J Pharm Pharm Sci [keywords]
- Similarities and Differences of International Practices and Procedures for the Regulation for Active Substance Master Files/Drug Master Files of Human Use: Moving Toward Regulatory Convergence. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):290-301.
A gap analysis survey of international practices for Active Substance Master Files (ASMFs)/Drug Master Files (DMFs) of human use was conducted as a project of the ASMF/DMF working group of the International Generic Drug Regulators Pilot (IGDRP) to identify similarities and differences among ASMF/DMF procedures of 10 IGDRP members and 2 observers.We conducted a questionnaire survey and compared the following aspects: overall ASMF/DMF procedures, submission requirements for ASMFs/DMFs, assessment processes for ASMFs/DMFs, the technical requirements for active pharmaceutical ingredients (APIs), generation of assessment reports for ASMFs/DMFs, procedures for changing ASMF/DMF details, and Good Manufacturing Practice (GMP) inspection/certification of API manufacturers. Twelve organizations participated in this project: the Brazilian Health Surveillance Agency (Anvisa), the European Union (EU), Health Canada (HC), the Singapore Health Sciences Authority (HSA), the South African Medicines Control Council (MCC), the South Korean Ministry of Food and Drug Safety (MFDS), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Swiss Agency for Therapeutic Products (Swissmedic), the Taiwan Food and Drug Administration (TFDA), the Australian Therapeutic Goods Administration (TGA), the European Directorate for the Quality of Medicines & HealthCare (EDQM) (Observer) and the Prequalification Team (PQT) of the World Health Organization (WHO), which includes the PQT-Medicines (Observer).Although there were many similarities among the participating agencies surveyed, there were also differences that should be discussed such as assessment processes of ASMFs/DMFs and Technical requirements for APIs.These differences revealed by this survey will be key considerations in order to facilitate the filing of ASMFs/DMFs globally and to establish a framework for sharing and utilizing information related to ASMFs/DMFs among IGDRP members in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
- Evaluation Outcomes Associated with Alternative Dosing Strategies for Piperacillin/Tazobactam: A Systematic Review and Meta-Analysis. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):274-89.
A better dosing strategy can improve clinical outcomes for patients. We systematically reviewed the literatures to determine whether any clinical benefits exist for piperacillin/tazobactam by extended or continuous infusion. Methods - A search of PubMed, Web of Science, ProQuest, ScienceDirect, Cochrane, Embase and related ICAAC and ACCP conferences were conducted up to September 5, 2015. Randomized controlled and observational studies that compared extended or continuous infusion with conventional intermittent infusion of piperacillin/tazobactam were identified from the databases above and analyzed. Two reviewers independently evaluated the methodology and extracted data from primary studies. A meta-analysis was performed using Revman 5.2 software. The quality of each study was assessed. Sensitivity analysis and publication bias were evaluated. Results - Three randomized controlled trials and twelve observational studies were included in this study. All included studies had high quality and no publication bias was found. Compared to the conventional intermittent infusion approach, the extended or continuous infusion group had a significant cost effectiveness (OR -0.89.02, CI (-114.69,-63.35), P<0.00001). No statistical difference was observed for clinical cure rate (OR 1.64, 95% CI (0.88, 3.30), P=0.12) between the two dosing regimens. The sensitivity analysis showed the results were stable. Conclusions - Our systematic review and meta-analysis found that the outcomes associated with alternative dosing strategies of piperacillin/tazobactam have changed compared with conclusions before for several literatures with large samples published. Further data on the outcomes should be generated for a better understanding of the extended or continuous infusion strategy. On the whole, our meta-analysis suggested that the extended or continuous infusion should be recommended for clinical use only considering its economic advantage, but there was no significantly higher clinical cure rate and lower mortality rate compared with the conventional intermittent infusion. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on
ABSTRACTon the issue's contents page.
- Organogels in Drug Delivery: A Special Emphasis on Pluronic Lecithin Organogels. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):252-73.
Organogels have emerged as an alternative carrier for small and macromolecules via transdermal, oral, rectal and ophthalmic routes. Pluronic lecithin organogels (PLO gels) are lecithin-based organogels widely used in compounding pharmacies as a vehicle for enhancing the transdermal permeability of many therapeutic drugs. However, the scientific and systematic evidence in support of how well PLO gels help in transdermal delivery is scanty. Recently, some clinical studies have reported nearly complete lack of bioavailability of certain topically administered drugs from PLO gels. The present review aims at summarizing gels and organogels, with a focus on the use of PLO gels in transdermal drug delivery. A special emphasis is placed on controversies looming over the use of PLO gels as a delivery platform for drugs via transdermal route. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on
ABSTRACTon the issue's contents page.
