Current Issue : July-September Volume : 2022 Issue Number : 3 Articles : 5 Articles
Few articles have reported drug concentrations of different ophthalmic dosage forms in the ocular tissues. This study aimed to determine the ocular pharmacokinetics of gatifloxacin 0.3% eye gel (GTX-Gel) and gatifloxacin 0.3% eye solution (GTX-Sol) at different time intervals after topical instillation in rabbits. A total of 126 healthy New Zealand rabbits were included, of which six rabbits did not receive antibiotics (control group). The remaining rabbits were randomly divided into four groups. GTX-Gel and GTX-Sol (50 μL) were topically instilled every hour in groups A1 and B1, respectively, and every two hours in groups A2 and B2, respectively, for 12 h. Ocular tissues were collected 2, 4, 8, 12, and 24 h after administration. Gatifloxacin concentration was measured using high-performance liquid chromatography coupled with tandem mass spectrometry. The drug reached peak concentrations (Cmax) in all tissues at 8–12 h. With the same administration frequency, the Cmax was higher with GTX-Gel than with GTX-Sol (p < 0.05). Except for the iris-ciliary body, other ocular tissues did not show significant difference (p > 0.05) in gatifloxacin concentration between either pair of groups. Gatifloxacin ophthalmic gel was found to attain significantly higher concentrations than the ophthalmic solution in ocular tissues....
Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure–toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug–drug interactions (DDI).We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies....
The optimal regimens of cefmetazole and flomoxef for the treatment of urinary tract infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacterales are not well defined. Our study found that the pharmacokinetic/pharmacodynamic targets for cefmetazole and flomoxef were 70% T > MIC, which is suggestive of bactericidal activity. A Monte Carlo simulation (MCS) was performed using the published data to calculate a new probability of target attainment (PTA ≥ 90%) for each renal function. The MCS was performed with 1000 replicates, and clinical breakpoints were calculated to attain PTA ≥ 90% for creatinine clearance (CCR) of 10, 30, 50, and 70 mL/min. The 90% ≥ PTA (70% T > MIC) of cefmetazole and flomoxef in patients who received a standard regimen (0.5 or 1 g, 1 h injection) for each renal function was calculated. Our results suggest that in patients with CCR of less than 30, 31–59, and more than 60 mL/min, the optimal dosage of cefmetazole would be 1 g q12 h, 1 g q8 h, and 1 g q6 h, respectively. Furthermore, in patients with CCR of less than 10, 10–50, and more than 50 mL/min, the optimal dosage of flomoxef would be 1 g q24 h, 1 g q8 h or 12 h, and 1 g q6 h, respectively....
Tildipirosin is a macrolide currently authorized for treating respiratory diseases in cattle and swine. The disposition kinetics of tildipirosin in plasma, milk, and somatic cells were investigated in dairy goats. Tildipirosin was administered at a single dose of 2 mg/kg by intravenous (IV) and 4 mg/kg by intramuscular (IM) and subcutaneous (SC) routes. Concentrations of tildipirosin were determined by an HPLC method with UV detection. Pharmacokinetic parameters were estimated by non-compartmental analysis. Muscle damage, cardiotoxicity, and inflammation were evaluated. After IV administration, the apparent volume of distribution in the steady state was 7.2 L/kg and clearance 0.64 L/h/kg. Plasma and milk half-lives were 6.2 and 58.3 h, respectively, indicating nine times longer persistence of tildipirosin in milk than in plasma. Moreover, if somatic cells are considered, persistence and exposure measured by the area under concentration–time curve (AUC) significantly exceeded those obtained in plasma. Similarly, longer half-lives in whole milk and somatic cells compared to plasma were observed after IM and SC administration. No adverse effects were observed. In brief, tildipirosin should be reserved for cases where other suitable antibiotics have been unsuccessful, discarding milk production of treated animals for at least 45 days or treating goats at the dry-off period....
Urea transporter (UT) inhibitors are a class of promising novel diuretics that do not cause the imbalance of Na+, K+, Cl−, and other electrolytes. In our previous studies, 25a, a promising diuretic candidate inhibiting UT, was discovered and showed potent diuretic activities in rodents. Here, a sensitive liquid chromatography–tandem mass spectrometry method for the quantitation of 25a in rat plasma, urine, feces, bile, and tissue homogenates was developed and validated to support the preclinical pharmacokinetic studies. The tissue distribution, excretion, and plasma protein binding were investigated in rats. After a single oral dose of 25a at 25, 50, and 100 mg/kg, the drug exposure increased linearly with the dose. The drug accumulation was observed after multiple oral doses compared to a single dose. In the distribution study, 25a exhibited a wide distribution to tissues with high blood perfusion, such as kidney, heart, lung, and spleen, and the lowest distribution in the brain and testis. The accumulative excretion rate of 25a was 0.14%, 3.16%, and 0.018% in urine, feces, and bile, respectively. The plasma protein binding of 25a was approximately 60% in rats and 40% in humans. This is the first study on the preclinical pharmacokinetic profiles of 25a....
Loading....