Bioequivalence risk assessment of oral formulations containing racemic ibuprofen through a chiral physiologically based pharmacokinetic model of ibuprofen enantiomers.

The characterization of the time course of ibuprofen enantiomers can be useful in the selection of the most sensitive analyte in bioequivalence studies. Physiologically based pharmacokinetic (PBPK) modelling and simulation represents the most efficient methodology to virtually assess bioequivalence outcomes. In this work, we aim to develop and verify a PBPK model for ibuprofen enantiomers administered as a racemic mixture with different immediate release dosage forms to anticipate bioequivalence outcomes based on different particle size distributions. A PBPK model incorporating stereoselectivity and non-linearity in plasma protein binding and metabolism as well as R-to-S unidirectional inversion has been developed in Simcyp®. A dataset composed of 11 Phase I clinical trials with 54 scenarios (27 per enantiomer) and 14,452 observations (7129 for R-ibuprofen and 7323 for S-ibuprofen) was used. Prediction errors for AUC0-t and Cmax for both enantiomers fell within the 0.8-1.25 range in 50/54 (93 %) and 42/54 (78 %) of scenarios, respectively. Outstanding model performance, with 10/10 (100 %) of Cmax and 9/10 (90 %) of AUC0-t within the 0.9-1.1 range, was demonstrated for oral suspensions, which strongly supported its use for bioequivalence risk assessment. The deterministic bioequivalence risk assessment has revealed R-ibuprofen as the most sensitive analyte to detect differences in particle size distribution for oral suspensions containing 400 mg of racemic ibuprofen, suggesting that achiral bioanalytical methods would increase type II error and declare non-bioequivalence for formulations that are bioequivalent for the eutomer.

Application of population physiologically based pharmacokinetic modelling to optimize target expression and clearance mechanisms of therapeutic monoclonal antibodies.

AIMS: To use population physiologically based pharmacokinetic (PopPBPK) modelling to optimize target expression, kinetics and clearance of HER1/2 directed therapeutic monoclonal antibodies (mAbs). Thus, to propose a general workflow of PopPBPK modelling and its application in clinical pharmacology. METHODS: Full PBPK model of pertuzumab (PTZ) was developed in patient population using Simcyp V21R1 incorporating mechanistic targeted-mediated drug disposition process by fitting known clinical PK and sparse receptor proteomics data to optimize target expression and kinetics of HER2 receptor. Trastuzumab (TTZ) PBPK modelling was used to validate the optimized HER2 target. Additionally, the simulator was also used to develop a full PBPK model for the HER1-directed mAb cetuximab (CTX) to assess the underlying targeted-mediated drug disposition-independent elimination mechanisms. RESULTS: HER2 final parameterisation coming from the PBPK modelling of PTZ was successfully cross validated through PBPK modelling of TTZ with average fold error (AFE), absolute AFE and percent prediction error values for area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of 1.13, 1.16 and 16, and 1.01, 1.07 and 7, respectively. CTX PBPK model performance was validated after the incorporation of an additional systemic clearance of 0.033 L/h as AFE and absolute AFE showed an acceptable predictive power of AUC and Cmax with percent prediction error of 13% for AUC and 10% for Cmax . CONCLUSIONS: Optimisation of both system and drug related parameters were performed through PBPK modelling to improve model performance of therapeutic mAbs (PTZ, TTZ and CTX). General workflow was proposed to develop and apply PopPBPK to support clinical development of mAbs targeting same receptor.

A physiologically based pharmacokinetic model for open acid and lactone forms of atorvastatin and metabolites to assess the drug-gene interaction with SLCO1B1 polymorphisms.

