Pharmacokinetics of Midazolam in preterm neonates with an insight in brain Tissue: A PBPK approach.

Physiological maturity is a gradual process taking place throughout infancy and childhood. Though for years anatomical growth has been the basis for dose calculation in pediatric population, physiological immaturity can-not be overlooked especially in neonates. The potential difference in physiology can significantly affect the outcomes of treatment and may result in under dosing or over-dosage. For many ethical and logistic constrains, carrying out pharmacokinetic studies of pharmacological agents in neonatal population remains a challenging task and such data is therefore, insufficient. This work presents Physiologically Based Pharmacokinetic modeling approach to predict the disposition of IV Midazolam in preterm neonates of different gestational ages, validated by the experimental studies. Furthermore, midazolam concentration in brain tissue of these neonates- the major site of its action- has been noted. The predicted and observed plasma pharmacokinetic parameters are comparable. This article demonstrates the usefulness of in-silico approach for finding out the PK parameters in neonates which may aid in deciding the frequency of drug administration in this population.

Anticancer effect of Indanone-based thiazolyl hydrazone derivative on p53 mutant colorectal cancer cell lines: An in vitro and in vivo study.

Colorectal cancer is a major health problem, and it is the third most diagnosed cancer in the United States. The current treatment for colorectal cancer includes irinotecan, a topoisomerase I inhibitor, and other targeted drugs, such as bevacizumab and regorafenib. The low response rates and incidence of high toxicity caused by these drugs instigated an evaluation of the anticancer efficacy of a series of 13 thiazolyl hydrazone derivatives of 1-indanone, and four compounds among them show favorable anticancer activity against some of the tested colorectal cancer cell lines with IC50 values ranging from 0.41 ± 0.19 to 6.85 ± 1.44 µM. It is noteworthy that one of the indanone-based thiazolyl hydrazone (ITH) derivatives, N-Indan-1-ylidene-N'-(4-Biphenyl-4-yl-thiazol-2-yl)-hydrazine (ITH-6), has a better cytotoxicity profile against p53 mutant colorectal cancer cells HT-29, COLO 205, and KM 12 than a p53 wild-type colorectal cancer cell line, such as HCT 116. Mechanistic studies show that ITH-6 arrests these three cancer cell lines in the G2/M phase and induces apoptosis. It also causes a rise in the reactive oxygen species level with a remarkable decrease in the glutathione (GSH) level. Moreover, ITH-6 inhibits the expression of NF-κB p65 and Bcl-2, which proves its cytotoxic action. In addition, ITH-6 significantly decreased tumor size, growth rate, and tumor volume in mice bearing HT-29 and KM 12 tumor xenografts. Moreover, CRISPR/Cas9 was applied to establish an NF-κB p65 gene knockout HT-29 cell line model to validate the target of ITH-6. Overall, the results suggest that ITH-6 could be a potential anticancer drug candidate for p53 mutant colorectal cancers.

WB-PBPK approach in predicting zidovudine pharmacokinetics in preterm neonates.

Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically. The present work describes the whole body physiologically based pharmacokinetic (WB-PBPK) model development for zidovudine in preterm neonates of varying gestational ages, to observe the pharmacokinetic behavior of the drug in this vulnerable group of the population. Along with the height, weight, post-natal, and gestational ages of the preterm neonates, metabolic enzymes CYP2A6, CYP2C8, etc. were incorporated for each neonate. The composition of the different organs in terms of water and lipid components, blood flow rates, etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 µmol min/L, Cmax 6.46 ± 0.74 µmol/L, half-life 8.98 ± 2.36 hr, mean residence time 12.23 ± 3.43 hr, and total plasma clearance 1.48 ± 0.19 ml/min/kg in comparison with the observed PK parameters of a clinical study by Mirochknic et al. in preterm neonates with AUC 2020.04 µmol/min/L, Cmax 6.10 µmol/L, and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational ages on the pharmacokinetic behavior of zidovudine in preterm neonates.

Enzyme and Transporter Kinetics for CPT-11 (Irinotecan) and SN-38: An Insight on Tumor Tissue Compartment Pharmacokinetics Using PBPK.

