Community Pharmacists' Identifying and Counseling of Breastfeeding Women: A Study from Jordan.

Background: This study explored the approaches of Jordanian community pharmacists to identifying and counseling breastfeeding mothers regarding medication usage. Methods: This cross-sectional study used self-administered questionnaires. A convenience sample (n=381) of Jordanian community pharmacists was recruited through social media. The responses were statistically analyzed using IBM SPSS ver. 25.0 (IBM Corp., USA). Results: The majority of recruited pharmacists were female (n=329, 86.4%). Asking every woman was Jordanian pharmacists' preferred approach to identifying breastfeeding women (n=211, 55.4%). The study showed that around one-third of the pharmacists (n=128, 33.6%) reported that they currently experienced queries regarding medication use during breastfeeding on a daily basis. Additionally, the majority (n=325, 85.3%) of pharmacists reported feeling confident, and 67.2% of them (n=256) reported feeling comfortable while giving advice to breastfeeding women. The surveyed pharmacists relied on different resources during their course of practice to answer queries related to medicine usage by breastfeeding mothers. Conclusion: Community pharmacists have continuous interactions with breastfeeding women. Pharmacists require reliable and updated data access to answer queries related to medication use while breastfeeding.

In vitro and in silico methods to investigate the effect of moderately increasing medium viscosity and density on ibuprofen dissolution rate.

Medium viscosity can affect drug dissolution rate, however, it is not usually considered in routine dissolution testing or less complex biorelevant media. The effects of moderately increasing medium viscosity on the in vitro and in silico dissolution of ibuprofen were investigated with two viscosity enhancing agents (VEA) (hydroxypropyl methylcellulose (HPMC) and sucrose), three viscosity levels (range 0.7-5.5 mPa.s), two solubilities and two fluid velocities in the paddle, flow-through and intrinsic dissolution apparatuses. A factorial design analysis highlighted which factors significantly affected key dissolution metrics. Experimental results in the flow-through apparatus (FTA) were compared with in silico dissolution profiles generated by an in-house simulation code (SIMDISSOTM). Increasing viscosity reduced the intrinsic dissolution rate of ibuprofen for both VEAs. The dissolution rate reduction was also observed in the FTA with sucrose, but less so with HPMC, suggesting particle wetting, motion and surface area effects. Particle motion simulations suggested reduced particle lifting times as viscosity increased, indicating an effect of viscosity on particle dispersal. The viscosity- and fluid density-mediated reduction in the dissolution rate observed with sucrose was accurately simulated by SIMDISSOTM, in particular at higher velocities. Velocity had a significant impact on dissolution rates in the paddle apparatus, with a significant viscosity-related reduction in dissolution observed in the low solubility-low velocity scenario. Even small increases in medium viscosity can reduce the dissolution rate of a BCS class II drug, and in silico particle motion and dissolution data can assist interpretation of particulate dissolution behaviour.

Application of an AI image analysis and classification approach to characterise dissolution and precipitation events in the flow through apparatus.

Imaging and artificial intelligence (AI) approaches have been used with increasing frequency in pharmaceutical industry in recent years. Characterisation of processes such as drug dissolution and precipitation is vital in quality control testing and drug manufacture. To support existing techniques like in vitro dissolution testing, novel process analytical technologies (PATs) can give an insight into these processes. The aim of this study was to create and explore the potential of an automated image classification model based on image analysis to identify events (dissolution and precipitation) occurring in the flow-through apparatus (FTA) test cell, and the ability to characterise a dissolution process over time. Several precipitation conditions were tested in a USP 4 FTA test cell with images recorded during early (plume formation) and late (particulate re-formation) stages of precipitation. An available MATLAB code was used as a base to develop and validate an anomaly classification model able to detect different events occurring during the precipitation process in the dissolution cell. Two variants of the model were tested on images from a dissolution test in the FTA, with a view to application of the image analysis system to quantitative characterization of the dissolution process over time. It was found that the classification model is highly accurate (>90%) in detecting events occurring in the FTA test cell. The model showed potential to be used to characterise the stages of dissolution and precipitation processes, and as a proof of concept demonstrates potential for deep machine learning image analysis to be applied to kinetics of other pharmaceutical processes.

Exploring bulk volume, particle size and particle motion definitions to increase the predictive ability of in vitro dissolution simulations.