Atorvastatin is the most prescribed 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used to lower cardiovascular risk and constitutes one of the best-selling drugs world-wide. Several physiologically based pharmacokinetic (PBPK) models have been developed to assess its non-straightforward pharmacokinetics (PK) as well as that of its metabolites and have been only applied to assess drug-drug interactions (DDI). Here we present a full PBPK model for atorvastatin and its metabolites able to predict within a 2-fold error their PK after the administration of a solid oral dosage form containing the calcium salt of atorvastatin in single and multiple dosing schedules at 20, 40, and 80 mg and 10 mg dose levels, respectively. Internal validation with data from Phase 1 clinical trials as well as external validation in predicting clinically relevant DDIs consolidated model structure and parameterization. The model has been used to quantitatively assess the drug-gene interaction (DGI) between SLCO1B1 polymorphisms and atorvastatin exposure and revealed that patients with a reduced activity in hepatic uptake of atorvastatin are at increased risk of suffering muscle discomfort because of a 30% lower clearance (p < 0.01), leading to a 40% and 33% higher (p < 0.05) atorvastatin AUC and Cmax, respectively. These findings could explain the reported hazard ratio of 1.4 (95% CI: 1.1-1.7, p = 0.02) for suffering statin-induced myopathies and the treatment discontinuation among these patients (odds ratio 1.67, p = 0.0001) observed in the context of routine clinical care.

Population Pharmacokinetic/Pharmacodynamic Modelling of Daptomycin for Schedule Optimization in Patients with Renal Impairment.

The aims of this study are (i) to develop a population pharmacokinetic/pharmacodynamic model of daptomycin in patients with normal and impaired renal function, and (ii) to establish the optimal dose recommendation of daptomycin in clinical practice. Several structural PK models including linear and non-linear binding kinetics were evaluated. Monte Carlo simulations were conducted with a fixed combination of creatinine clearance (30-90 mL/min/1.73 m2) and body weight (50-100 kg). The final dataset included 46 patients and 157 daptomycin observations. A two-compartment model with first-order peripheral distribution and elimination kinetics assuming non-linear protein-binding kinetics was selected. The bactericidal effect for Gram+ strains with MIC ≤ 0.5 mg/L could be achieved with 5-12 mg/kg daily daptomycin based on body weight and renal function. The administration of 10-17 mg/kg q48 h daptomycin allows to achieve bactericidal effect for Gram+ strains with MIC ≤ 1 mg/L. Four PK samples were selected as the optimal sampling strategy for an accurate AUC estimation. A quantitative framework has served to characterize the non-linear binding kinetics of daptomycin in patients with normal and impaired renal function. The impact of different dosing regimens on the efficacy and safety outcomes of daptomycin treatment based on the unbound exposure of daptomycin and individual patient characteristics has been evaluated.

Pharmacometric characterization of entero-hepatic circulation processes of orally administered formulations of amiodarone under complex binding kinetics.

AIMS: The aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of amiodarone (AM) in rats in order to optimize the development of new oral (OR) formulations. METHODS: Intravenous (IV) formulation consisted on a solution of a commercial injectable of AM chlorhydrate. OR formulations included the IV commercial formulation (Trangorex®) (Solution I), an aqueous supramicellar solution of AM chlorhydrate with Polysorbate at 5% (Solution II) and a suspension from Trangorex® tablets (Tablet). Data from 96 male Wistar rats, including 985 AM observations, were analyzed using NONMEM v7.4. RESULTS: The population pharmacokinetic (PK) model assumes linear absorption processes, showing ka of AM from Solution II (Polysorbate 80, 5%) and Solution I increased by 2.5- and 1.62-fold compared to Tablet formulation. OR bioavailability of AM from Tablet, Solution I and Solution II was 37%, 40%, and 50%, respectively. The structural model of AM disposition was adapted from a previously population PK model and expanded by incorporating entero-hepatic reabsorption (EHR) processes, which estimated a 12.3% biliary excretion of AM and complete re-absorption from lumen. CONCLUSIONS: The current population PK model of AM demonstrated the absorption rate enhancement when AM is formulated with supramicellar concentrations of Polysorbate 80. The study design allowed to characterize the EHR of AM and its contribution in the overall AM disposition.

Impact of Pharmacokinetic and Pharmacodynamic Properties of Monoclonal Antibodies in the Management of Psoriasis.

