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.

Clinical Efficacy and Safety of Injectable Levetiracetam Versus Phenytoin as Second-Line Therapy in the Management of Generalized Convulsive Status Epilepticus in Children: An Open-Label Randomized Controlled Trial.

BACKGROUND AND PURPOSE: There is sparsity of quality evidence for the use of drugs after first-line benzodiazepines in convulsive status epilepticus in children. The aim of the study was to compare the clinical efficacy and safety of intravenous levetiracetam versus intravenous phenytoin as second-line drugs in the management of generalized convulsive status epilepticus in children. METHODS: This open-label randomized controlled trial was conducted in the Emergency Department of The Children's Hospital and The Institute of Child Health, Multan, Pakistan over a period of 4 years and 6 months from January 2014 to June 2018. This study included 600 children with generalized convulsive status epilepticus: 300 in the 40 mg/kg levetiracetam group, and 300 in the 20 mg/kg phenytoin group. Cessation of a clinical seizure (seizure cessation rate) within 30 minutes after the end of drug administration was the primary outcome in this study, and the presence or absence of adverse effects was noted as the secondary outcome. Data were analyzed using SPSS (version 20.0). RESULTS: The children in the levetiracetam and phenytoin were aged 3.5±0.2 and 3.4±0.2 years (mean±SD), respectively, their seizure durations before the start of treatment were 25.1±0.6 and 23.8±0.4 minutes, and their treatment efficacies were 278/300 (92.7%) and 259/300 (83.3%). Levetiracetam was significantly more effective than phenytoin (p=0.012), with no significant difference in safety. Adverse events were observed in eight children in the phenytoin group. CONCLUSIONS: Levetiracetam is significantly more effective than phenytoin for the treatment of convulsive status epilepticus in children who have failed to respond to benzodiazepines.

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.

Current Status and Future Suggestions for Improving the Pharm. D Curriculum towards Clinical Pharmacy Practice in Pakistan.

Objectives & Background: Good curriculum is reflected as the backbone for standard universities to develop competitive professionals having great potential. Pharmacy education in Pakistan has gone through the same developmental stages as in other countries, but is still striving for improvement. In the present study, we want (i) to know the opinion on whether the current pharmacy curriculum requires any improvement in order to meet the training needs of pharmacy professionals regarding clinical knowledge and pharmacy practice; and (ii) to present some humble suggestions to decision-making authorities in order to improve it with respect to patient-focused programs (PFP). Methods: The study was conducted in two sessions. In first session, a questionnaire was distributed to pharmacy students of eight public/private sector universities of Karachi (N = 354) offering Pharm. D degrees. The second session dealt with the pharmacy teachers, deans, and practicing pharmacists in health care facilities (who are in any ways also related to academia), in order to take their opinions on and suggestions for the development of a better Pharm. D curriculum (N = 135). Results: Our results showed that 75.2% of respondents agree that the Pharm. D curriculum does not meet the international standards of practice, and 88.4% of respondents support the addition of more clinical aspects than industrial ones, as Pharm. D could be both clinically and industrially oriented, according to the needs of the Pakistani people. Furthermore, 80.2% of respondents are of the view that an apprenticeship should be included in last two years, while 88.4% demand a 'paid residency program' to facilitate the hospital, clinical and compounding areas of pharmacy. In addition, we also received a number of verbal suggestions for improving the Pharm. D curriculum being followed in Pakistan. Discussion & Conclusions: We conclude that our Pharm. D curriculum needs additions in terms of clinical practice by providing residencies and electives in health care settings. Accordingly, the need for a clinically oriented curriculum is highlighted in Pakistan, keeping in mind the continuing importance of the industrial viewpoint. Various studies have criticized the pharmacy curriculum in Pakistan in the past. Conversely, we suggest some changes in the curriculum, as change is always needed for a better tomorrow.

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.

Adverse drug reactions (ADRS) reporting: awareness and reasons of under-reporting among health care professionals, a challenge for pharmacists.

OBJECTIVES: To measure awareness about adverse drug reaction (ADRs) reporting among doctors, pharmacists and nurses and to determine reasons of ADRs under-reporting in Pakistan. METHODS: In present study, a self-administered questionnaire was used to measure the awareness level about ADRs reporting among health care professionals (HCPs) of Pakistan. This was a cross sectional study. RESULTS: Out of the respondents 51 % were physicians, 29.7 % pharmacists and 19.3 % were nurses. 65.5 % of HCP population observed ADRs, out of which only 57.4 % reported these in their respective hospitals. About 77.3 % of population understood the importance of reporting ADRs while 67.3 % of population agrees that pharmacists are chief personnel for the development of system. 71.8 % of HCPs agrees that ADRs are not reported because Community pharmacy lacks legally qualified pharmacists. Only 14.3 % of HCPs population knows that there is any ADR reporting organization in Pakistan. CONCLUSION: The study recommends the need of such reporting system and more than half of the studied population agreed that pharmacists are required in developing such system.