The definition of the local dissolution environment is central to accurate particle dissolution simulation, and is determined by the apparatus and conditions used. In the flow-through apparatus dissolution occurs in the cell, often in a low velocity environment, with the reservoir considered the relevant volume for dissolution kinetics. Dissolution simulations were conducted using a reduced-order model based on the Ranz-Marshall correlation for mass transfer from spherical particles. Using ibuprofen as a model drug, the effect of defining a local volume to simulate dynamic bulk concentration conditions in the flow-through and paddle apparatus was assessed by comparing use of a near particle volume (NPV), extending a distance of one radius from the particle surface, with a flow-through apparatus cell volume or paddle apparatus vessel volume as the relevant instantaneous volume for dissolution. The instantaneous inlet concentration to NPV or cell volume is the reservoir/vessel concentration at that simulation time point, reflecting the continuous input to the cell of more dilute solution from the reservoir (closed system). Additionally, inputting particle size distribution (PSD) instead of a median particle size (MPS) and enabling or disabling particle motion were investigated, in two media (resulting in low and high solubility) and with two fluid velocity conditions in each apparatus. The NPV predicted effects of fluid velocity differences on dissolution in the high solubility medium in the flow-through apparatus, but had no effect on predictive ability in the paddle apparatus. In both apparatuses, simulations were reasonable for the high solubility environment but underpredicted dissolution in the low solubility environment. The PSD option and disabling particle motion increased the predictive ability of the simulations in low solubility media in the flow-through apparatus. The results highlight the necessity to incorporate the local dynamic dissolution conditions in the flow-through apparatus for accurate dissolution simulation, and the challenges of defining an effective particle size for dissolution simulation and of reflecting hydrodynamic complexity in simulating dissolution in the paddle apparatus.

Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF).

BACKGROUND: Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. METHODS: This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. RESULTS: A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs-Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. CONCLUSIONS: PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

Development of Professional Attributes through Integration of Science and Practice at First-Year Pharmacy Level.

The design, implementation and evaluation of a year 1 pharmacy-integrated learning component, using the World Health Organisation's (WHO) analgesic ladder as a scaffold for case-based learning, is described. A novel aspect of the integrated component is the mapping of the cases to the national Core Competency Framework (CCF) for Pharmacists in Ireland and to the school's own cross-cutting curricular integration themes. The integrated cases were student led and delivered through peer-to-peer teaching for 68 first-year pharmacy students. The integrated cases mapped strongly to three of the CCF's domains, namely, personal skills, organisation and management skills and supply of medicines. With regard to the school's curricular integrative themes, the cases mapped strongly to the curricular integration themes of professionalism and communications; medicines sourcing, production and use; and safe and rational use of medicines. Highlights from an anonymous online student survey were the recognition by students of the importance of core science knowledge for practice, the enabling of integrated learning and the suitability of the integrated component for entry-level. While a majority of students were found to favour individual work over group work, future iterations will need to consider a greater degree of group work with a view to reducing the volume of content and time required to complete the cases.

In vitro conditions for performance evaluation of products for intravascular administration: Developing appropriate test media using Amphotericin B as a model drug.

Currently, there are no compendial in vitro release tests specifically indicated for parenteral formulations. Consideration of biorelevant and clinically relevant test media represents a valuable approach for the development of in vitro tests that ideally can provide information on the formulation performance in vivo. The aim of this study was to investigate the effect of different media components on the solubility of Amphotericin B (a poorly soluble highly protein-bound drug) in order to develop biorelevant and clinically relevant media for future in vitro release testing from its liposomal formulation. Three categories of media were considered in the development approach: Category 1 media: effect of albumin concentration; category 2 media: effect of biorelevant concentrations of plasma components (bile salts, phospholipids, cholesterol, albumin); category 3 media: attaining clinically relevant solubility with biorelevant and synthetic surfactants with and without albumin and setting the basis for the development of a simulated hypoalbuminaemic plasma medium. All the surfactants tested increased Amphotericin B solubility while the simultaneous presence of albumin had a negative effect on solubility. Clinically relevant media with the use of biorelevant or synthetic surfactants and albumin were developed. One medium in which the solubility of Amphotericin B was reduced was identified as potential candidate medium to simulate hypoalbuminaemic plasma. The development of biorelevant and clinically relevant media and understanding the effect of media components and their interactions, supports future development of meaningful in vivo predictive release tests for parenteral formulations.

Design and Implementation of an Integrated Competency-Focused Pharmacy Programme: A Case Report.