The treatment of psoriasis has been revolutionized by the emergence of biological therapies. Monoclonal antibodies (mAb) generally have complex pharmacokinetic (PK) properties with nonlinear distribution and elimination. In recent years, several population pharmacokinetic/pharmacodynamic (PK/PD) models capable of describing different types of mAb have been published. This study aims to summarize the findings of a literature search about population PK/PD modeling and therapeutic drug monitoring (TDM) of mAb in psoriasis. A total of 22 articles corresponding to population PK/PD models of tumor necrosis factor (TNF)-α inhibitors (adalimumab and golimumab), interleukin (IL)-23 inhibitors (guselkumab, tildrakizumab, and risankizumab), IL-23/IL-12 inhibitor (ustekinumab), and IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) were collected. A summary of the clinical trials conducted so far in psoriasis was included, together with the current structural population PK and PD models. The most significant and clinical covariates were body weight (BW) and the presence of immunogenicity on clearance (CL). The lack of consensus on PK/PD relationships has prevented establishing an adequate dosage and, therefore, accentuates the need for TDM in psoriasis.

Quantitative assessment of the exposure-efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy.

AIMS: The aims of this study are (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher-type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT), and (ii) to establish an exposure-efficacy relationship for bone marrow infiltration to propose dose adjustments according to patient covariate values. METHODS: A prospective follow-up, semi-experimental multi-centre study was conducted in four hospitals to evaluate the pharmacokinetics, efficacy and safety of ERT in GD1 patients. Twenty-five individuals with 266 glucocerebrosidase (GCase) observations in plasma and leukocytes and 14 individuals with 68 Spanish magnetic resonance imaging (S-MRI) observations were enrolled. RESULTS: A two concatenated compartment model with zero-order endogenous production and first-order distribution (CL1 = 3.85 × 10-1 L/d) and elimination (CL2 = 1.25 L/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (kT = 6.14 × 10-1 d-1 ) effect on CL1 was incorporated. The final exposure-efficacy model was a longitudinal logistic regression model with a first-order Markov element. An Emax function (EC50 = 15.73 U/L and Emax = 2.33) linked steady-state concentrations of GCase in leukocytes to the probability of transition across the different S-MRI stages. CONCLUSION: A population pharmacokinetic model successfully characterized the leukocyte activity-time profiles of GCase following intravenous administration of ERT in GD1 patients together with an exposure-efficacy relationship in bone marrow using Markovian elements. The information obtained from this study could be of high clinical relevance in individualization of ERT in GD1 patients, as this could lead to anticipative decision-making regarding clinical response in bone and optimal dosing strategy.

Estimators and confidence intervals of f2 using bootstrap methodology for the comparison of dissolution profiles.

BACKGROUND AND OBJECTIVES: The most widely used method to compare dissolution profiles is the similarity factor f2. When this method is not applicable, the confidence interval of f2 using bootstrap methodology has been recommended instead. As neither details of the estimator nor the types of confidence intervals are described in the guidelines, the suitability of five estimators and fourteen types of confidence intervals were investigated in this study by simulation. METHODS: One million individual dissolution profiles were simulated for the reference and test populations with predefined target population f2 values, where random samples of different sizes were drawn without replacement. From each pair of random samples, five f2 estimators were calculated, and fourteen types of confidence intervals were obtained using 5000 bootstrap samples. The whole process was repeated 10000 times and the percentage of the similarity conclusions was measured. In addition, the uncertainty associated with the current practice of using f^2 point estimate alone for the statistical inference was evaluated. RESULTS: When combined with different types of confidence intervals, the estimated f2 (f^2), the bias-corrected f2 (f^2,bc), and the variance- and bias-corrected f2 (f^2,vcbc) are not suitable estimators due to higher-than-acceptable type I errors. The estimator f^2,exp, calculated based on the mathematical expectation of f^2, and f^2,vcexp, the variance-corrected f^2,exp, showed acceptable type I errors when combined with any of the ten percentile intervals. However, they have the drawback of low power, which might be addressed by increasing the sample size. To properly control the type I error, samples with at least 12 units should be used. CONCLUSION: The best combinations of estimator and type of confidence interval are f^2,exp and f^2,vcexp combined with any of the ten types of percentile intervals. When the sample f2 value is close to 50, the use of the confidence interval of f2 is recommended even when the variability of the dissolution profiles is low and the prerequisites defined in the regulatory guidelines for using the conventional f2 method are fulfilled in order to control the type I error rate.

