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Oteo I.,University of the Basque Country | Lukas J.C.,Dynakin SL | Leal N.,Dynakin SL | Suarez E.,University of the Basque Country | And 7 more authors.
European Journal of Clinical Pharmacology | Year: 2013

Purpose: To define and validate a pharmacokinetic (PK) model for tacrolimus (TAC) that includes patient pathophysiology and has clinical applicability in the first 2 weeks post-liver transplantation (PLT). Methods: Routine monitoring records [dose, trough levels (Cmin), demographics, biochemistry] from 75 patients treated with TAC (Prograf®) PLT were used to develop a population PK model (employing NONMEM®) testing for predictors of oral clearance (CL/F) according to bedside evidence and primarily with aspartate aminotransferase (AST), albumin (ALB), and hematocrit (HCT). Patients were catergorized into subgroups with above and below "normal" thresholds for AST (500 U/L), ALB (2.5 g/dL), and HCT (28 %), respectively. The model was validated with ten patients from the same period and 15 more recent patients. An empirical Bayes method was developed and applied to the prediction of individual profiles serving as a dose adjustment tool. Results: The number of days PLT (Days PLT) was a key variable during the first 2 weeks, with a dichotomy in the mono-compartmental parameters for 0-3 Days PLT and 4-15 Days PLT. During 0-3 Days PLT, AST levels, indicative of allograft functionality (and TAC metabolism), were crucial predictors of elimination. Three groups were identified with the following clearances: CL/F0-3 = 8.93 L/h for AST ≥500 U/L and CL/F0-3 = 11.0 L/h for AST <500 U/L. During 4-15 Day PLT, low values of ALB (<2.5 g/dL) and HCT (<28 %) combined were determinant of a patient subgroup with a tendency to underexposure and complexity in empirical dose adjustment. The CL/F4-15 = 25.1 L/h for this subgroup compared to CL/F4-15 = 17.1 L/h for the others in that period. The elimination half-life for individual patients varied over tenfold so that a large number of subjects were not at steady state, making the use of a PK model necessary to achieve rapidly and safely the target concentration for TAC in LT. Validation of the model demonstrated that both bias and precision were within acceptable limits. Conclusion: For TAC therapy, covariate models using mixed effects methods are most useful when combined with patient-specific biochemical assays as well as clinical evidence. In such cases, the observed Cmin and Bayes methods can provide the most likely individual PK parameters, hence the optimal next dose to reach individualized target levels for each patient. © 2012 Springer-Verlag.


Oteo I.,University of the Basque Country | Lukas J.C.,University of the Basque Country | Lukas J.C.,Dynakin SL | Leal N.,Dynakin SL | And 6 more authors.
European Journal of Clinical Pharmacology | Year: 2011