This paper describes the design and implementation of elements of an integrated competency-focused pharmacy programme in the School of Pharmacy and Pharmaceutical Sciences (SoPPS), Trinity College Dublin (TCD), Ireland. Following a national review of pharmacy education and training in Ireland in 2010, and subsequent publication of legislation in 2014, the School has implemented a five-year integrated programme of pharmacy education and training, leading to the award of a Master's degree in Pharmacy (M. Pharm.). Curricular integration has been achieved by underpinning the new programme with a national competency framework for pharmacists and through the utilisation of curricular integration themes. Programme integration also encompasses embedded experiential learning placements in Years 2, 4 and 5 of the five-year programme. The new five-year integrated pharmacy programme, which commenced in 2015, replaced the 4 + 1 model of education and training where a four-year Bachelor's degree was followed by a one-year internship, which was a distinct and separate element of the students' training.

Understanding the Potential for Dissolution Simulation to Explore the Effects of Medium Viscosity on Particulate Dissolution.

Viscosity, influenced by medium composition, will affect the hydrodynamics of a dissolution system. Dissolution simulation methods are valuable tools to explore mechanistic dissolution effects, with an understanding of limitations of any simulation method essential to its appropriate use. The aims of this paper were a) to explore, using dissolution simulation, the effects of slightly viscous media on particulate dissolution and b) to illustrate approaches to, and limitations of, the dissolution simulations. A lumped parameter fluid dynamics dissolution simulation model (SIMDISSO™) was used to simulate particulate (20 and 200 µm diameter) dissolution in media with viscosity at 37 °C of water (0.7 mPa.s), milk (1.4 mPa.s) and a nutrient drink (12.3 mPa.s). Effects of flow rate, modality (constant vs pulsing), viscosity and gravitational and particle motion/sedimentation effects on simulated dissolution were explored, in the flow through and paddle apparatuses as appropriate. Shadowgraph imaging (SGI) was used to visualise particle suspension behaviour. Flow rate, hydrodynamic viscous effects and disabling particle motion and gravitational effects affected simulated dissolution of larger particles. SGI imaging revealed retention of particles in suspension in 1.4 mPa.s medium, which sedimented in water. The effect of diffusion adjusted for viscosity was significant for both particle sizes. The limitations of this 1D simulation approach would be greater for larger particles in low velocity regions of the paddle apparatus. Even slightly viscous media can affect dissolution of larger particles with dissolution simulation affording insight into the mechanisms involved, provided the assumptions and limitations of the simulation approach are clarified and understood.

Investigation and simulation of dissolution with concurrent degradation under healthy and hypoalbuminaemic simulated parenteral conditions- case example Amphotericin B.

Guidance on dissolution testing for parenteral formulations is limited and not often related in vivo performance. Critically ill patients represent a target cohort, frequently hypoalbuminaemic, to whom certain parenteral formulations are administered. Amphotericin B (AmB) is a poorly soluble, highly protein-bound drug, available as lipid-based formulations and used in critical illness. The aim of this study was to develop media representing hypoalbuminaemic and healthy plasma, and to understand and simulate the dissolution profile of AmB in biorelevant media. Dissolution media were prepared with bovine serum albumin (BSA) in Krebs-Ringer buffer, and tested in a flow through cell apparatus and a bottle/stirrer setup. Drug activity was tested against Candida albicans. BSA concentration was positively associated with solubility, degradation rate and maximum amount dissolved and negatively associated with dissolution rate constant and antifungal activity. In the bottle/stirrer setup, a biexponential model successfully described simultaneous dissolution and degradation and increased in agitation reduced the discriminatory ability of the test. The hydrodynamics provided by the flow-through cell apparatus was not adequate to dissolve the drug. Establishing discriminating test methods with albumin present in the dissolution media, representing the target population, supports future development of biorelevant and clinically relevant tests for parenteral formulations.

Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy.

Objectives: To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively. Results: Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions: Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.

The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers.