BACKGROUND: Computational tools are becoming more and more powerful and comprehensive as compared to past decades in facilitating pharmaceutical, pharmacological and clinical practice. Anticancer agents are used either as monotherapy or in combination therapy to treat malignant conditions of the body. A single antineoplastic agent may be used in different types of malignancies at different doses according to the stage of the disease. OBJECTIVE: To study the behavior of CPT-11 (Irinotecan) and its metabolite SN-38 in tumor tissue compartment through the Whole Body-Physiologically Pharmacokinetics (WB-PBPK) and to determine the activity of metabolic enzymes and transporters participating in the disposition of CPT-11 and SN-38 working in their physiological environment inside the human body. METHODS: Whole body PBPK approach is used to determine the activity of different metabolic enzymes and transporters involved in the disposition of CPT-11 and its active metabolite, SN-38. The concentrations and pharmacokinetic parameters of the parent compound and its metabolite administered at clinically applicable dose via the intravenous route in the tumor tissue are predicted using this approach. RESULTS: The activity rate constants of metabolic enzymes and transporters of CPT-11 are derived at their natural anatomic locations. Concentration-time curves of CPT-11 and SN-38 with their 5th to 95th percentage range are achieved at the tumor tissue level. Mean tumor tissue pharmacokinetics of both compounds are determined in a population of 100 individuals. CONCLUSION: Tumor tissue concentration-time curves of CPT-11 and SN-38 can be determined via PBPK modeling. Rate constants of enzymes and transporters can be shown for healthy and tumor bearing individuals. The results will throw light on the effective concentration of active compound at its target tissue at the clinically applied IV dose.

Prediction of Clearance and Dose of Midazolam in Preterm and Term Neonates: A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling.

Children are not small adults because besides size there are subtle physiological and biochemical differences between children and adults. Like adults, children also require medicine for the management or cure for the underlying diseases. To select a right dose in children, pharmacokinetic (PK) information is warranted. However, in many instances, a PK study in neonates and infants may not be possible. Therefore, various methods are used to predict PK parameters in this group of population, and these predicted parameters may help to calculate a safe dose for the very young children. Allometry is widely used for the prediction of PK parameters in children and subsequently one can predict dose from these predicted PK parameters. Physiologically based pharmacokinetic modeling (PBPK) has also become a useful tool to achieve these goals. Therefore, the objective of this study was to compare the predictive performance of allometry and PBPK for a test compound, midazolam in preterm, and term neonates. In this study, there were 5 preterm neonates (gestational age ranging from 34 to 37 weeks) and 5 term neonates (gestational age ranging from 38 to 41 weeks). PBPK modeling was performed using PK-Sim 6.0 and clearance, as well as midazolam dose in neonates was predicted. Clearance and midazolam dose in neonates was also predicted by allometric scaling. In this study, the allometric exponents for the prediction of midazolam clearance in preterm neonates and term neonates were 1.2 and 1.1, respectively. Similarly, for the prediction of midazolam neonatal dose, the exponent of allometry was either 0.9 or 1.0. The predicted midazolam clearance and dose by both methods were then compared with observed midazolam clearance and dose in neonates. The results of the study showed a slightly better prediction of midazolam clearance in neonates by PBPK than allometric scaling. However, the projected dose of midazolam in neonates was comparable between the 2 methods. Overall, it was noted that both PBPK and allometric model can be used to predict clearance and dose of midazolam in neonates.

Physiologically based pharmacokinetic modeling for predicting irinotecan exposure in human body.

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application. Mainly metabolized by hepatic route, and excreted through biliary tract, this dug has been found to possess high variation in patients in its pharmacokinetic (PK) profile. Physiologically based pharmacokinetic (PBPK) models using compartmental approach have attained their position to foresee the possible PK behavior of different drugs before their administration to patients and such models have been proposed for several anticancer agents. In this work, we used WB-PBPK technology to develop a model in a population of tumor patients who used IV irinotecan therapy. This model depicted the concentration of drug and its pharmacologically active metabolite in human body over a specific period of time. Knowledge about pharmacokinetic parameters is extracted from this profile and the model is evaluated by the observed results of clinical study presented in literature. The predicted behavior of the drug by this approach is in good agreement with the observed results and can aid in further exploration of PK of irinotecan in cancer patients, especially in those concomitantly suffer from other morbidity.

