Population Pharmacokinetics of Dasatinib in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Dasatinib is one of the tyrosine kinase inhibitors. The main use of these agents is inhibition of cancerous cell proliferation. The therapeutic importance of tyrosine kinase inhibitors raises the necessity of many types of investigations, especially the pharmacokinetic analysis of these drugs in humans. This analysis, along with other investigations and clinical research, will contribute to the overall knowledge of the drug. This study focused on the population pharmacokinetics of dasatinib. The objective of the study was to investigate the sources of the variability of dasatinib in a population pharmacokinetics study in healthy participants. METHODS: We utilized 4180 plasma observations from 110 subjects who were administered SPRYCEL® on two separate occasions under fasting conditions; data from 20% of the subjects (22 subjects) were extracted for the purpose of internal model evaluation and data from 88 subjects were used in modeling. The model was evaluated by visual predictive check of three different datasets. A two-compartmental model with first order absorption and transit compartment was considered the simplest base model to describe the data based on the corrected Bayesian information criterion evaluation. Covariates were tested through conditional sampling for the stepwise approach-screening procedure in Monolix 2020R1 version. Conditional sampling for the stepwise approach was used to include the correlated covariates within the base model in the forward inclusion step and then to eliminate them backwardly to ensure that the key covariates were kept in the model at the final stage. RESULTS: The effect of body mass index on the absorption rate constant was considered as significant covariate in the final established model. Visual predictive check for simulations, 20% of the original dataset (internal dataset) and an external dataset demonstrated the appropriateness of the final model. CONCLUSIONS: Population pharmacokinetic modeling was performed to describe dasatinib pharmacokinetics in healthy subjects. Body mass index was considered as a factor that might be used in the future along with studies on patients to adjust the dosing regimens. KEY POINTS: Dasatinib is classified as a highly variable drug; this variability was demonstrated in the study by the effect of body mass index on the absorption rate constant.

Effect of low-pressure pneumoperitoneum on pain and inflammation in laparoscopic cholecystectomy: a randomized controlled clinical trial.

OBJECTIVE: We aim to assess the effect of low-pressure pneumoperitoneum on post operative pain and ten of the known inflammatory markers. BACKGROUND: The standard of care pneumoperitoneum set pressure in laparoscopic cholecystectomy is set to 12-14 mmHg, but many societies advocate to operate at the lowest pressure allowing adequate exposure of the operative field. Many trials have described the benefits of operating at a low-pressure pneumoperitoneum in terms of lower post operative pain, and better hemodynamic stability. But only few describe the effects on inflammatory markers and cytokines. METHODS: A prospective, double-blinded, randomised, controlled clinical trial, including patients who underwent elective laparoscopic cholecystectomy. Patients randomised into low-pressure (8-10 mmHg) vs. standard-pressure (12-14 mmHg) with an allocation ratio of 1:1. Perioperative variables were collected and analysed. RESULTS: one hundred patients were allocated, 50 patients in each study arm. Low-pressure patients reported lower median pain score 6-hour post operatively (5 vs. 6, p-value = 0.021) in comparison with standard-pressure group. Eight out of 10 inflammatory markers demonstrated better results in low-pressure group in comparison with standard-pressure, but the effect was not statistically significant. Total operative time and surgery difficulty was not significantly different between the two groups even in the hands of inexperienced surgeons. CONCLUSION: low-pressure laparoscopic cholecystectomy is associated with less post operative pain and lower rise of inflammatory markers. It is feasible with comparable complications to the standard of care. Registered on ClinicalTrials.gov (NCT05530564/ September 7th, 2022).

Population Pharmacokinetics Modeling of Lamotrigine in Jordanian Epileptic Patients Using Dried Blood Spot Sampling.