AIMS: The aim of this study was to determine the pharmacokinetic interaction between ivacaftor and ritonavir. METHODS: A liquid chromatography mass spectrometry (LC-MS) method was developed for the measurement of ivacaftor in plasma. An open-label, sequential, cross-over study was conducted with 12 healthy volunteers. Three pharmacokinetic profiles were assessed for each volunteer: ivacaftor 150 mg alone (study A), ivacaftor 150 mg plus ritonavir 50 mg daily (study B), and ivacaftor 150 mg plus ritonavir 50 mg daily after two weeks of ritonavir 50 mg daily (study C). RESULTS: Addition of ritonavir 50 mg daily to ivacaftor 150 mg resulted in significant inhibition of the metabolism of ivacaftor. Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf obv ) increased significantly in both studies B and C compared to study A (GMR [95% CI] 19.71 [13.18-31.33] and 19.77 [14.0-27.93] respectively). Elimination half-life (t1/2 ) was significantly longer in both studies B and C compared to study A (GMR [95% CI] 11.14 [8.72-13.62] and 9.72 [6.68-12.85] respectively). There was no significant difference in any of the pharmacokinetic parameters between study B and study C. CONCLUSION: Ritonavir resulted in significant inhibition of the metabolism of ivacaftor. These data suggest that ritonavir may be used to inhibit the metabolism of ivacaftor in patients with cystic fibrosis (CF). Such an approach may increase the effectiveness of ivacaftor in 'poor responders' by maintaining higher plasma concentrations. It also has the potential to significantly reduce the cost of ivacaftor therapy.

Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy.

The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).

Modelling and shadowgraph imaging of cocrystal dissolution and assessment of in vitro antimicrobial activity for sulfadimidine/4-aminosalicylic acid cocrystals.

PURPOSE: The aim of this work was to evaluate the influence of crystal habit on the dissolution and in vitro antibacterial and anitiprotozoal activity of sulfadimidine:4-aminosalicylic acid cocrystals. METHODS: Cocrystals were produced via milling or solvent mediated processes. In vitro dissolution was carried out in the flow-through apparatus, with shadowgraph imaging and mechanistic mathematical models used to observe and simulate particle dissolution. In vitro activity was tested using agar diffusion assays. RESULTS: Cocrystallisation via milling produced small polyhedral crystals with antimicrobial activity significantly higher than sulfadimidine alone, consistent with a fast dissolution rate which was matched only by cocrystals which were milled following solvent evaporation. Cocrystallisation by solvent evaporation (ethanol, acetone) or spray drying produced flattened, plate-like or quasi-spherical cocrystals, respectively, with more hydrophobic surfaces and greater tendency to form aggregates in aqueous media, limiting both the dissolution rate and in vitro activity. Deviation from predicted dissolution profiles was attributable to aggregation behaviour, supported by observations from shadowgraph imaging. CONCLUSIONS: Aggregation behaviour during dissolution of cocrystals with different habits affected the dissolution rate, consistent with in vitro activity. Combining mechanistic models with shadowgraph imaging is a valuable approach for dissolution process analysis.

Teicoplanin use in adult patients with haematological malignancy: Exploring relationships between dose, trough concentrations, efficacy and nephrotoxicity.

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P<0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group.

A critical review of properties of darunavir and analytical methods for its determination.

Darunavir is a synthetic non-peptidic protease inhibitor that has been shown to be extremely potent against wild-type HIV, and it is an important component of highly active antiretroviral treatment (HAART), which is considered as one of the most significant advances in the field of HIV therapy. However, there are some concerns about darunavir quality control. Darunavir shows pseudo-polymorphism: in different ambient conditions one pseudo-polymorphic form can change to another. This behavior of darunavir is problematic because the dosage form is exposed to different ambient conditions around the world, since HIV/AIDS is prevalent globally. Issues around differences in the solubility and effects that different forms of darunavir can cause are of concern, and a more stable form is preferable. Important investigations of darunavir such as dissolution behavior, polymorphism, stability and degradation studies, and the impact of that on the quality of the product are being conducted by our working group. A cure for HIV/AIDS remains a long-term commitment, and there is much yet to achieve. This article discusses, by a critical review of the literature, the impact of the use of darunavir in the treatment of HIV-infected patients, its physical-chemical properties, the analytical methods to determine it, and challenges that remain in order to ensure the quality and stability of darunavir.

Quality risk analysis in a cGMP environment: multiple models for comprehensive failure mode identification during the computer system lifecycle.

Pharmaceutical quality systems use various inputs to ensure product quality and prevent failures that might have patient consequences. These inputs are generally data from failures that have already occurred, for example process deviations or customer complaints. Risk analysis techniques are well-established in certain other industries and have become of interest to pharmaceutical manufacturers because they allow potential quality failures to be predicted and mitigating action taken in advance of their occurring. Failure mode and effects analysis (FMEA) is one such technique, and in this study it was applied to implement a computerized manufacturing execution system in a pharmaceutical manufacturing environment. After introduction, the system was monitored to detect failures that did occur and these were analyzed to determine why the risk analysis method failed to predict them. Application of FMEA in other industries has identified weaknesses in predicting certain error types, specifically its dependence on other techniques to model risk situations and its poor analysis of non-hardware risks, such as human error, and this was confirmed in this study. Hierarchical holographic modeling (HHM), a technique for identifying risk scenarios in wide-scope analyses, was applied subsequently and identified additional potential failure modes. The technique for human error rate prediction (THERP) has previously been used for the quantitative analysis of human error risk and the event tree from this technique was adapted and identified further human error scenarios. These were input to the FMEA for prioritization and mitigation, thereby strengthening the risk analysis in terms of failure modes considered.