Prediction of Clearance in Neonates and Infants (≤ 3 Months of Age) for Drugs That Are Glucuronidated: A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling.

The objective of this study was to evaluate the predictive performances of allometric models and a physiologically based pharmacokinetic model (PBPK) to predict clearance of glucuronidated drugs in neonates (≤ 3 months of age). From the literature, clearance values for 9 drugs (glucuronidated) for neonates and adults were obtained. Three allometric models were used to predict clearances of these glucuronidated drugs. A PBPK model was developed using the physicochemical, biopharmaceutical, and metabolic properties together with known pediatric physiology and enzymatic ontogeny. The model was first developed for adult subjects and then verified using external data and then applied to simulations in neonates. The predictive performances of allometric and PBPK models were evaluated by comparing the predicted values of clearance with the observed clearance values in the neonates. For 9 drugs, there were 13 age groups (preterm and term neonates) for which prediction error in mean clearance values within 0.5- to 1.5-fold was observed in 10 and 11 age groups by 2 allometric models and a PBPK model, respectively. The proposed allometric methods can predict mean clearances of glucuronidated drugs in preterm and term neonates (≤ 3 months of age) with reasonable accuracy (within 0.5- to 1.5-fold or 50% error) and are of practical value during neonatal drug development. The predicted mean clearance values of glucuronidated drugs in neonates ≤ 3 months of age by 2 allometric methods were comparable with the PBPK model.

Analyses of bile from gallbladders of Arius platystomus, Arius tenuispinis, Pomadasys commersonni and Kishinoella tonggol.

Bile from gallbladders of Arius platystomus (Singhara), Arius tenuispinis (Khagga), Pomadasys commersonni (Holoola) and Kishinoella tonggol (Dawan) were derivatised and analysed by GC-MS for identification of bile acids and bile alcohols. Cholic acid and Chenodeoxycholic acid were found as major bile acids in Arius platystomus, Arius tenuispinis and Pomadasys commersonni. Other bile acids identified in Arius platystomus were allochenodeoxycholic acid, allodeoxycholic acid, 3α,7α,12α-trihydroxy-24-methyl-5ß-cholestane-26-oic acid, and 3α,7α,12α, 24-tetrahydroxy-5α-cholestane-26-oic acid. Cholesterol was found as major bile alcohol in Arius platystomus, Arius tenuispinis and Pomadasys commersonni. Cholic acid was the major bile acid identified in the bile of Kishinoella tonggol while other bile acids included 3α,7α,12α-tridydroxy-5α-cholestanoic acid and 3α,7α,12α-tridydroxy-5ß-cholestanoic acid. Bile alcohol 5ß-cyprinol was present in significant amounts with 5ß-cholestane-3α,7α,12α,24-tetrol being the other contributors in the bile of Kishinoella tonggol.

Antineoplastic activity of Holoptelea integrifolia (Roxb.) Planch bark extracts (in vitro).

Cancer remains the major public health concern with a number of cancer patients relying on chemotherapy as a treatment option. Although, advances in biomedical research have led to increased anticancer agents in recent years, the treatment is not always effective due to resistance, toxicity or other factors. Phytochemicals and their active components isolated from plants have provided diversified effective drugs many of them are currently used against cancer and other diseases. Holoptelea integrifolia (Roxb) Planch (Ulmaceae) is a widely distributed plant in many parts of the world, also grown in gardens of Pakistan. It is an ornamental plant with certain medicinal characteristics due to many valuable and active phyto constituents in various parts of the plant. We looked at in vitro antineoplastic effects of four different extracts, in butanol (BMBU), hexane (BMHx), ethyl acetate (BMET) and chloroform (BMCHF), from bark of Holoptelea integrifolia on small cell lung cancer, breast, prostate, coloretal and hepatocellular cancer cell lines. Plant extracts BMHx and BMET showed significant cytotoxic effects on breast and prostate cancer cells. These preliminary studies are encouraging to proceed further this research in future, regarding the isolation of active phytoconstituents in these extracts as well as its mechanism in chemoprevention and combination anticancer therapy.