AIMS: To characterize the population pharmacokinetics of lamotrigine in Jordanian epileptic patients and to identify factors affecting therapeutic parameters. PATIENTS AND METHODS: A population pharmacokinetics model for lamotrigine was established based on a prospectively collected data of 52 steady-state concentrations from 38 adult and pediatric patients with epilepsy. Lamotrigine concentrations were determined by a dried blood spot liquid chromatography method. Data were analyzed according to a one-compartment model with first-order absorption and elimination using the nonlinear mixed effect modeling program. The covariates effect of total body weight, gender, age, and co-medication with topiramate, carbamazepine, phenytoin, phenobarbital, and valproic acid on lamotrigine clearance were investigated using a stepwise forward addition followed by a stepwise backward elimination. RESULTS: The final population pharmacokinetics model for lamotrigine clearance was as follows: CL/Fpop=θ1*exp (θ3*age)*exp (θ5*carbamazepine)*exp (θ6*valproic acid) , where θ1 is the relative clearance (L/hr) estimated, and θ3, θ5, and θ6 are the fixed parameters relating to age and co-medication with carbamazepine and valproic acid, respectively.The population mean value of lamotrigine total clearance generated in the final model (with covariates) was 2.12 L/hr. Inter-individual variability and residual unexplained variability expressed as the coefficient of variation was 37.1 and 26.1%, respectively. CONCLUSION: Lamotrigine total clearance in the Jordanian patients is comparable to that reported by others for Caucasian patients. Age and concomitant therapy with carbamazepine and valproic acid significantly affected lamotrigine clearance, and accounted for 48% of its inter-individual variability.

Efficacy of serratiopeptidase after impacted third molar surgery: a randomized controlled clinical trial.

BACKGROUND: Serratiopeptidase has been clinically used in controlling surgical and non-surgical inflammatory conditions. This study was conducted to assess the therapeutic effect of Serratiopeptidase in patients undergoing surgical removal of impacted mandibular third molar. METHODS: This randomized clinical trial investigated the efficacy of Serratiopeptidase and Paracetamol after surgical removal of impacted third molar for 5 days (n = 67) as compared with an equivalent dose of placebo and Paracetamol (n = 66). Outcome measures were reported pain, trismus and swelling using Laskin method. All outcome measures were recorded on days 0, 1, 2, 4, and 5 post-surgeries. RESULTS: In this clinical trail 133 patients (mean age 23 years, 54% female) completed the study. Baseline characteristics were comparable across treatment groups. Serratiopeptidase significantly improved trismus compared with control on the 4th day (27.30 ± 7.3 mm and 32.06 ± 7.7 mm, respectively (P < 0.001) Swelling markedly improved, The distance from the lower edge of the earlobe to the midpoint of the symphysis for cases vs control were 111.49 ± 8.1 mm and 115.39 ± 9.9 mm, respectively (P < 0.001). Reported pain, showed no statistical significance difference. CONCLUSION: Serratiopeptidase resulted in better inflammation improvement than placebo over 5 days. Further studies are warranted to assess longer-term and clinical outcomes, as well as safety. CLINICAL RELEVANCE: Serratiopeptidase administered postoperatively helps in improving trismus and swelling after removal of impacted lower third molars. Trial registration The study was registered in ClinicalTrial.gov under the number NCT02493179. Registered 1st of June 2015, https://clinicaltrials.gov/ct2/results?cond=serratiopeptidase .

Population Pharmacokinetics of Ibrutinib in Healthy Adults.

BACKGROUND AND OBJECTIVES: Ibrutinib is an antineoplastic agent that reduces B-cell proliferation by inhibiting Bruton's tyrosine kinase. We describes population pharmacokinetics of ibrutinib in healthy adults, and explores potential patient characteristics associated with ibrutinib pharmacokinetics. METHODS: A population pharmacokinetic modeling approach was applied to 39 healthy subjects. Modeling was performed using Monolix (v.2019R2). Serial blood samples to measure the plasma ibrutinib concentration were collected following the oral administration of 140 mg ibrutinib on two different occasions under fasting conditions. Demographic and clinical information were evaluated as possible predictors of ibrutinib pharmacokinetics during model development. Simulations (using mlxR: R package v.4.0.2) following the administration of therapeutic doses were performed to explore the clinical implications of identified covariates on ibrutinib steady-state concentrations. RESULTS: A two-compartment model with zero order absorption best fit the data. Inter-individual and inter-occasion variability were quantified by the proposed model. We identified smoking status as a significant covariate associated with ibrutinib clearance. Smoking was found to increase ibrutinib clearance by approximately 60%, which resulted in a reduction in simulated steady-state concentrations by around 40%. CONCLUSION: The model can be used to simulate clinical trials or various dosing scenarios. The proposed model can be used to optimize ibrutinib dosing based on the smoking status.

Wound infiltration with bupivacaine 0.5% with or without adrenaline does not decrease pain after thyroidectomy. A randomized controlled study.

