Correlation analysis of target selectivity and side effects of FDA-approved kinase inhibitors

Kinase inhibitors (KIs) represent a popular class of therapeutic agents and chemical probes but most of them tend to be polypharmacological. Receptor and non-receptor Tyrosine KIs can target more than 100 kinases simultaneously compare to other KIs. We here analyze the molecular targets of 41 U.S. Food and Drug Administration (FDA)-approved KIs. We chose 18 drugs (Tyrosine KIs) and sought out to evaluate their selectivity profile and engagement with a number of targets in vivo at clinically relevant doses . We also wanted to see whether there prevails any correlation between the target engagement profile and the reported side effects for specific KIs chosen as test cases. To explore all clinical targets of the 18 KIs, we considered the free (unbound) maximum serum concentration (Cmax) of each KI and only chose targets for which the cognate affinities lie within the reported free Cmax values, thereby allowing plausible interaction in clinical doses. We retrieved the side effects of those KIs that is reported in the FDA adverse event reporting system. We illustrate how correlation analysis of target−side effect can give a new insight into the off target of KIs and their effect on increasing the toxicity of KIs. These analyses could aid our understanding of the structural-activity relationship of KIs.

Factors influencing infusion-related reactions following dosing of reference rituximab (RTX) and PF-05280586, a RTX biosimilar.

e20049 Background: Rituximab (RTX) is an effective therapy for some patients with CD20 positive (CD20+), B-cell malignancies. Infusion-related reactions (IRRs) are the most common adverse event (AE) associated with infusion of RTX. The objective of this analysis was to assess if IRRs were correlated with infusion rates of the first dose of the RTX biosimilar PF-05280586 (RTX-PF) or reference RTX sourced from the EU (RTX-EU). Methods: This analysis incorporates data from a randomized, double-blind comparative trial of 394 patients (RTX-PF, n = 196; RTX-EU, n = 198) with low tumor burden follicular lymphoma. RTX was administered at a dose of 375 mg/m2 on days 1, 8, 15 and 22 (one cycle), with a follow-up period through 52 weeks. Logistic regression analysis was performed with infusion rate and treatment or maximum serum concentration (Cmax) as independent variables. Treatment or Cmax was excluded from the model if not significant. Descriptive statistics of baseline CD20+ B-cell level, baseline anti-drug antibody (ADA) status and baseline tumor burden (Ann Arbor stage and bone marrow biopsy lymphoma results) were summarized by occurrence of IRR (yes/no). Results: The median RTX infusion duration on day 1 was 3.50 h for each of the two treatments. There was a significant positive correlation between infusion rate and all-grade IRR AEs occurring within 24 h after infusion (p < 0.0001). The estimated probability of developing an IRR was 0.16 and 0.29 at infusion rates of 189 mg/h and 227 mg/h, respectively. The estimated odds ratio with an increase in rate of 100 mg/h was 7.7. Treatment (RTX-PF or RTX-EU) was not a significant covariate and was excluded from the model. There was a non-significant trend between Cmax of RTX and developing an IRR; the estimated probability of developing an IRR was 0.26 at the median Cmax (196.5 μg/mL) of RTX. Patients who developed IRRs had a higher median baseline CD20+ B-cell level. The trough plasma concentration (Ctrough), collected before the second dose, and baseline tumor burden did not correlate with increased IRR incidence. Baseline ADA status did not predict IRR outcome. Conclusions: The results of this analysis suggest that higher infusion rates of RTX, administered as RTX-PF or RTX-EU, are positively correlated with IRR after the first dose. Clinical trial information: NCT02213263 .

Steady-State Pharmacokinetics of Oral Ciprofloxacin in Continuous Cycling Peritoneal Dialysis Patients: Brief Report

Steady-state pharmacokinetics of oral ciprofloxacin in 3 continuous cycling peritoneal dialysis (CCPD) outpatients given ciprofloxacin 750 mg b.i.d. for 5 doses was determined. Mean steady-state maximum serum concentration and half-life were 4.4 ±1.5 mg/L and 10.3 ± 2.6 hours, respectively. Mean maximum dialysate concentration in the daytime long dwell and overnight continuous cycling dwell were 7.4 ± 1.2 mg/L and 3.3 ± 1.2 mg/L, respectively. Oral ciprofloxacin 750 mg b.i.d. may be reasonable for bloodstream and peritoneal infections caused by susceptible bacteria in CCPD patients.

