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.

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.

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.

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.

A preclinical study to model taurine pharmokinetics in the undernourished rat.

Malnutrition is a common feature of chronic and acute diseases, often associated with a poor prognosis, including worsening of clinical outcome, owing, among other factors, to dysfunction of the most internal organs and systems affecting the absorption, metabolism and elimination of drugs and nutrients. Taurine is involved in numerous biological processes and is required in increased amounts in response to pathological conditions. The aim of this study was to describe the behaviour of taurine in well-nourished (WN) rats and to analyse the influence of protein-energy undernutrition on the pharmacokinetic (PK) parameters of taurine, using a PK model. Wistar rats were randomly distributed into two groups, WN and undernourished (UN), and taurine was administered intravenously or orally at different doses: 1, 10 and 100 mg. Population pharmacokinetic modelling of plasma levels was performed using the NONMEM 7.2 program. Several distribution and absorption models were explored in combination with dose and/or time covariate effects. Covariates such as nutritional status, serum albumin, body weight and score of undernutrition were used. A two-compartment population pharmacokinetic model with zero-order endogenous formation, passive absorption, first-order kinetics distribution and non-linear elimination with parallel Michaelis-Menten excretion and reabsorption processes best described taurine pharmacokinetics. Undernutrition acted as a covariate reducing the V max of the active elimination process. Data analysis showed linear absorption and distribution, and non-linear elimination processes for taurine. Elimination of taurine was reduced in UN animals, suggesting that the reabsorption process via the secretion transporter was modified in that group.

Usefulness of Caco-2/HT29-MTX and Caco-2/HT29-MTX/Raji B Coculture Models To Predict Intestinal and Colonic Permeability Compared to Caco-2 Monoculture.

The Caco-2 cellular monolayer is a widely accepted in vitro model to predict human permeability but suffering from several and critical limitations. Therefore, some alternative cell cultures to mimic the human intestinal epithelium, as closely as possible, have been developed to achieve more physiological conditions, as the Caco-2/HT29-MTX coculture and the triple Caco-2/HT29-MTX/Raji B models. In this work the permeability of 12 model drugs of different Biopharmaceutical Classification System (BCS) characteristics, in the coculture and triple coculture models was assessed. Additionally, the utility of both models to classify compounds according to the BCS criteria was scrutinized. The obtained results suggested that the coculture of Caco-2/HT29-MTX and the triple coculture of Caco-2/HT29-MTX/Raji B were useful models to predict intestinal permeability and to classify the drugs in high or low permeability according to BCS. Moreover, to study thoroughly the transport mechanism of a specific drug, using a more complex model than Caco-2 monocultures is more suitable because coculture and triple coculture are more physiological models, so the results obtained with them will be closer to those obtained in the human intestine.

Impact of Undernutrition on the Pharmacokinetics and Pharmacodynamics of Anticancer Drugs: A Literature Review.

The etiology of undernourishment in cancer patients is multifactorial: tumor-related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can induce or worsen undernutrition. The evident role of undernutrition in cancer treatment outcomes suggests the need of considering nutritional status when evaluating anticancer drugs. In order to merge the available data and offer researchers and clinicians a global view of this phenomenon, the present manuscript reviews on a drug-by-drug basis the undernutrition-related pharmacokinetic and pharmacodynamic aspects of anticancer treatments. This review notes interesting trends in the relationship between undernourishment and pharmacokinetics across studies, and indicates that dosing modifications of these drugs may be necessary to optimize chemotherapeutic treatments. Furthermore, this review has compiled evidence regarding undernourishment's capacity of enhancing treatment-related myelosuppression, cardiotoxicity, ototoxicity, neurotoxicity, and malignancies.

Closed-Loop Doluisio (Colon, Small Intestine) and Single-Pass Intestinal Perfusion (Colon, Jejunum) in Rat-Biophysical Model and Predictions Based on Caco-2.

PURPOSE: The effective rat intestinal permeability (P eff ) was deconvolved using a biophysical model based on parameterized paracellular, aqueous boundary layer, transcellular permeabilities, and the villus-fold surface area expansion factor. METHODS: Four types of rat intestinal perfusion data were considered: single-pass intestinal perfusion (SPIP) in the jejunum (n = 40), and colon (n = 15), closed-loop (Doluisio type) in the small intestine (n = 78), and colon (n = 74). Moreover, in vitro Caco-2 permeability values were used to predict rat in vivo values in the rat data studied. RESULTS: Comparable number of molecules permeate via paracellular water channels as by the lipoidal transcellular route in the SPIP method, although in the closed-loop method, the paracellular route appears dominant in the colon. The aqueous boundary layer thickness in the small intestine is comparable to that found in unstirred in vitro monolayer assays; it is thinner in the colon. The mucosal surface area in anaesthetized rats is 0.96-1.4 times the smooth cylinder calculated value in the colon, and it is 3.1-3.6 times in the small intestine. The paracellular permeability of the intestine appeared to be greater in rat than human, with the colon showing more leakiness (higher P para ) than the small intestine. CONCLUSION: Based on log intrinsic permeability values, the correlations between the in vitro and in vivo models ranged from r2 0.82 to 0.92. The SPIP-Doluisio method comparison indicated identical log permeability selectivity trend with negligible bias.

Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats.

The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well- and under-nourished rats. Absorption studies were performed in male Wistar rats. Concentration-time profiles in proximal and distal intestine were analysed through non-linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best-described erlotinib absorption from lumen to enterocyte. The developed model indicates that levofloxacin exerts an inhibition on erlotinib efflux transporters of the gut epithelium. Undernourishment proved to significantly decrease the maximum capacity of the secretion process. Simulations evidenced that erlotinib absorption only takes place at high enough drug concentrations to overcome the effect of efflux transporters. On the other hand, when levofloxacin is present in the intestinal lumen of undernourished rats, erlotinib drug absorption takes place even at low erlotinib concentrations. In the clinical setting, this interaction may result in increased exposure to erlotinib, especially in undernourished cancer patients. Copyright © 2017 John Wiley & Sons, Ltd.

Multi-output model with Box-Jenkins operators of linear indices to predict multi-target inhibitors of ubiquitin-proteasome pathway.

The ubiquitin-proteasome pathway (UPP) plays an important role in the degradation of cellular proteins and regulation of different cellular processes that include cell cycle control, proliferation, differentiation, and apoptosis. In this sense, the disruption of proteasome activity leads to different pathological states linked to clinical disorders such as inflammation, neurodegeneration, and cancer. The use of UPP inhibitors is one of the proposed approaches to manage these alterations. On other hand, the ChEMBL database contains >5,000 experimental outcomes for >2,000 compounds tested as possible proteasome inhibitors using a large number of pharmacological assay protocols. All these assays report a large number of experimental parameters of biological activity like EC50, IC50 percent of inhibition, and many others that have been determined under many different conditions, targets, organisms, etc. Although this large amount of data offers new opportunities for the computational discovery of proteasome inhibitors, the complexity of these data represents a bottleneck for the development of predictive models. In this work, we used linear molecular indices calculated with the software TOMOCOMD-CARDD and Box-Jenkins moving average operators to develop a multi-output model that can predict outcomes for 20 experimental parameters in >450 assays carried out under different conditions. This generated multi-output model showed values of accuracy, sensitivity, and specificity above 70% for training and validation series. Finally, this model is considered multi-target and multi-scale, because it predicts the inhibition of the UPP for drugs against 22 molecular or cellular targets of different organisms contained in the ChEMBL database.

Study of the Influence of Bone Cement Type and Mixing Method on the Bioactivity and the Elution Kinetics of Ciprofloxacin.

The objectives of this study were to examine ciprofloxacin release from three trademarks of bone cements (Simplex®, Lima® and Palacos®) and its bioactivity using as variables, the mixing method, the chemical form of the antibiotic and the antibiotic combination. The antibiotic amount released in base form represents 35% of antibiotic amount released when hydrochloride form is incorporated. Moreover, the combination (vancomycin and ciprofloxacin) shows a stronger release (132%) than hydrochloride ciprofloxacin alone. Three cements show equal drug release profile (P > 0.05). A bioactivity simulation exercise showed that until 72 hours post-surgery, ciprofloxacin concentrations in the implant would be higher than 0.1 µg/mL in 100% of the patients. After drain removal, it is expected that bioactivity would increase since drug clearance from implant would decrease.

In vitro-in vivo correlations: general concepts, methodologies and regulatory applications.

The major objective of in vitro-in vivo correlations is to be able to use in vitro data to predict in vivo performance serving as a surrogate for an in vivo bioavailability test and to support biowaivers. Therefore, the aims of this review are: (i) to clarify the factors involved during bio-predictive dissolution method development; and (ii) the elements that may affect the mathematical analysis in order to exploit all information available. This article covers the basic aspects of dissolution media and apparatus used in the development of in vivo predictive dissolution methods, including the latest proposals in this field as well as the summary of the mathematical methods for establishing the in vitro-in vivo relationship and their scope and limitations. The incorporation of physiological relevant factors in the in vitro dissolution method is essential to get accurate in vivo predictions. Standard quality control dissolution methods do not necessarily reflect the in vivo behavior, so they rarely are useful for predicting in vivo performance. The combination of physiological based dissolution methods with physiological-based pharmacokinetics models incorporating gastrointestinal variables will lead to robust tools for drug and formulation development, nevertheless their regulatory use for biowaiver application still require harmonization of the mathematical methods proposed and more detailed recommendations about the procedures for setting up dissolution specifications.

Chitosan-xanthan gum microparticle-based oral tablet for colon-targeted and sustained delivery of quercetin.