OBJECTIVES: To study the effect of local wound infiltration with and without adrenaline on pain perception after thyroidectomy using the visual analog score (VAS).  Methods: A prospective randomized controlled double-blinded study was conducted between May 2015 and June 2016 at The University of Jordan Hospital, Amman, Jordan. Eighty-nine patients undergoing planned thyroidectomy were included in the study. Patients were divided randomly into 3 groups: Group A, local wound infiltration with bupivacaine 0.5% was administered; Group B, bupivacaine 0.5% with adrenaline was administered; Group C (control), no infiltration was performed. Standardized thyroidectomies were performed in the 3 groups. Pain perception was measured using VAS at 2, 4, 6, 12, and 24 hours after surgery. A comparison between the 3 groups was carried out. Results: No significant differences among the 3 groups were observed at all time points (p=0.246). Visual analog scores were significantly lower at 12 and 24 hours after operations.  Conclusion: Local wound infiltration with bupivacaine 0.5% does not decrease pain perception after thyroidectomy performed under general anesthesia, and adding adrenaline does not enhance its effect.

Development of a biphasic dissolution test for Deferasirox dispersible tablets and its application in establishing an in vitro-in vivo correlation.

In a biphasic dissolution medium, the integration of the in vitro dissolution of a drug in an aqueous phase and its subsequent partitioning into an organic phase is hypothesized to simulate the in vivo drug absorption. Such a methodology is expected to improve the probability of achieving a successful in vitro-in vivo correlation. Dissolution of Dispersible tablets of Deferasirox, a biopharmaceutics classification system type II compound, was studied in a biphasic dissolution medium using a flow-through dissolution apparatus coupled to a paddle apparatus. The experimental parameters associated with dissolution were optimized to discriminate between Deferasirox dispersible tablets of different formulations. The dissolution profiles obtained from this system were subsequently used to construct a level A in vitro-in vivo correlation.

Pharmacokinetic comparison of two 4 mg tablet formulations of tizanidine.

OBJECTIVES: To assess the bioequivalence of two Tizanidine 4 mg tablet formulations (Tizanidine® of the Pharma International company, as test product, and Sirdalud® of Novartis as a reference product), and to investigate possible effects of smoking on pharmacokinetics of tizanidine. METHODS: A single-blind, randomized, single dose, two treatment, two-period, two-sequence, crossover bioequivalence study with 1 week washout period in 36 healthy volunteers. The drug was administered with 240 ml of water after 10-hour overnight fasting. After dosing, serial blood samples were collected for a period of 14 hours. Plasma harvested from blood was analyzed for tizanidine by a newly developed method using HPLC coupled with an MS/MS detector. The limit of quantitation of tizanidine was 0.080 ng/ml. Matrix-based calibration curves were linear over the range 0.080 - 8.00 ng/ml for tizanidine. The between- day coefficient of variation for quality control samples was less than 10%. RESULTS: The average bioavailability measures and pharmacokinetic parameters of the two tizanidine tablets were as follows: peak plasma concentration, Cmax, was 1.21 ± 0.84 ng/ml and 1.28 ± 1.11 ng/ml for Tizanidine PIC® and Sirdalud®, respectively. The time to peak plasma concentrations tmax were 0.83 ± 0.43 and 1.01 ± 0.5 hours, while the plasma half-life (t1/2) values were 1.20 ± 0.84 and 1.29 ± 0.57 hours. The area under the plasma concentration-time profiles AUC0→last were 2.53 ± 2.10 ng×h/ml and 2.46 ± 2.23 ng×h/ ml, whereas the AUC0→∞were 2.81 ± 2.27 ng×h/ml and 2.75 ± 2.37 ng×h/ml for Tizanidine PIC® and Sirdalud®, respectively. The mean residence time (MRT) values were 2.16 ± 0.693 hours and 2.33 ± 0.65 hours. The 90% confidence intervals for test/reference ratio of Cmax, AUC0→last and AUC0→∞ were found within the acceptable limits of 0.00 -125.00%, consequently no significant difference was found between the test and reference. CONCLUSION: Based on the pharmacokinetic and statistical results, it was concluded that; Tizanidine PIC® 4 mg tablets is bioequivalent to Sirdalud® 4 mg tablets of Novartis and smoking decreases Cmax and AUC of tizanidine.

Influence of ethanol on swelling and release behaviors of Carbopol(®)-based tablets.