- Microdialysis-directed Intra-tumor Pharmacokinetic Modeling of Methotrexate in Mice and Humans. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):239-51.
To develop a quantitative pharmacokinetic model to characterize the disposition of methotrexate (MTX) at tumor site in tumor-bearing mice and to predict MTX concentrations in the human tumor.The plasma profiles of MTX were obtained from normal mice, while microdialysis technique was employed to characterize the time course of MTX in tumor from breast tumor-bearing mice. Disposition profiles of plasma and tumor were analyzed by a hybrid physiologically-based pharmacokinetic (hPBPK) model that incorporates physiologically-relevant parameters such as tumor blood flow and volume, while plasma concentrations were used as a forcing input into the vascular-interstitial spaces of the tumor. The plasma profiles were initially described by a biexponential decay model to obtain a forcing function that enters into the vascular-interstitial spaces in the tumor. Using a defined forcing function, the tumor free concentrations were fitted to the hPBPK model. Based on the model developed, sensitivity analysis was conducted with a perturbation of PK parameters to predict different scenarios of intratumoral MTX transport. The relevant physiological PK parameters from the mouse model were then scaled-up and utilized to simulate human tumor concentrations.The mouse hPBPK model adequately characterized the concentration-time profiles of MTX in both plasma and tumor and produced various transfer rate constants between plasma and tumor. Our model was also able to reasonably predict MTX concentrations in the human tumor when human physiological data were utilized.The hPBPK model was able to quantitatively characterize the atypical transport of MTX in the tumor, supporting the idea that microdialysis is a valuable tool to study tumor biodistribution of drugs and to predict tumor concentrations in humans based on the pre-clinical data. This information can ultimately aid in the development of anticancer drugs with improved PK profiles. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
- Targeting Angiogenesis in Cancer Treatments: Where do we Stand? [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):226-38.
Since early seventies of the twentieth century, through seminal work of Judah Folkman, angiogenesis, the process of new blood vessel sprouting from the existing vasculature, was recognized as a necessary part of wound healing, development of placenta, tissue growth and regeneration as well as cancer progression. This process is induced by low tissue oxygenation and it is a crucial prerequisite for rapid tissue growth, providing proper oxygen supply and removal of toxic metabolites. Suppression of angiogenesis as a way of slowing down tumor progression continues to be one of the most important areas of cancer research. The angiogenic process is relatively complex and it is regulated by numerous pro- and anti-angiogenic factors. Intensive research in the last twenty years resulted in identification of more than 300 angiogenesis inhibitors, a trend that is expected to continue. Unfortunately, most of these treatments have demonstrated unacceptable toxicities or failed to show activity in clinical studies. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple activating and inhibiting factors. Vascular endothelial growth factor (VEGF) and its cognate receptors appear to play a central role in angiogenesis activation. Thus, initial efforts to develop anti-angiogenic treatments focused largely on inhibiting VEGF action. Such approaches, however, often lead to transient responses due to multiple pathways able to compensate for a single pathway inhibited. Accordingly, more recent treatments have focused on simultaneous inhibition of multiple signaling pathways. This review concentrates on identifying those anti-angiogenic treatments that made to the clinic by receiving approval by USA Food and Drug Administration (FDA) as treatments for cancer. Regardless of observed problems, it is an imperative that research in angiogenesis regulation continues. Consequently, pharmacological manipulation of angiogenesis may yet to introduce truly new pharmacological therapies into the field of cancer therapy, the field that was rather dormant in the last several decades. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on
ABSTRACTon the issue's contents page.
- Bioavailability Improvement Strategies for Poorly Water-Soluble Drugs Based on the Supersaturation Mechanism: An Update. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):208-25.
The formulation development for poorly soluble drugs still remains a challenge. Supersaturating drug delivery systems (SDDS) or drug delivery systems based on supersaturating provide a promising way to improve the oral bioavailability of poorly water-soluble drugs. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when exposed to gastrointestinal fluids, and the supersaturation state is maintained long enough to be absorbed, resulting in compromised bioavailability. In this article, the mechanism of generating and maintaining supersaturation and the evaluation methods of supersaturation assays are discussed. Recent advances in different drug delivery systems based on supersaturating are the focus and are discussed in detail.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on
ABSTRACTon the issue's contents page.
- Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):198-207.
To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers.An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods.Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞ were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively.These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
- Inhibitory Effects of Eight Green Tea Catechins on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activities. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):188-97.