Effect of three anticoccidials on pharmacokinetics of tilmicosin in broiler chickens

The disposition kinetic of tilmicosin (25mg/kg) was studied following oral administration alone, pretreated with amprolium (240 ppm), pretreated with diclazuril (2.5 ppm) and pretreated with toltrazuril (25 ppm) in broiler chickens. The serum tilmicosin concentrations were determined by microbiological assay technique using Bacillus subtilis (ATCC 6633) as the test organism. Following oral administration of tilmicosin, the disposition curve was best described by two-compartment open model. The maximum serum concentration (Cmax) was 1.90 ± 0.11, 1.27 ± 0.13, 1.50 ± 0.14 and 1.41 ± 0.11µg/ml for tilmicosin alone and in the presence of amprolium, diclazuril and toltrazuril, respectively. The elimination half-life (T0.5 (el)) was significantly decreased (5.28 ± 0.30, 5.88 ± 0.33, 6.03 ± 0.25 h, respectively) in amprolium, diclazuril and toltrazuril pretreated broiler chicken compared to tilmicosin alone (7.30 ± 0.41 h). The outcomes illustrated a significant decrease in the interval between doses in amprolium, diclazuril and toltrazuril pretreated broiler chicken compared to tilmicosin alone. Amprolium diclazuril and toltrazuril, resulted in a significance decrease in AUC (12.02 ± 1.14, 15.50 ± 1.26 and 14.56 ± 1.46 µg.h.ml-1, respectively) compared to tilmicosin alone (21.98±1.83 µg.h.ml-1). It is concluded that the administration of amprolium, diclazuril and toltrazuril before tilmicosin would altered its pharmacokinetic profile in broiler chicken.

Influence of Flunixin on the Disposition Kinetic of Cefepime in Goats

The pharmacokinetic profile of cefepime (10 mg/kg b.w.) was studied following intravenous and intramuscular administration of cefepime alone and coadministered with flunixin (2.2 mg/kg b.w.) in goats. Cefepime concentrations in serum were determined by microbiological assay technique usingEscherichia coli(MTCC 443) as test organism. Following intravenous injection of cefepime alone and in combination with flunixin, there are no significant changes in the pharmacokinetic parameters. Following intramuscular injection of cefepime alone and in combination with flunixin, the maximum serum concentration was significantly increased in flunixin coadministered group compared with cefepime alone. However, no significant changes were reported in other pharmacokinetic parameters. The result ofin vitroprotein binding study indicated that 15.62% of cefepime was bound to goat’s serum protein. The mean bioavailability was 92.66% and 95.27% in cefepime alone and coadministered with flunixin, respectively. The results generated from the present study suggest that cefepime may be coadministered with flunixin without change in dose regimen. Cefepime may be given intramuscularly at 12 h intervals to combat susceptible bacterial infections.

Helicobacter pylori Eradication by Sitafloxacin-Lansoprazole Combination and Sitafloxacin Pharmacokinetics in Mongolian Gerbils and ItsIn VitroActivity and Resistance Development

ABSTRACTA total of 293 strains ofHelicobacter pylori, including strains resistant to levofloxacin, clarithromycin, metronidazole, or amoxicillin, were examined forin vitrosusceptibility to 10 antimicrobial agents. Among these agents, sitafloxacin (a fluoroquinolone) showed the greatest activity (MIC90, 0.06 μg/ml), with high bactericidal activity and synergy in sitafloxacin-lansoprazole (a proton pump inhibitor) combination. In a Mongolian gerbil model with aH. pyloriATCC 43504 challenge, marked eradication effects were observed at ≥1 mg/kg for sitafloxacin, ≥10 mg/kg for levofloxacin, and ≥10 mg/kg for lansoprazole, reflecting MIC levels for each agent (0.008, 0.25, and 2 μg/ml, respectively). The therapeutic rates were 83.3% for the sitafloxacin (0.3 mg/kg)-lansoprazole (2.5 mg/kg) combination and 0% for either sitafloxacin or lansoprazole alone. The maximum serum concentration (Cmax) of sitafloxacin was 0.080 ± 0.054 μg/ml at 30 min, when orally administered at 1 mg/kg. The simultaneous administration of lansoprazole resulted in no difference. In the resistance development assay, MICs of levofloxacin increased 64- to 256-fold withgyrAmutations (Ala88Pro and Asn87Lys), while MICs of sitafloxacin only up to 16-fold with the Asn87Lys mutation. The data suggest that sitafloxacin exhibited superior anti-H. pyloriactivity with low rates of resistance developmentin vitroand that, reflecting highin vitroactivities, sitafloxacin-lansoprazole combination exhibited strong therapeutic effects in Mongolian gerbils with aCmaxof sitafloxacin that was 10-fold higher than the MIC value at a 1-mg/kg administration.