The aim of this work was to investigate the effect of ethanol on the in vitro swelling and release behaviors of Carbopol(®)-based tablets. The swelling behavior of drug-free compacts and the release of model drugs (metformin HCl, caffeine and theophylline) from matrix tablets were evaluated in acidic and buffered media with 0, 20 and 40% (v/v) ethanol. Release data were analyzed by fitting to Higuchi and Peppas models and calculation of similarity factor (f2). ANOVA tests were performed to determine significant factors on swelling and release. It was found that ethanol affects swelling and erosion of drug-free Carbopol(®) compacts, and the effect was highly dependent on medium pH. For matrix tablets, no dose dumping due to ethanol was manifested. The release rate and mechanism, however, were significantly affected by ethanol concentration as indicated by ANOVA applied to the constant, KH, from Higuchi model and the exponent, n, from Peppas model, respectively. The effect of ethanol on release was further confirmed by similarity factor results, which indicated that ethanol led to different release profiles (f2 < 50) in seven of eight cases for matrices containing metformin HCl and in three of eight cases for matrices containing caffeine and theophylline.

Comprehensive assessment of treatment related problems in hospitalized medicine patients in Jordan.

OBJECTIVES: The aim of this study was to identify the prevalence and characteristics of treatment related problems (TRPs) in hospitalized internal medicine patients in Jordan as well as to identify diseases and drugs associated with each specific TRP. We have also aimed at investigating physicians' acceptance of recommendations made by clinical pharmacist and to identify the outcomes of pharmacist interventions. SETTING: Internal medicine department of a general hospital in Jordan. METHODS: We have utilized a systematic, prospective, bedside, comprehensive clinical assessment approach that allowed us to effectively identify, communicate and follow up TRPs. MAIN OUTCOME MEASURES: prevalence and nature of identified TRPs, clinical significance of TRPs, associated diseases and drugs and clinical outcomes of clinical pharmacist interventions. RESULTS: 402 patients were included in the study. The average number of the identified TRPs was 9.35. Fifty-three percent of identified TRPs were classified as major and 28% were classified as moderate. Ninety-one percent of the recommendations were accepted by physicians. Efficacy related problems were the most common TRP category followed by safety related problems and indication related problems. Sixty-four percent of the TRPs were resolved or prevented through the clinical pharmacist intervention. CONCLUSIONS: We have found that prevalence of TRPs is substantially high among patients hospitalized at the internal medicine department. TRPs related to Dosage regimens, untreated conditions, patient monitoring, drug interactions, and drug choices were the most common. Most of TRPs identified by pharmacists were clinically significant. Pharmacists' interventions contributed substantially to the resolving of many of the identified TRPs. Patients suffering from higher number of medical conditions and receiving higher number of medications should be given the priority for clinical pharmacy service in hospitalized internal medicine patients.

The effects of pummelo juice on pharmacokinetics of sildenafil in healthy adult male Jordanian volunteers.

PURPOSE: The main purpose of this work was to investigate the effect of pummelo juice on the pharmacokinetics of sildenafil after oral administration. METHODS: This was a comparative, randomized, two-period, two-treatment, two-sequence, single dose, crossover study investigating the effect of pummelo juice on the pharmacokinetics of sildenafil citrate tablets (equivalent to 50 mg sildenafil) in healthy male participants under fasting conditions compared with water as a control. Six healthy normal adult males were administered 50 mg sildenafil with pummelo juice or water at two different periods in a crossover study. RESULTS: Study results showed that pummelo juice reduced the rate and extent of sildenafil bioavailability to around 60% [maximum plasma concentration (C(max)); from 212.44 ng/ml to 134.07 ng/ml, 90% confidence interval (90% CI) 44.70-89.11, and area under the plasma concentration time curve from zero to infinity (AUC(infinity)); from 564.51 ng.hr/ml to 336.87 ng.hr/ml, 90% CI 39.17-90.92]. This interaction was opposite to that expected and is speculated to be due to either an effect on transporters or a physicochemical interaction between sildenafil and some components of the juice. CONCLUSION: Patients should be advised not to drink pummelo juice before or immediately after taking sildenafil.

Development of a predictive in vitro dissolution for clarithromycin granular suspension based on in vitro-in vivo correlations.