Purpose: To explore the main factors that make it difficult to empirically monitor tacrolimus (TAC) in the early period post-liver transplantation (LTx), with a specific focus on those aspects related to patient idiosyncrasy and clinical status as well as to the pharmacokinetic (PK) assumptions on which drug individualization in clinical practice is based. Methods: Retrospective monitoring data from 75 de novo liver transplant patients treated with twice daily with TAC and followed for up to 15 days were analyzed. An extensive battery of laboratory measurements were available. Dose adjustment was performed empirically using trough levels (Cmin). The population was separated into two major background groups according to low or high values of aspartate aminotransferase (AST) (Group 1 and 2, respectively) based on AST measurements made during the first 4 days post-LTx. Each of these two major groups was then further subdivided into two subgroups based on elevated (Groups 1A, 2A) or reduced (Groups 1B, 2B) combined albumin (cut-off 2.5 g/dl) and hematocrit (cut-off 28%). Results: The Cmin/Dose ratio [inversely proportional to systemic clearance (CL)] had a variability [coefficient of variation (CV) >80%) that was incongruently higher for the ratio than for Cmin and Dose separately. This was attributed to most patients not being at steady state or physiologically stable in the early post-LTx period. Group 1 patients were more predictable than Group 2 patients, who were responsible for the variability in the ratio. Cmin was lower in the reduced ALB and HCT patient groups when AST conditions were similar (1A vs. 1B and 2A vs. 2B), likely due to increased TAC metabolic clearance (reduced Cmin/Dose). This situation existed for two periods: 0-15 days post-LTx and 4-15 days post-LTx observations. Group 2A patients were the main source of the paradoxical variability in Cmin/Dose (higher ratio of 2.7; CV = 100%), suggesting a lower clearance and difficulty in the recovery of stability. In contrast, Group 2B patients had the lower ratio (1.4; 47%) but required the highest number of dose adjustments as the variability was hard to identify clinically. Group 1A patients were the most predictable empirically. When observations from 15 new patients who entered the clinic in 2007 and 2008 were used for the analysis, the same sub-groups existed in the same proportions in both years. Conclusion: The difficulty in empirical dose adjustment of TAC is associated to the inevitable non-fulfillment of PK assumptions early post-LTx and also to the inherent complexity of the clinical condition, leading to increased uncertainty for the clinician regarding dose selection. Identifying these sub-categories provides a rational means of classifying patients akin to a phenotype. The complexity of the kinetics in LTx and TAC treatment does not invalidate Cmin as a biomarker, but a Bayes algorithm including a full PK structure and these covariates would be optimal. © 2011 Springer-Verlag.


Carral N.,University of the Basque Country | Lukas J.C.,University of the Basque Country | Lukas J.C.,Dynakin S.L. | Oteo I.,University of the Basque Country | Suarez E.,University of the Basque Country
International Journal of Antimicrobial Agents | Year: 2015

The purpose of this report was to assess the impact of poor compliance on the efficacy of levofloxacin (LFX) and moxifloxacin (MOX), two fluoroquinolones with different pharmacokinetic (PK) and pharmacodynamic (PD) properties, in respiratory infections. The fAUC0-24 h and fAUC0-24 h/MIC90 ratio, a PK/PD index predictive of bacterial eradication, were extracted from previously described population PK models for LFX and MOX. The MIC90 was according to EUCAST. Monte Carlo simulations were used with LFX 500 mg every 24 h (q24 h) or every 12 h (q12 h), LFX 750 mg q24 h and MOX 400 mg q24 h in non-compliance scenarios to derive the proportion of patients achieving target ratios of fAUC0-24 h/MIC90 > 33.8 for Streptococcus pneumoniae and >100 for Haemophilus influenzae and Moraxella catarrhalis (PTA > 90%). In non-adherent dosing scenarios, LFX 500 mg q24 h was not able to reach the PK/PD index guaranteeing clinical efficacy. With LFX 500 mg q12 h or 750 mg q24 h, this probability was maintained although patients can take the dose with delays of up to 12 h and 11 h, respectively, for the three bacterial types. With MOX 400 mg q24 h, the probability of achieving this PK/PD index is maintained with delay in dosing up to 16 h. In conclusion, LFX 500 mg q24 h is the least robust treatment against S. pneumoniae, H. influenzae and M. catarrhalis in a non-adherence situation. A good choice is LFX 500 mg q12 h, but in order to favour patient adherence, LFX 750 mg q24 h or MOX 400 mg q24 h appears as more appropriate. © 2014 Elsevier B.V. and the International Society of Chemotherapy.


Encinas E.,University of the Basque Country | Calvo R.,Dynakin SL PTB | Lukas J.C.,University of the Basque Country | Lukas J.C.,Dynakin SL | And 3 more authors.
Pediatric Drugs | Year: 2013

