples for pharmacokinetic assessments were taken before infusion as well as 0.25, 0.5, 1, 2, 2.5, 4, 6, 8, 12, 24, 36, and 48 h and 4, 7, 10, and 14 days after start of dosing. Plasma concentrations of KBPA-101 were detected with mean maximum concentrations of drug in plasma of 1,877, 7,571, 24,923, and 83,197 ng/ml following doses of 0.1, 0.4, 1.2, and 4.0 mg/kg body weight, respectively. The mean elimination half-life was between 70 and 95 h. The mean volume of distribution was between 4.76 and 5.47 liters. Clearance ranged between 0.039 and 0.120 liters/h. At the highest dose of 4.0 mg/kg, plasma KBPA-101 levels were greater than 5,000 ng/ml for 14 days. KBPA-101 exhibited linear kinetics across all doses. No anti-KBPA-101 antibodies were detected after dosing in any subject. Overall, the human monoclonal antibody KBPA-101 was well tolerated over the entire dose range in healthy volunteers, and no serious adverse events have been reported.

Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers.

BackgroundThe FG loop peptide (FGLL), a novel mimetic of the neural cell adhesion molecule (NCAM), is in clinical development for neurodegenerative disorders such as Alzheimer’s disease. Preclinical studies in rats, dogs and monkeys have demonstrated exposure in plasma and cerebrospinal fluid after parenteral or intranasal administration of FGLL, with no systemic toxicity. This article reports on the results of the first administration of FGLL in humans.ObjectiveTo determine the tolerability, safety and pharmacokinetics of ascending, single intranasal doses of FGLL 25, 100 and 200mg in healthy subjects.MethodsIn an 8-day, open-label, phase I study, 24 healthy male volunteers (mean age 42 [range 24–55] years) received single intranasal doses of FGLL (25, 100 and 200mg) in accordance with an ascending dose, sequential-cohort design.ResultsAll three intranasal doses of FGLL were well tolerated and there were no clinical notable abnormalities in ECG recordings, vital signs or laboratory tests. Three subjects (13%) reported five adverse events. A transient (<3 minutes) burning sensation in the nose was reported in two subjects at the 200mg dose level while runny eyes (<2 minutes) were experienced in one subject at 25mg. These events had an onset immediately following intranasal administration, and a relationship to FGLL was suspected. One of the latter subjects who had experienced a burning sensation in the nose also experienced dizziness, vomiting and headache with onset >2 days after single-dose administration of FGLL; no relationship to the study drug was suspected. Quantifiable plasma concentrations of FGLL were observed up to 1 hour after intranasal administration of the 100mg dose and up to 4 hours after the 200mg dose (plasma FGLL concentrations were undetectable at all timepoints for the 25mg dose). Increasing doses of FGLL were associated with higher systemic exposures: mean Cmax 0.52 ng/mL and 1.38 ng/mL (100mg and 200mg, respectively); mean AUC24 1.27 ng · h/mL and 4.05 ng · h/mL (100mg and 200mg, respectively).ConclusionsIntranasal administration of FGLL (25, 100 and 200mg) was well tolerated in healthy male volunteers, with no safety concerns and a pharmacokinetic profile that was generally dose related. Further studies are currently being planned to evaluate the effects of FGLL in patients with Alzheimer’s disease.

Human pharmacokinetics and safety profile of finafloxacin, a new fluoroquinolone antibiotic, in healthy volunteers.

ABSTRACT Finafloxacin is a new fluoroquinolone antibiotic with the unique property of increasing antibacterial activity at pH values lower than neutral. Whereas its antibacterial activity at neutral pH matches that of other quinolones in clinical use, it is expected to surpass this activity in tissues and body fluids acidified by the infection or inflammation processes. Pharmacokinetic parameters of oral single and multiple doses of up to 800 mg of finafloxacin and safety/tolerability observations were assessed in a phase I study including 95 healthy volunteers. Finafloxacin is well absorbed after oral administration, generating maximum concentrations (Cmaxs) in plasma at least comparable to those of other fluoroquinolones, with a half-life of around 10 h. About one-third of the dose is excreted unchanged in the urine. Renal elimination appears to be a saturable process leading to slight increases of the area under the concentration-time curve extrapolated to infinity and dose normalized (AUC∞,norm) at dosages of 400 mg and above. Safety and tolerability data characterize finafloxacin as a drug with a favorable safety profile. In particular, adverse reactions regarded as class-typical of fluoroquinolones, such as, e.g., electrocardiogram (ECG) changes, neurotoxic effects, or hypoglycemia, were not observed in the study population.

Sotrastaurin and cyclosporine drug interaction study in healthy subjects.

Introduction. Sotrastaurin is an immunosuppressant that inhibits protein kinase C and blocks T‐lymphocyte activation. The authors determined the effect of combining sotrastaurin with the calcineurin inhibitor cyclosporine on the pharmacokinetics and biomarker responses to both drugs. Methods. This was a randomized, 4‐period, crossover study in 20 healthy subjects who received single oral doses of (1) sotrastaurin 100 mg, (2) cyclosporine 400 mg, (3) 100 mg sotrastaurin with 100 mg cyclosporine and (4) 100 mg sotrastaurin with 400 mg cyclosporine. Blood samples were collected to measure drug levels and biomarkers of T‐lymphocyte activation (interleukin‐2 and tumor necrosis factor producing T‐cells and interleukin‐2 messenger RNA levels) and of T‐lymphocyte proliferation (thymidine uptake). Results. Sotrastaurin did not alter cyclosporine AUC; however, low‐dose and high‐dose cyclosporine increased sotrastaurin AUC by 1.2‐fold [90% confidence interval, 1.1–1.4] and 1.8‐fold [1.6–2.1], respectively. Adding high‐dose cyclosporine to a low‐therapeutic dose of sotrastaurin significantly enhanced the inhibition of cytokine production by 31% [95% confidence interval, 25–36%], of interleukin‐2 messenger RNA levels by 13% [7–19%], and of thymidine uptake by 37% [32–42%] compared with sotrastaurin alone. Addition of low‐dose cyclosporine elicited slightly lower enhancements in inhibition by 21% [14–28%], 6% [−4–16%], and 26% [21–30%], respectively, compared with sotrastaurin alone. Conclusions. Sotrastaurin did not alter the pharmacokinetics of cyclosporine, but cyclosporine increased sotrastaurin AUC up to 1.8‐fold. The combined drugs elicited a significantly greater inhibition of T‐cell activation and proliferation than sotrastaurin alone. Copyright

Humoral immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with MK-7123, a selective CXCR2 antagonist

Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34-65 years) dosed once daily for 30 days either with 30 mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty-eight days postvaccination, seroconversion (anti-HAV IgG titer≥10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (±SE) titers were 27.3±5.5 and 21.4±4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123.