The objective of this study was to evaluate the in vitro behavior of different clarithromycin granular suspensions based on a developed in vitro-in vivo correlation model, using one reference and two test formulations. In vitro release rate data were obtained for each product using the USP apparatus II, operated at 50 rpm under different pH conditions. The dissolution efficiency was used to analyze the dissolution data. In vivo study was performed on six healthy male volunteers under fasting condition. Correlation was made between in vitro release and in vivo absorption. A linear model was developed using percent absorbed data versus percent dissolved data from the three products. Dissolution condition of 0.1N HCl for 1 h and then phosphate buffer at pH 6.8 was found to be the most discriminating dissolution method. Rate of absorption for the reference as estimated by Wagner-Nelson deconvolution was correlated with in vitro release with a correlation coefficient of 0.99. The in vivo results for the two test products were compared to the predicted values using the reference model with a correlation coefficient of 0.94. Furthermore, multiple level C correlations were obtained for some pharmacokinetic parameters with the corresponding in vitro kinetic parameters with correlation coefficients exceeding 0.90. Moreover, the interpretation of the in vitro and in vivo data with reference to formulations was discussed.

Sustained release characteristics of tablets prepared with mixed matrix of sodium carrageenan and chitosan: effect of polymer weight ratio, dissolution medium, and drug type.

The interpolymeric complexation of carrageenan and chitosan was investigated for its effect on drug release from polymeric matrices in comparison to single polymers. For this purpose, matrices with carrageenan: chitosan (CG:CS) ratios of 100%, 75%, 50%, 25%, and 0% were prepared at 1:1 drug to polymer ratio. The effect of dissolution medium and drug type on drug release from the formulations was addressed. Two model drugs were utilized: diltiazem HCl (DZ) as a salt of a basic drug and diclofenac Na (DS) as a salt of an acidic drug. Three dissolution media were used: water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). Some combinations of the two polymers showed remarkable sustained release effect on DZ in comparison to the single polymers in water and SGF. However, no apparent effect for the combination on DZ release was shown in SIF. The medium effect was explained by the necessity of chitosan ionization, which could be attained by the acidic SGF or microacidic environment created by the used acidic salt of DZ in water, but not in SIF. An interaction between the medium type and CG:CS ratio was also found. With DS, the polymer combinations had similar dissolution profiles to those of the single polymers in water and SIF, which was explained by the lack of chitosan ionization by the medium or the drug basic salt. The dissolution profiles could not be obtained in SGF, which was attributed to the conversion of DS into diclofenac free acid. The importance of chitosan ionization for its interaction with CG to have an effect on the release of DS was demonstrated by performing dissolution of SGF presoaked tablets of DS in SIF, which showed an effect of combining the two polymers on sustaining the drug release.

QSPR modeling of pseudoternary microemulsions formulated employing lecithin surfactants: application of data mining, molecular and statistical modeling.

Data mining, computer aided molecular modeling, descriptor calculation, genetic algorithm and multiple linear regression analysis techniques were combined together to generate predictive quantitative structure property relationship (QSPR) models explaining the formation of lecithin-based W/O microemulsions. Ninety-four microemulsion phase diagrams were collected from five different references published over the past few years. Computer-based molecular modeling techniques were then applied on the components of the collected microemulsion systems to generate corresponding plausible three-dimensional (3D) structures. The resulting 3D models were utilized to calculate a group of molecular physicochemical descriptors. Thereafter, genetic algorithm and backward stepwise regression analysis were separately assessed as means for selecting optimal descriptor sets for statistical modeling. The selected descriptors were correlated with microemulsion existence areas employing multiple linear regression analysis. The resulting W/O models were statistically validated and found to be of significant predictive power. The models allowed better understanding of the process of microemulsion formation. Unfortunately, all QSPR modeling efforts directed towards O/W microemulsions failed completely.

Development of quantitative structure-property relationship models for pseudoternary microemulsions formulated with nonionic surfactants and cosurfactants: application of data mining and molecular modeling.

Data mining, computer-aided molecular modeling, descriptor calculation and multiple linear regression techniques were utilized to produce statistically significant and predictive models for O/W and W/O microemulsions. The literature was scanned over the last 20 years, subsequently, 68 phase diagrams from eight different references were collected. Molecular modeling techniques were then applied on the components of the microemulsion systems to generate plausible 3-D structures. Subsequently, various physicochemical descriptors were calculated based on the resulting 3-D structures. The generated descriptors were correlated with microemulsion existence areas utilizing multiple linear regression analysis (MLR). The generated models were statistically cross-validated and were found to be of significant predictive power. Furthermore, the resulting models allowed better understanding of the process of microemulsion formation.