Pharmacokinetics of amphotericin B lipid complex in critically ill patients undergoing continuous venovenous haemodiafiltration.

The objective of this study was to examine the effect of continuous venovenous haemodiafiltration (CVVHDF) on the pharmacokinetics of amphotericin B (AmB) in critically ill patients following administration of amphotericin B lipid complex (ABLC). Plasma and ultrafiltrate (UF) samples were collected from patients administered ABLC and either receiving or not receiving CVVHDF. Pharmacokinetic (PK) analysis was performed on eight profiles from patients receiving CVVHDF and six profiles from patients not receiving CVVHDF. For patients receiving CVVHDF, the following median PK data were calculated: area under the concentration-time curve (AUC) = 13.9 h·µg/mL, volume of distribution at steady state (V(ss)) = 1476L and drug clearance (CL) = 27.4 L/h; for patients not receiving CVVHDF, the corresponding median PK data were 11.5 h µg/mL, 2048 L and 43.7 L/h, respectively. The median half-lives calculated during the dosage interval (t(1/2int)) were 30.9 h and 32.5 h on and off CVVHDF, respectively, and the total range of t(1/2int) values was 15.6-180.4 h. Observed median peak concentrations on Day 1 were 0.563 µg/mL and 0.468 µg/mL in patients on and off CVVHDF, respectively. From AmB present in the UF, clearance via CVVHDF contributed<1% of total plasma clearance. The AmB concentration-time profiles for patients administered ABLC on and off CVVHDF were compared and no statistically significant differences in AUC, CL, t(1/2int) and V(ss) were observed. In conclusion, CVVHDF had no clinically significant effect on the pharmacokinetics of AmB following administration of ABLC.

An open prospective study of amikacin pharmacokinetics in critically ill patients during treatment with continuous venovenous haemodiafiltration.

BACKGROUND: The objectives of the current study were to determine amikacin pharmacokinetics in patients undergoing treatment with continuous venovenous haemodiafiltration (CVVHDF) in an Intensive Care Unit (ICU), and to determine whether peak and trough concentration data could be used to predict pharmacokinetic parameters. An open prospective study was undertaken, comprising five critically ill patients with sepsis requiring CVVHDF. METHODS: Peak and trough plasma concentrations and multiple serum levels in a dosage interval were measured and the latter fitted to both a one- and two-compartment model. Blood and ultrafiltrate samples were collected and assayed for amikacin to calculate the pharmacokinetic parameters; total body clearance (TBC), elimination rate constant (k) and volume of distribution (Vd). The concentration of amikacin in ultrafiltrate was used to determine the clearance via CVVHDF. CVVHDF was performed at prescribed dialysate rates of 1-2l h-1 and ultrafiltration rate of 2l h-1. Blood was pumped at 200ml/min using a Gambro blood pump and Hospal AN69HF haemofilter. Amikacin dosing was according to routine clinical practice in the Intensive Care Unit. RESULTS: The multi serum level study indicated that the one compartment model was adequate to characterize the pharmacokinetics in these patients suggesting that peak and trough plasma level data may be used to estimate individual patient pharmacokinetic parameters and to optimise individual patient dosing during treatment with CVVHDF. CVVHDF resulted in an amikacin k of 0.109+/-0.025 h, t1/2 of 6.74 +/- 1.69h, TBC of 3.39+/-0.817 h-1, and Vd of 31.4 +/- 3.27. The mean clearance due to CVVHDF of 2.86 l h-1 is similar to the creatinine clearance of 2.74 +/-0.4 lh-1. Amikacin was significantly cleared by CVVHDF, and its half life in patients on CVVHDF was approximately 2-3 times that reported in subjects without renal impairment and not undergoing haemodiafiltration for any reason. CONCLUSIONS: CVVHDF contributes significantly to total clearance of amikacin. The use of pharmacokinetic parameter estimates obtained from two steady state serum-drug concentrations (peak and trough) can be used to guide individualised dosing of critically ill patients treated with CVVHDF. This is considered a useful strategy in this patient cohort, particularly in avoiding the risk of underdosing.