Green tea is a traditional beverage that has been enjoyed by the Japanese to this day. Recently, there has been an increase in the consumption of green tea beverage having high concentrations of catechins, such as (-)-epigallocatechin-3-O-gallate (EGCG). Many people tend to ingest large amounts of catechins through the frequent consumption of green tea beverage, and this dietary habit may lead to unwanted interactions between the catechins in green tea and medicinal drug.The inhibitory effects of eight green tea catechins on drug metabolizing enzymes, cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4, were investigated in human liver microsomes. Incubation was initiated by the addition of cocktail probe drugs that served as specific substrates for each CYP, and the resulting metabolites were analyzed by LC-MS.From a comparison of the fifty percent inhibitory concentration (IC50) values of the eight green tea catechins, it was found that non-gallated catechins did not inhibit CYPs, whereas gallated catechins inhibited all CYPs except CYP2D6. Among them, CYP2C9 was most strongly inhibited by (-)-catechin-3-O-gallate (CG) (7.60 µM), and CYP1A2 was most strongly inhibited by EGCG (8.93 µM). Catechin gallate exhibited non-competitive inhibition of CYP2C9, and its Ki value was 9.76 ± 0.47µM. The present study is the first to report the inhibitory effect of CG on CYP2C9. In contrast, EGCG showed competitive inhibition of CYP1A2, and its Ki value was 14.3 ± 0.09 µM.Previous reports had predicted that plasma EGCG concentration reached 7.4 µM after ingesting green tea having high concentrations of catechins. That concentration of EGCG is equivalent to one-half to one-third of its Ki value for CYP1A2 and CYP3A4 in this study. The ingestion of beverages containing large amounts of green tea catechins together with drugs that are metabolized by CYP1A2, CYP2C9, and CYP3A4 should be avoided. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
- Modifications of the Method for Calculating Absolute Drug Bioavailability. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):181-7.
Absolute bioavailability (F) is calculated as the ratio of the area under the plasma drug concentration-time curve (AUC) between extravascular administration and intravenous injection. However, as distribution of a drug after intravenous administration does not reach an equilibrium in the body during the distribution phase, the plasma drug concentration at this phase does not reflect the total amount of drug in the body. The goal of this paper was to analyze the insufficiencies of the method for calculating on absolute bioavailability and to propose a modification to improve the calculation.Literature reporting absolute bioavailability published during 1983-2014 was searched for ten drug candidates. Plasma drug concentrations representing the amount of drug in the body were then calculated at each time point during the distribution phase according to the plasma drug concentration-time relationship during the elimination phase.The AUC values based on the distribution equilibrium drug concentrations following intravenous injection were 75%±11% of the actually measured drug concentrations in the literature. The absolute bioavailability values in the literature were 76%±12% of the actual bioavailability based on the AUCs from distribution-equilibrium drug concentrations.The present method underestimates the absolute drug bioavailability and should be modified to represent the data more accurately. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
- Nanotoxicity of Inert Materials: The Case of Gold, Silver and Iron. [Journal Article]
- J Pharm Pharm Sci 2016 Apr-Jun; 19(2):161-80.
Nanotechnology has opened a new horizon of research in various fields including applied physics, chemistry, electronics, optics, robotics, biotechnology and medicine. In the biomedical field, nanomaterials have shown remarkable potential as theranostic agents. Materials which are considered inert are often used in nanomedicine owning to their nontoxic profile. At nanoscale, these inert materials have shown unique properties that differ from bulk and dissolved counterparts. In the case of metals, this unique behavior not only imparts paramount advantages but also confers toxicity due to their unwanted interaction with different cellular processes. In the literature, the toxicity of nanoparticles made from inert materials has been investigated and many of these have revealed toxic potential under specific conditions. The surge to understand underlying mechanism of toxicity has increased and different means have been employed to overcome toxicity problems associated with these agents. In this review, we have focused nanoparticles of three inert metallic materials i.e. gold, silver and iron as these are regarded as biologically inert in the bulk and dissolved form. These materials have gained wider research interest and studies indicating the toxicity of these materials are also emerging. Oxidative stress, physical binding and interference with intracellular signaling are the major role player in nanotoxicity and their predominance is highly dependent upon size, surface coating and administered dose of nanoparticles. Current strategies to overcome toxicity have also been reviewed in the light of recent literature. The authors also suggested that uniform testing standards and well-designed studies are needed to evaluate nanotoxicity of these materials that are otherwise considered as inert. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on