Background and Objectives: Fentanyl is a synthetic opioid commonly used as an anesthetic and also increasingly popular as a sedative agent in neonates. Initial dosage regimens in this population are often empirically derived from adults on a body weight basis. However, ontogenic maturation processes related to drug disposition are not necessarily always body weight correlates. We developed a predictive pharmacokinetic/pharmacodynamic model that includes growth and maturation physiologic changes for fentanyl in neonatal care. Methods: Key pharmacokinetic variables and principles (protein binding, clearance, distribution) as related to fentanyl pharmacokinetic/pharmacodynamic behavior in adults (tricompartmental model) and to neonatal physiologic data (organ weights and blood flows, body composition, renal and hepatic function, etc.) were used to guide the building of a semi-physiologic ontogenic model. The model applies to a normal-term neonate without any other intervention. Then, extension to a pharmacokinetic/pharmacodynamic link model for fentanyl was made. The final model was evaluated by predicting the time course of plasma concentrations and the effect of a standard regimen of 10.5 μg/kg over a 1-h period followed by 1.5 μg/kg/h for 48 h. Results: Hepatic clearance was linked to ontogeny of unbound fraction and of α1-acid glycoprotein. All parameters were reduced in the neonate compared to adults but in a differing proportion due to qualitative changes in physiology that are analyzed and accounted for. Systemic clearance (CLS), volume of the central compartment (V1) and steady-state volume of distribution predicted by the model were 0.028 L/min, 1.26 L, and 22.04 L, respectively. Weight-corrected parameters generally decreased in adults compared with neonates, but differentially, e.g., CLS = 0.0093 versus 0.0088 L/min/kg, while V1 = 0.42 versus 0.18 L/kg (neonates vs. adults). Under such complexity a pharmacokinetic/pharmacodynamic model is the appropriate method for rational efficacy targeting. Fentanyl pharmacodynamics in neonates were considered to be similar to those in adults except for the equilibrium rate constant, which was also scaled on an ontogenic basis. The model adequately predicted the reported mean expected concentration-time profiles for the standard regimen. Conclusions: Integrated pharmacokinetic/pharmacodynamic modeling showed that the usually prescribed dosage regimens of fentanyl in neonates may not always provide the optimum degree of sedation. The model could be used in optimal design of clinical trials for this vulnerable population. Prospective clinical testing is the reasonable next step. © 2013 Springer International Publishing Switzerland.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2011.4.2-1 | Award Amount: 7.78M | Year: 2011

Dobutamine and adrenaline are widely used as second line therapy for systemic hypotension in infants. Dopamine is currently the most widely used first line drug. In neonates, sustained hypotension may, and impaired organ perfusion will, cause brain injury and poor neurodevelopmental outcomes. All three catecholamines are currently used off-label and have different modes of action which may result in potentially harmful haemodynamic effects. No reliable safety or efficacy data exists for the use of these drugs in neonates or newborns. Furthermore, no uniform criteria exist to define hypotension and there is little evidence to support current intervention strategies, which vary widely. Recently, superior vena cava (SVC) flow has been proposed as a more reliable indicator of circulatory failure than low blood pressure and preliminary results suggest Dobutamine is the optimum therapeutic in such cases. NEO-CIRC proposes 1) a randomised placebo controlled trial to provide safety and efficacy data for Dobutamine as a first line inotrope for all gestational ages 2) to perform pre-clinical; pharmacokinetic; pharmacodynamic; metabolomic and pharmacogenomic studies 3) to develop improved biomarkers of hypotension 4) to develop and adapt a formulation of Dobutamine suitable for newborns with the aim to apply for a Paediatric Use Marketing Authorisation. The NEO-CIRC consortium includes international experts in neonatal medicine, pharmacology, pharmacogenomics, drug formulation and pre-clinical neonatal models and an experienced group of experienced multicentre clinical trials NICUs. Outcomes anticipated include improved biomarkers of organ perfusion; a new consensus definition of neonatal circulatory failure and answers to key clinical practice uncertainties, including variability of response to Dobutamine in common pathophysiologies seen in newborn infants impact on longer term developmental outcomes so important to the patients, families and wider society.


