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Blanco M.E.,University of the Basque Country | Encinas E.,University of the Basque Country | Gonzalez O.,University of the Basque Country | Gonzalez O.,Leiden University | And 4 more authors.
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 (≤100μL) 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 13C6-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 13C6-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 (5μg/kg bolus immediately followed by a 90-min infusion of 3μg/kg/h). © 2015 John Wiley & Sons, Ltd.

Carral N.,University of the Basque Country | Lukas J.C.,University of the Basque Country | Lukas J.C.,Dynakin SL | 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.

Valdivieso N.,University of the Basque Country | Oteo I.,University of the Basque Country | Valdivieso A.,Liver Unit | Valdivieso A.,University of the Basque Country | And 7 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2013

Aim: To determine how changes in tacrolimus (TAC) immunosuppression clinical practice, in the first 15 days post liver transplantation (LT) and across a decade, impact a clinical covariate - pharmacokinetic (PK) model, developed in data from 1998, thus testing its utility in dose individualization across time. Patient cohorts from 1998 (Reference: R-1998) and 2007 (Evaluation: E-2007) were compared. Methods: Analysis of monitoring observations (Cmin and Cmin/dose) and the biochemical variables aspartate aminotransferase (AST), hematocrit (HCT), albumin (ALB) and serum creatinine (SCr) was done for 0 - 3 and 4 - 15 days post transplantation (PT). The population PK model developed for R-1998 [1] was re-evaluated for the two cohorts. Results: Significant differences in R-1998 vs. E-2007 existed in Cmin and Cmin/dose and in covariates AST (as hepatic function marker) and SCr (as toxicity marker). E-2007 had lower levels of Cmin and Cmin/dose (1/CL), lower AST with faster recovery and lower variability in Cmin/dose for similar dose. AST was a covariate on CL/F in the 0 - 3 day PT period. In 4 - 15 days PT for E-2007, low levels of HCT and ALB as CL/F predictors confirmed a subgroup with higher CL/F (23.8 l/h vs. 19.3 l/h). The R-1998 model's original structure was confirmed. Conclusions: Ten years of use of TAC shows gain in therapeutic targeting efficiency, due to improvement in LT methods, knowledge of the drug and consideration of PK steady state. The remaining uncertainty with TAC monitoring in LT can be resolved with application of PK principles combined with patients' idiosyncrasies in the model developed for TAC dose individualization in R-1998. The applicability of the model as nucleus in Bayes individualization remains intact across a decade. © 2013 Dustri-Verlag Dr. K. Feistle.

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.

Lucero M.L.,FAES FARMA S.A. | Gonzalo A.,FAES FARMA S.A. | Ganza A.,FAES FARMA S.A. | Leal N.,Dynakin SL | 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.

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