CONTEXT: Quercetin (QUE) is a flavonoid with antioxidant/anti-inflammatory properties, poorly absorbed when orally administered. OBJECTIVES: To prepare chitosan/xanthan gum microparticles to increase QUE oral bioavailability and optimize its release in the colon. MATERIALS AND METHODS: Chitosan/xanthan gum hydrogel embedding QUE was spray-dried to obtain microparticles characterized by size, scanning electron microscopy, differential scanning calorimetry and X-ray diffraction. Microparticles were compressed into tablets, coated with Eudragit® to further prevent degradation in acidic pH. The swelling degree and QUE release in simulated gastric and intestinal pH were investigated. RESULTS: Microparticles were smooth and spherical, around 5 µm, with successful QUE loading. Microparticle tablets provided resistance to acidic conditions, allowing complete drug release in alkaline pH, mimicking colonic environment. The release was controlled by non-Fickian diffusion of the dissolved drug out of the swollen polymeric tablet. DISCUSSION AND CONCLUSION: Microparticle tablets represent a promising dosage form for QUE delivery to the colon in the oral therapy of inflammatory-based disorders.

Impact of Time on Parameters for Assessing the Microstructure Equivalence of Topical Products: Diclofenac 1% Emulsion as a Case Study.

The demonstration of bioequivalence proposed in the European Medicines Agency's (EMA's) draft guideline for topical products with the same qualitative and quantitative composition requires the confirmation of the internal structure equivalence. The impact of the shelf-life on the parameters proposed for internal structure comparison has not been studied. The objectives of this work were: (1) to quantify the effect of the time since manufacturing on the mean value and variability of the parameters proposed by the EMA to characterize the internal structure and performance of topical formulations of a complex topical formulation, and (2) to evaluate the impact of these changes on the assessment of the microstructure equivalence. A total of 5 batches of a topical emulgel containing 1% diclofenac diethylamine were evaluated 5, 14, and 23 months after manufacture. The zero-shear viscosity (η0), viscosity at 100 s-1 (η100), yield stress (σ0), elastic (G') and viscous (G″) moduli, internal phase droplet size and in vitro release of the active ingredient were characterized. While no change in variability over time was detected, the mean value of all the parameters changed, especially the droplet size and in vitro release. Thus, combining data from batches of different manufacturing dates may compromise the determination of bioequivalence. The results confirm that to assess the microstructural similarity of complex formulations (such as emulgel), the 90% confidence interval limit for the mean difference in rheological and in vitro release parameters should be 20% and 25%, respectively.

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.

Enzyme-responsive silica mesoporous supports capped with azopyridinium salts for controlled delivery applications.

The preparation of a new capped silica mesoporous material, Rh-Azo-S, for on-command delivery applications in the presence of target enzymes is described. The material consists of nanometric mesoporous MCM-41-like supports loaded with Rhodamine B and capped with an azopyridine derivative. The material was designed to show "zero delivery" and to display a cargo release in the presence of reductases and esterases, which are usually present in the colon, mainly due to intestinal microflora. The opening and cargo release of Rh-Azo-S in vitro studies were assessed and seen to occur in the presence of these enzymes, whereas no delivery was noted in the presence of pepsine. Moreover, Rh-Azo-S nanoparticles were used to study controlled Rhodamine B dye delivery in intracellular media. HeLa cells were employed for testing the "non"-toxicity of nanoparticles. Moreover, delivery of the dye in these cells, through internalization and enzyme-mediated gate opening, was confirmed by confocal microscopy. Furthermore, the nanoparticles capped with the Azo group and loaded with a cytotoxic camptothecin (CPT) were also prepared (solid CPT-Azo-S) and used as delivery nanodevices in HeLa cells. When this solid was employed, the cell viability decreased significantly due to internalization of the nanoparticles and delivery of the cytotoxic agent.

Improving oral bioavailability and pharmacokinetics of liposomal metformin by glycerolphosphate-chitosan microcomplexation.

The purpose of this study was to develop a new delivery system capable of improving bioavailability and controlling release of hydrophilic drugs. Metformin-loaded liposomes were prepared and to improve their stability surface was coated with chitosan cross-linked with the biocompatible ß-glycerolphosphate. X-ray diffraction, differential scanning calorimetry, as well as rheological analysis were performed to investigate interactions between chitosan and ß-glycerolphosphate molecules. The entrapment of liposomes into the chitosan-ß-glycerolphosphate network was assessed by scanning electron microscopy and transmission electron microscopy. Swelling and mucoadhesive properties as well as drug release were evaluated in vitro while the drug oral bioavailability was evaluated in vivo on Wistar rats. Results clearly showed that, compared to control, the proposed microcomplexes led to a 2.5-fold increase of metformin T(max) with a 40% augmentation of the AUC/D value.

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.

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.

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.