Jesús Novalbos Reina
@iis-princesa.org
Servicio de Farmacología Clínica
Fundación para la Investigación Biomédica del Hospital Universitario de La Princesa
Senior Researcher, Fundación de Investigación del Hospital de la Princesa in Madrid, since June. My role is to support research projects and provide technical and scientific advice in other functions of the Clinical Pharmacology Service, such as: expert reports on drugs, bioequivalences ...
Previous experience: In the 12 years working in the pharmaceutical industry, I have held various positions, from head of research and development of generic drugs, different positions in medical and training departments, to being the head of a business unit, reporting directly from the departments of marketing, sales, and medical, and with reporting international projection.
Therapeutic areas:Experience in: Phase I clinical trials in healthy volunteers and patients: pharmacokinetics, pharmacodynamics, dose-ranging, bioequivalence, more than 80 studies that was performed starting in 1997; Phase II and III clinical trials in: Women´s health, hormones and drugs for fertility treatments, pharmacogeneti
EDUCATION
Degree in Biology Science 1996, Masters in Clinical Trial Monitoring 2000, Doctor of Medicine -pHd (area of Pharmacology) 2003, and Master in Fertility and Embryology.
RESEARCH INTERESTS
Farmacogenetic, Drug Clinical Trials, Bioequivalence
Scopus Publications
Scopus Publications
Joaquim Calaf, Josep Perelló-Capó, Ignasi Gich-Saladich, Iñaki Lete, and Jesús Novalbos
Elsevier BV
Sarahí Valdez-Acosta, Pablo Zubiaur, Miguel Angel Casado, Jesús Novalbos, Ana Casajús, Diana Campodónico, Itziar Oyagüez, and Francisco Abad-Santos
MDPI AG
A cost analysis of thiopurine treatment was carried out in 257 patients, with 153 preemptively genotyped for TPMT and 104 retrospectively genotyped in a Spanish setting. The healthcare cost was significantly higher in patients retrospectively genotyped compared to those who were preemptively genotyped (p < 0.001). TPMT intermediate metabolizers (IMs) (n = 23) showed a 3.3-fold higher healthcare cost when compared to normal metabolizers (NMs) (p < 0.001). The healthcare cost in patients with a TPMT IM phenotype whose physician adhered to the genotype-informed recommendation was similar than the cost in TPMT NMs and was significantly lower than IMs whose physician did not adhere to the therapeutic recommendation (3.8-fold, p = 0.016). Myelotoxicity occurrence was significantly lower in patients preemptively vs. retrospectively genotyped (2.0% and 21.2%, respectively, p < 0.001). Patients who developed myelotoxicity showed a significantly higher healthcare cost than those who did not (4.10-fold, p < 0.001). Overall, 87% of patients whose dose was not adjusted despite being TPMT IMs suffered myelotoxicity, while only one of the eight patients (13%) whose dose was adjusted suffered myelotoxicity (p < 0.001). In conclusion, TPMT preemptive genotyping and physician adherence to genotype-informed therapeutic recommendations prevents myelotoxicity and significantly reduces the healthcare cost, and it is therefore essential for the sustainability of the Spanish healthcare system.
E. Muñoz‐Aceituno, B. Butrón‐Bris, M. C. Ovejero‐Benito, A. Sahuquillo‐Torralba, O. Baniandrés Rodríguez, E. Herrera‐Acosta, R. Rivera‐Diaz, M. Ferran, J. L. Sánchez‐Carazo, J. Riera‐Monroig,et al.
Wiley
AbstractBackgroundPrediction of the response to a biological treatment in psoriasis patients would allow efficient treatment allocation.ObjectiveTo identify polymorphisms associated with secukinumab response in psoriasis patients in a daily practice setting.MethodsWe studied 180 SNPs in patients with moderate‐to‐severe plaque psoriasis recruited from 15 Spanish hospitals. Treatment effectiveness was evaluated by absolute PASI ≤3 and ≤1 at 6 and 12 months. Individuals were genotyped using a custom Taqman array. Multiple logistic regression models were generated. Sensitivity, specificity and area under the curve (AUC) were analysed.ResultsA total of 173 patients were studied at 6 months, (67% achieved absolute PASI ≤ 3 and 65% PASI ≤ 1) and 162 at 12 months (75% achieved absolute PASI ≤ 3 and 64% PASI ≤ 1). Multivariable analysis showed the association of different sets of SNPs with the response to secukinumab. The model of absolute PASI≤3 at 6 months showed best values of sensitivity and specificity. Four SNPs were associated with the capability of achieving absolute PASI ≤ 3 at 6 months. rs1801274 (FCGR2A), rs2431697 (miR‐146a) and rs10484554 (HLCw6) were identified as risk factors for failure to achieve absolute PASI≤3, while rs1051738 (PDE4A) was protective. AUC including these genotypes, weight of patients and history of biological therapy was 0.88 (95% CI 0.83–0.94), with a sensitivity of 48.6% and specificity of 95.7% to discriminate between both phenotypes.ConclusionWe have identified a series of polymorphisms associated with the response to secukinumab capable of predicting the potential response/non‐response to this drug in patients with plaque psoriasis.