Bacterial Strain-to-Strain Variation in Pharmacodynamic Index Magnitude, a Hitherto Unconsidered Factor in Establishing Antibiotic Clinical Breakpoints

ABSTRACT Antibiotic pharmacodynamic modeling allows variations in pathogen susceptibility and human pharmacokinetics to be accounted for when considering antibiotic doses, potential bacterial pathogen targets for therapy, and clinical susceptibility breakpoints. Variation in the pharmacodynamic index (area-under-the-concentration curve to 24 h [AUC24]/MIC; maximum serum concentration of drug in the serum/MIC; time the serum concentration remains higher than the MIC [T > MIC]) is not usually considered. In an in vitro pharmacokinetic model of infection using a dose-ranging design, we established the relationship between AUC24/MIC and the antibacterial effect for moxifloxacin against 10 strains of Staphylococcus aureus. The distributions of AUC24/MIC targets for 24-h bacteriostatic effect and 1-log, 2-log, and 3-log drops in bacterial counts were used to calculate potential clinical breakpoint values, and these were compared with those obtained by the more conventional approach of taking a single AUC24/MIC target. Consideration of the AUC24/MIC as a distribution rather than a single value resulted in a lower clinical breakpoint.

Pharmacokinetics of Calcitriol and Maxacalcitol Administered into Peritoneal Dialysate Bags in Peritoneal Dialysis Patients

Objectives It is well known that injection of calcitriol (CT) or maxacalcitol (OCT) is very effective in hemodialysis patients with secondary hyperparathyroidism (2HPT). However, it is difficult to use these drugs with peritoneal dialysis (PD) patients with 2HPT because these drugs must be injected two or three times per week. The objective of the present study was to evaluate the stability of physiological activities of CT and OCT in PD bags and to determine the CT or OCT dosage for intraperitoneal (IP) administration. Materials and Methods We added CT 1.5 μg or OCT 10 μg to Dianeal PD-2 (approximate pH = 5.0, calcium = 0.87 mmol/L; Baxter, Tokyo, Japan), Midpeliq 250 (approximate pH = 7.0, Ca = 1.0 mmol/L; Terumo Corporation, Tokyo, Japan), and Peritoliq 250 (approximate pH = 5.5, Ca = 1.0 mmol/L; Terumo Corp.). Dialysis solutions were collected from the PD bags at 0, 1, 4, 8, 12, 24, 48, and 72 hours after addition of CT and OCT. The activities of CT and OCT in the dialysis effluent were measured by radioimmunoassay. The levels of serum and effluent OCT after a single IP administration of 10 μg OCT were examined in 4 PD patients with advanced 2HPT. Results Although the levels of CT and OCT in PD bags made of polyvinyl resins decreased by 70% – 75% immediately after injection, levels in PD bags made of polypropylene resins decreased only slightly. The concentration of CT mixed into the acidic solution in glass containers was stable; the decreased concentration of CT in the PD solution might be due to adsorption onto polyvinyl resins. The maximum serum concentration after IP administration of 10 μg OCT was 750 pg/mL after 5 minutes, and remained at 500 pg/mL at 60 minutes. These results show good peritoneal transport of OCT but not rapid disappearance, unlike intravenous administration. Conclusions If peritoneal administration of vitamin D derivatives is contemplated, it is important to select the composition of PD bag resins, type of vitamin D analog, and time lag to use when deciding the dosage of injectable vitamin D preparations, such as OCT or CT, for IP administration to PD patients. It appears that IP administration in overnight dwells might be useful for PD patients as a complementary vitamin D preparation.