Current Evidence, Challenges, and Opportunities of Physiologically Based Pharmacokinetic Models of Atorvastatin for Decision Making.

Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation in special sub-groups of the population, leading to regulatory recognition. Several PBPK models of ATS have been published in the recent years, addressing different aspects of the PK properties of ATS. Therefore, the aims of this review are (i) to summarize the physicochemical and pharmacokinetic characteristics involved in the time-course of ATS, and (ii) to evaluate the major highlights and limitations of the PBPK models of ATS published so far. The PBPK models incorporate common elements related to the physicochemical aspects of ATS. However, there are important differences in relation to the analyte evaluated, the type and effect of transporters and metabolic enzymes, and the permeability value used. Additionally, this review identifies major processes (lactonization, P-gp contribution, ATS-Ca solubility, simultaneous management of multiple analytes, and experimental evidence in the target population), which would enhance the PBPK model prediction to serve as a valid tool for ATS dose optimization.

In vitro skin penetration of bronidox, bronopol and formaldehyde from cosmetics.

The objective was to evaluate the influence of the formulation in the in vitro transdermal absorption through pig ear skin of three preservatives, bronopol, bronidox and formaldehyde as well as the absorption of formaldehyde from bronopol and dimethyloldimethyl hydantoin (DMDM hydantoin). An aqueous solution, an O/W emulsion and a hydrogel were assayed. Bronidox and bronopol absorption depends on the formulation. The O/W emulsion was the system that least promoted absorption of bronidox while the absorption of bronopol was lower from the hydrogel. The aqueous solution provided maximal transdermal absorption of both preservatives. Moreover, the transdermal absorption of formaldehyde released from bronopol also depends on the formulation, being the aqueous solution the system that allowed greater absorption. Transdermal absorption of formaldehyde, applied directly or released from DMDM hydantoin, is not conditioned by the excipients. The degree of transdermal absorption of all the preservatives tested is low and therefore the concentrations allowed by regulations are safely used. Nonetheless, since formaldehyde was detected in the receptor compartment after a long time exposure to bronopol and DMDM hydantoin it would be important to consider the possibility of limiting the use of these two preservatives to rinse off products as is the case of bronidox.

Physico-Chemical Stability of Admixtures of Vinflunine Used in Clinical Practice.

Procedure of administration of vinflunine is complex and consists of an Y-site injection with fluid at different speeds. Dose is diluted with 100 mL of 0.9% sodium chloride or 5% glucose and infused with half of the 500 mL bag of the fluid over 20 min; after that, the remaining fluid is administered at 300 mL/h. In this study, chemical stability and physical compatibility of vinflunine diluted with in 500 mL of both fluids were evaluated to simplify the administration procedure (infusion of mixture on 20 min followed by 250 mL of fluid at 300 mL/h). Physical compatibility and chemical stability were evaluated at two temperatures and protected from and exposed to light. Physical compatibility was evaluated by visual inspection, gravimetric control and measure of pH. A chromatographic method was developed to evaluate chemical stability. The dilution of vinflunine with 500 mL of fluid to final concentrations of 0.75 and 1.54 mg/mL is viable at doses used in clinical practice since admixtures are stable for 2 days at room temperature and at least 7 days under refrigeration. These results extend the expiration date of mixtures of vinflunine administered by the usual procedure and confirm the viability of the proposed procedure since administration is simplified and stability of vinflunine is guaranteed.

Evaluation of ABC gene polymorphisms on the pharmacokinetics and pharmacodynamics of capecitabine in colorectal patients: Implications for dosing recommendations.