PubMed | Dynakin SL and University of the Basque Country
Type: Journal Article | Journal: Drug testing and analysis | Year: 2015

In this study, a selective and sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method requiring low sample volume (100L) was developed and validated for the quantitative determination of the opioid drug fentanyl in plasma and cerebrospinal fluid (CSF). A protein precipitation extraction with acetonitrile was used for plasma samples whereas CSF samples were injected directly on the HPLC column. Fentanyl and (13) C6 -fentanyl (Internal Standard) were analyzed in an electrospray ionization source in positive mode, with multiple reaction monitoring (MRM) of the transitions m/z 337.0/188.0 and m/z 337.0/105.0 for quantification and confirmation of fentanyl, and m/z 343.0/188.0 for (13) C6 -fentanyl. The respective lowest limits of quantification for plasma and CSF were 0.2 and 0.25ng/mL. Intra- and inter-assay precision and accuracy did not exceed 15%, in accordance with bioanalytical validation guidelines. The described analytical method was proven to be robust and was successfully applied to the determination of fentanyl in plasma and CSF samples from a pharmacokinetic and pharmacodynamic study in newborn piglets receiving intravenous fentanyl (5g/kg bolus immediately followed by a 90-min infusion of 3g/kg/h).


Togawa M.,Taiho Pharmaceutical Co | Yamaya H.,Taiho Pharmaceutical Co | Rodriguez M.,DynaKin S.L. | Nagashima H.,Shinjuku Research Park Clinic
Clinical Drug Investigation | Year: 2016

Background and objectives: Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. Methods: In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). Results: After single oral doses, maximum plasma concentrations (Cmax) were reached at 1.0–1.5 h postdose. Plasma exposure [Cmax and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10–50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for Cmax or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. Conclusion: Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies. © 2016 The Author(s)


Lucero M.L.,Faes Farma S.A. | Gonzalo A.,Faes Farma S.A. | Ganza A.,Faes Farma S.A. | Leal N.,DynaKin S.L. | And 5 more authors.
Drug and Chemical Toxicology | Year: 2012

Membrane transporters play a significant role in facilitating transmembrane drug movement. For new pharmacological agents, it is important to evaluate potential interactions (e.g., substrate specificity and/or inhibition) with human transporters that may affect their pharmacokinetics, efficacy, or toxicity. Bilastine is a new nonsedating H1 antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The in vitro inhibitory effects of bilastine were assessed on 12 human transporters: four efflux [multidrug resistance protein 1 (MDR1) or P-glycoprotein, breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2), and bile salt export pump) and eight uptake transporters (sodium taurocholate cotransporting polypeptide, organic cation transporter (OCT)1, organic anion transporter (OAT)1, OAT3, OCT2, OATP2B1, OATP1B1, and OATP1B3). Only mild inhibition was found for MDR1-, OCT1-, and OATP2B1-mediated transport of probe substrates at the highest bilastine concentration assayed (300 μM; half-maximal inhibitory concentration: ≥300 μM). Bilastine transport by MDR1, BCRP, OAT1, OAT3, and OCT2 was also investigated in vitro. Only MDR1 active transport of bilastine was relevant, whereas it did not appear to be a substrate of OCT2, OAT1, or OAT3, nor was it transported substantially by BCRP. Drug-drug interactions resulting from bilastine inhibition of drug transporters that would be generally regarded as clinically relevant are unlikely. Additionally, bilastine did not appear to be a substrate of human BCRP, OAT1, OAT3, or OCT2 and thus is not a potential victim of inhibitors of these transporters. On the other hand, based on in vitro evaluation, clinically relevant interactions with MDR1 inhibitors are anticipated. © 2012 Informa Healthcare USA, Inc.


Vozmediano V.,Dynakin SL | Ortega I.,FAES Farma SA | Lukas J.C.,Dynakin SL | Gonzalo A.,FAES Farma SA | And 2 more authors.
European Journal of Drug Metabolism and Pharmacokinetics | Year: 2014

Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes. © 2013 Springer-Verlag.


PubMed | Taiho Pharmaceutical Co, Shinjuku Research Park Clinic and DynaKin S.L.
Type: Journal Article | Journal: Clinical drug investigation | Year: 2016

Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects.In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50mg (Part I), and once daily for 14days at 20 and 50mg (Part II).After single oral doses, maximum plasma concentrations (C Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

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