Dostarlimab: Review on success story and clinical trials.

The PD-1/PD-L1 pathway plays a significant role in inhibiting, escaping from immune response, and promoting self-tolerance of the tumour. Dostarlimab is a selective humanized monoclonal antibody designed to target PD-1 and block its activity with PD-L1, which further prevents the escape of tumour cells from immune surveillance. It got accelerated approval from the FDA for treating adults with mismatch repair deficient, recurrent, or advanced endometrial cancer, and studies confirmed its beneficial effects. A recently published clinical trial reported 100 % remission of advanced rectal cancer without significant side effects in the participants. This clinical trial is still going on and enrolling patients with different types of cancer, including ovarian cancer, melanoma, head and neck cancer, and breast cancer therapy. The clinical trial result gave hope and proof to the medical fraternity and patients for better treatment. The focus of this review is to summarise pre-clinical and clinical studies of Dostarlimab.

A study to explore the appropriateness of dosing regimen of vancomycin in critically ill patients in a tertiary care unit of India.

Introduction: Vancomycin is used in proven or suspected MRSA and MRE infections. An AUC/MIC ratio of ≥400 is the current accepted critical PK/PD"efficacy" target of vancomycin activity. The present study was conducted to ascertain the appropriateness of practice of current dosage regimen of vancomycin (1 g BD) based on population pharmacokinetic approach. Methods: A single-center prospective study with the ICU setting of a tertiary care center was conducted. A total of 15 adult patients with sepsis treated with vancomycin were included over 15 months from May 2019 to July 2020. Blood samples were obtained at 5, 10, and 30 minutes and thereafter at 2 and 6 hours following the completion of the vancomycin infusion. The data obtained from HPLC estimation was analyzed using a population pharmacokinetic approach with NLME, Phoenix 8.3.2.166. The pharmacokinetic model was based on covariates such as bodyweight and urinary creatinine clearance to predict drug concentrations. Results: A total of 83 vancomycin blood samples were analyzed. The mean AUC0-last and AUC0-∞ in patients who improved and died were (AUC(0-last)=293 (152.97); AUC(0-∞)=535.14 (353.67) and (AUC(0-last)=137.19 (51.37); AUC(0-∞)=582.12 (1036.09) respectively, the difference between the two outcome groups was not statistically significant (p=0.104). The pharmacokinetic model was best described by a two-compartment linear model. The goodness-of-fit plots showed that the final covariate pharmacokinetic model (having bodyweight and urinary creatinine clearance) adequately described the observed vancomycin concentrations. Conclusions: Based on the finding of the study it was concluded that 1 g BD dosing of vancomycin is inappropriate. Including covariates such as urinary creatinine clearance and weight in the pharmacokinetic model helped predict drug concentrations more accurately. However, further studies are required to demonstrate efficacy regarding applying this strategy.

Pharmacokinetic and pharmacodynamic evaluation of nano-fixed dose combination for hypertension.

OBJECTIVE: The current study was planned to formulate, characterize and evaluate the pharmacokinetics, and pharmacodynamics of a novel 'NanoFDC' comprising hydrochlorothiazide, candesartan (CNDT) and amlodipine. METHODOLOGY: The candidate drugs were loaded in poly(DL-lactide-co-glycolide) by emulsion-diffusion-evaporation method. The formulations were evaluated for their size, morphology, drug loading and in-vitro release individually. Repeat dose pharmacokinetic and pharmacodynamic study of the nano-fixed dose combination (FDC) was done in dexamethasone-induced animal model. RESULTS: The entrapment efficiencies ranged from 44 ±â€Š2.1, 32.2 ±â€Š4 and 40.5 ±â€Š2.6% for amlodipine, hydrochlorothiazide and CNDT, respectively. The nanoparticles ranged in size from 164 to 215 nm. In-vitro release profile of the nanoformulation showed unto 90% release by day 7 in simulated gastric fluid and simulated intestinal fluid, respectively. In pharmacokinetic analysis a sustained-release for 7 days was observed in nano-FDC group. Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect which was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model. CONCLUSION: Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect and was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model. This study provides proof of concept of feasibility of once weekly dosing of a nano-FDC comprising three antihypertensive drugs, which can lead to significant improvement in patient adherence to therapy.

Effect of Acyclovir Solid Lipid Nanoparticles for the Treatment of Herpes Simplex Virus (HSV) Infection in an Animal Model of HSV-1 Infection.

BACKGROUND: Acyclovir use is limited by a high frequency of administration of five times a day and low bioavailability. This leads to poor patient compliance. OBJECTIVES: To overcome the problem of frequent dosing, we used nanotechnology platform to evaluate the proof of concept of substituting multiple daily doses of acyclovir with a single dose. METHODS: Acyclovir was formulated as solid lipid nanoparticles (SLN). The nanoparticles were characterized for particle size, surface charge and morphology and in vitro drug release. The pharmacokinetic and pharmacodynamic of SLN acyclovir were compared with conventional acyclovir in a mouse model. RESULTS: SLN showed drug loading of 90.22% with 67.44% encapsulation efficiency. Particle size was found to be of 131 ± 41.41 nm. In vitro drug release showed 100% release in SIF in 7 days. AUC0-∞ (119.43 ± 28.74 µg/ml h), AUMC0-∞ (14469 ± 4261.16 µg/ml h) and MRT (120.10 ± 9.21 h) were significantly higher for ACV SLN as compared to ACV AUC0-∞ (12.22 ± 2.47 µg/ml h), AUMC0-∞ (28.78 ± 30.16 µg/ml h) and MRT (2.07 ± 1.77 h), respectively (p<0.05). In mouse model, a single dose of ACV SLN was found to be equivalent to ACV administered as 400mg TID for 5 days in respect to lesion score and time of healing. CONCLUSION: The proof of concept of sustained-release acyclovir enabling administration as a single dose was thus demonstrated.