AIMS: The aims are to develop a population pharmacokinetic model of capecitabine (CAP) and its main metabolites after the oral administration of CAP in colorectal cancer patients with different polymorphisms of the ATP-binding cassette (ABC) gene and a population pharmacokinetic/pharmacodynamic model capable of accounting for the neutropenic effects, and to optimize the dosing strategy based on the polymorphisms of the ABC gene and/or the administration regimen as a single agent or in combination. METHODS: Forty-eight patients diagnosed with colorectal cancer were included, with 432 plasma levels of CAP, 5'-desoxi-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU), and 370 neutrophil observations. Capecitabine doses ranged from 1250 to 2500 mg/m2 /24 h. Plasma measurements of CAP, 5'-DFUR and 5-FU were obtained at 1, 2 and 3 hours post administration. Neutrophil levels were measured between day 15 and day 24 post administration. RESULTS: The pharmacokinetic model incorporates oxaliplatin as a covariate on absorption lag time, rs6720173 (ABCG5 gene) on clearance of 5'-DFUR (182% increase for mutated rs6720173) and rs2271862 (ABCA2 gene) on clearance of 5-FU (184% increase for mutated rs2271862). System- (Circ0 = 3.54 × 109 cells/mL, MTT = 204 hours and γ = 6.0 × 10-2 ) and drug-related (slope [SLP] = 3.1 × 10-2 mL/mg). Co-administration of oxaliplatin resulted in a 2.84-fold increase in SLP. The predicted exposure thresholds to G3/4 neutropenia in combination and monotherapy were 26 and 70 mg·h/L, respectively. CONCLUSIONS: The population pharmacokinetic/pharmacodynamic model characterized the time course of capecitabine and its metabolites in plasma. Dose recommendations of capecitabine in patients with mutated and wild allele for single nucleotide polymorphisms rs2271862 of ≤3000 and ≤2400 mg/m2 /24 h in monotherapy and ≤1750 and ≤600 mg/m2 /24 h in combination with oxaliplatin, respectively, have been proposed.

Personalized pharmacotherapy in oncology: Application of pharmacokinetic-pharmacodynamic criteria.

OBJECTIVE: Indication of personalized pharmacotherapy in oncologic patients is  based on the selection of the optimal treatment (drugs, dosing, routes and  methods of administration and duration) and on the most appropriate dosing  method to achieve maximum antineoplastic efficacy, expressed in terms of  remission or relapse-free time and acceptable toxicity for the patients. The aim  of this study was to explore the contribution of therapeutic monitoring of  plasma concentrations and of the application of the pharmacokinetic and  pharmacodynamic information available for some widely used drugs to  therapeutic personalization to the care of oncologic patients. METHOD: A complete non-systematic literature review was carried out of the  pharmacokinetic and pharmacodynamic properties of antineoplastic agents, as  well as of the results of their use in clinical practice. The search for high quality  articles included primary and secondary bibliographic sources. The  benefits of therapeutic monitoring were evaluated for parenteral cytotoxic  rugs, oral antineoplastic drugs, monoclonal antibodies and other biological  therapies used in clinical practice. RESULTS: Therapeutic personalization of antineoplastic drugs based on therapeutic monitoring of plasma concentrations together with the information provided by pharmacokinetic-pharmacodynamic models makes it  possible to reduce toxicity and increase the effectiveness of treatment. When  personalized treatment is established with high-dose methotrexate in patients  with osteosarcoma, target maximum concentrations are reached in 70% of the  cycles (49% when fixed doses are used). When 5-fluorouracil is used in  patients with colorectal cancer, the response rate is 33.7% (18.3% with fixed  doses). Similar benefit rates are obtained with asparaginase, busulfan, oral  antineoplastics and monoclonal antibodies. CONCLUSIONS: Due to the narrow therapeutic range of antineoplastic drugs and  the highly variable clinical response they elicit, both in terms of  effectiveness and safety, the monitoring of their plasma concentrations and the  application of pharmacokinetic and pharmacodynamic principles and  models constitute feasible and promising tools in the personalization of  oncologic treatment.

OBJETIVO: La indicación de una farmacoterapia personalizada en oncología se  sustenta en la selección del tratamiento óptimo (fármacos, dosis, vías y  métodos de administración y duración) y en el método de ajuste de la dosis  para alcanzar la máxima eficacia antineoplásica, expresada en términos de  remisión de la enfermedad o de tiempo libre de recaída, con una toxicidad  aceptable para el paciente. El objetivo de este trabajo es explorar la  contribución, en la personalización terapéutica en oncología clínica asistencial,  de la monitorización terapéutica de las concentraciones plasmáticas y la  aplicación de la información farmacocinética y farmacodinámica disponible para  algunos fármacos ampliamente utilizados.Método: Se ha realizado una revisión bibliográfica no sistemática completa de  los criterios farmacocinéticos y farmacodinámicos de los antineoplásicos, así  como de los resultados derivados de su utilización en la práctica clínica  asistencial. En la búsqueda de artículos de alta calidad sobre los temas  planteados se han incluido fuentes bibliográficas primarias y secundarias. La  tilidad de la monitorización terapéutica se ha centrado en fármacos citotóxicos  parenterales, antineoplásicos orales, anticuerpos monoclonales y otras terapias  biológicas utilizadas en la práctica clínica asistencial. Resultados: La personalización terapéutica de fármacos antineoplásicos basada en la monitorización terapéutica de las  oncentraciones  plasmáticas, y la información que proporcionan los modelos farmacocinéticos- farmacodinámicos, permite reducir la toxicidad y aumentar la efectividad  asociada al tratamiento. Cuando se instaura un tratamiento personalizado con  metotrexato a altas dosis en pacientes con osteosarcoma se alcanza la  concentración máxima objetivo en un 70% de los ciclos (49% en dosis fijas), y  con 5-fluorouracilo en pacientes con cáncer colorrectal la tasa de respuesta es  del 33,7% (18,3% en dosis fijas). Con asparaginasa, busulfán, antineoplásicos  orales y anticuerpos monoclonales se obtienen tasas de beneficios similares. CONCLUSIONES: Debido al bajo intervalo terapéutico de los medicamentos antineoplásicos y a su alta variabilidad en la respuesta clínica,  tanto en términos de efectividad como de seguridad, la monitorización de sus  concentraciones plasmáticas, y la aplicación de los principios y de los modelos farmacocinéticos y farmacodinámicos, constituyen herramientas  actibles y prometedoras en la personalización de los tratamientos en oncología.

Influence of Inter- and Intra-Batch Variability on the Sample Size Required for Demonstration of Equivalent Microstructure of Semisolid Dosage Forms.

Inter- and intra-batch variability of the quality attributes contribute to the uncertainty for demonstrating equivalent microstructure of post-approval changes and generic/hybrids of semisolid topical products. Selecting a representative sample size to describe accurately the in vitro properties of semisolids and to reach enough statistical power to demonstrate similarity between two semisolid topical products is currently challenging. The objective of this work is to establish the number of batches and units per batch to be compared based on different inter-batch and intra-batch variability to demonstrate equivalence in the physical characteristics of the products that ensure a similar microstructure of the semisolid. This investigation shows that the minimum number of batches to be compared of each product is 3 and the minimum number of units per batch could be 6 in the case of low intra- and inter-batch variability. If the products are not identical, i.e., 2.5-5% differences that are expected due to differences in the manufacturing process or the suppliers of excipients, 12 units and 6 batches are needed. If intra- or inter-batch variability is larger than 10%, the number of batches and/or the number of units needs to be increased. As the interplay between inter- and intra-batch variability is complex, the sample size required for each combination of inter- and intra-batch variability and expected difference between products can be obtained in the attached tables.

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice.

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.

Erratum: Mangas-Sanjuán, V.; et al. Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence. Pharmaceutics 2019, 11, 503.

The authors wish to make the following corrections to this paper [...].

Quality Improvement Project to Evaluate Discharge Prescriptions in Children With Cystic Fibrosis.

Cystic Fibrosis (CF) requires multiple pharmaceutical treatments, elevating the risk of medication errors (ME), which may compromise patient safety. This study aimed to improve the quality of discharge prescriptions (DPs) using indicators following admissions for IV antibiotics in pediatric CF patients. METHODS: This project involved a longitudinal observational retrospective descriptive study followed by a longitudinal quasi-experimental prospective phase between January 2013 and December 2016 in CF patients admitted to a London Children's Hospital. The CF pharmacist reviewed DPs. Six rights of medication administration were defined (6R): dose, drug, frequency, duration of treatment, pharmaceutical form, and route of administration. We classified ME according to 6R, including subtype of error: committed/omitted. We calculated quality indicators by dividing the number of each correct parameter defined by 6R by number of DPs. Retrospective results were used prospectively to describe and implement improvement strategies and safety actions. RESULTS: The retrospective study phase included 42 CF children (100 hospital admissions and 1,343 drugs). The prospective phase included thirty-five children (55 admissions and 822 drugs). The total number of ME identified was 148 (78 committed; 70 omitted) in retrospective phase and 135 (19 committed; 116 omitted) in prospective phase. Quality indicators for drug and dose showed significant improvement after implementing safety strategies. The global quality indicator increased from 22% (retrospective) to 41.82% (prospective), but we did not achieve the previously defined quality standard value (50%). CONCLUSIONS: A retrospective review of DP by a CF Pharmacist identified failures in DP quality. Implementing improvement strategies improved prescribing. Integrating pharmacist within multidisciplinary team improves DP reducing errors.

Relationship between rheological properties, in vitro release and in vivo equivalency of topical formulations of diclofenac.

Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations, such as the comparison of rheological properties, droplet size and in vitro release rates. Nevertheless, defining the appropriate acceptance range to consider equivalence between test and reference formulation is complex. To shed more light into this issue, in vitro release and rheological properties were compared to in vivo bioequivalence data (systemic blood measurements within a clinical trial) after topical application of a single dose. Test and reference formulations of diclofenac diethylamine emulgels were evaluated. While the test formulation met the requirements for equivalence in both the in vivo bioequivalence and in vitro release study, the rheological properties were considered equivalent depending on the criteria used. The 90% confidence interval of the ratios between geometric mean values of both formulations were within the limits of 75-133%, but outside the 90-111% limit under discussion in the scientific community. Altogether these data indicate that differences beyond ±10% between rheological parameters of test and reference formulation might not translate into meaningful release nor bioavailability divergence.

Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence.

Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters were calculated with parametric and non-parametric approaches. Both methods conclude that equivalent microstructure between batches cannot be demonstrated with a reasonable sample size when the acceptance range was set at ±10%, since several physical parameters exhibit inter-batch variability >10%. An acceptance range of ±10% is therefore too strict to conclude equivalence in the microstructure of semisolid dosage forms, given the inter-batch variability observed between batches of the reference product. A wider fixed acceptance range or an acceptance range widened based on the inter-batch variability of the reference product would be advisable.

Development of antibiotic loaded biodegradable matrices to prevent superficial infections associated to total knee arthroplasty.

Development of a pharmaceutical form for the superficial infections related with arthroplasties would be helpful for clinical practice. In this context, we set out to evaluate ciprofloxacin and gentamicin elution from systems based on chitosan. Films and semisolid hydrogels containing chitosan alone (2%) or in combination with gelatin (6%) or different proportions (from 12% to 36%) of tetrakis-(hydroxymethyl)-phosphonium-chloride (THPC) were tested as delivery systems. Different antibiotic doses were assayed (0.5 mg/cm2,1 mg/cm2 and 2 mg/cm2). Antibiotic release was studied for each formulation. In vitro cytocompatibility studies and a simulation exercise for bioactivity evaluation were performed. Samples containing chitosan or chitosan-gelatin released the antibiotics at very high rates. On the contrary, ciprofloxacin released was kept for 6 days from THPC-chitosan films and hydrogels. From hydrogel formulations release could be changed by varying the percentage of THPC. The system containing 12%-THPC-chitosan with 2 mg/cm2 of ciprofloxacin showed that 100% of patient would be covered during 72 h post-surgery. The concentration of 12%-THPC did not show cytotoxicity in NIH3T3 mouse fibroblasts after 48 h. THPC is suitable as crosslinker for chitosan when ciprofloxacin is incorporated showing a sustained release during 6 days.