Pablo Zubiaur, Laura Figueiredo-Tor, Gonzalo Villapalos-García, Paula Soria-Chacartegui, Marcos Navares-Gómez, Jesús Novalbos, Miriam Matas, Sofía Calleja, Gina Mejía-Abril, Manuel Román,et al.
Elsevier BV
Pablo Zubiaur, Miriam Matas, Samuel Martín-Vílchez, Paula Soria-Chacartegui, Gonzalo Villapalos-García, Laura Figueiredo-Tor, Sofía Calleja, Marcos Navares-Gómez, Alejandro de Miguel, Jesús Novalbos,et al.
MDPI AG
Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson’s disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.
Ana Casajús, Pablo Zubiaur, Marta Méndez, Diana Campodónico, Antía Gómez, Marcos Navares-Gómez, Gonzalo Villapalos-García, Paula Soria-Chacartegui, Jesús Novalbos, Manuel Román,et al.
Springer Science and Business Media LLC
Pablo Zubiaur, David Nicolás Prósper-Cuesta, Jesús Novalbos, Gina Mejía-Abril, Marcos Navares-Gómez, Gonzalo Villapalos-García, Paula Soria-Chacartegui, and Francisco Abad-Santos
MDPI AG
The process of clinical pharmacogenetics implementation depends on patients’ and general population’s perceptions. To date, no study has been published addressing Spanish patients’ opinions on pharmacogenetic testing, the availability of the results, and the need for signing informed consent. In this work, we contacted 146 patients that had been previously genotyped at our laboratory and 46 healthy volunteers that had participated in a bioequivalence clinical trial at the Clinical Pharmacology Department of Hospital Universitario de La Princesa and consented to pharmacogenetic testing for research purposes. From the latter, 108 and 34, respectively, responded to the questionnaire (i.e., a response rate of 74%); Participants were scheduled for a face-to-face, telephone, or videoconference interview and were asked a total of 27 questions in Spanish. Great or almost complete acceptance of pharmacogenetic testing was observed (99.3%), age and university education level being the main predictors of acceptance rates and understanding (multivariate analysis, p = 0.004, R2 = 0.17, age being inversely proportional to acceptance rates and understanding and university level being related to higher acceptance rates and understanding compared to other education levels). Mixed perceptions were observed on the requirement of written informed consent (55.6% in favor); therefore, it seems recommendable to continue requesting it for the upcoming years until more perceptions are collected. The majority of participants (95.8%) preferred storing pharmacogenetic results in medical records rather than in electronic sources (55.6%) and highly agreed with the possibility of carrying their results on a portable card (91.5%). Patients agreed to broad genetic testing, including biomarkers unrelated to their disease (93.7%) or with little clinically relevant evidence (94.4%). Patients apparently rely on clinician’s or pharmacogeneticist’s interpretation and seem, therefore, open to the generation of ethically challenging information. Finally, although most patients (68.3%) agreed with universal population testing, some were reluctant, probably due to the related costs and sustainability of the Spanish Health System. This was especially evident in the group of patients who were older and with a likely higher proportion of pensioners.
Iñaki Lete, Esther de la Viuda, Ezequiel Pérez-Campos, María Ángeles Gómez Martínez, Rainel Sanchez-de la Rosa, Jesús Novalbos, and Rafael Sánchez-Borrego
Informa UK Limited
Abstract Objectives: This observational, multicentre, prospective phase IV study examined change in health-related quality of life (QOL) from baseline to 6 months in women initiating combined oral contraception (COC) based on natural estrogen. Methods: Eligible women attending a baseline and 6-month gynaecology appointment belonged to one of three groups: group 1 used barrier contraception (condoms) and elected to continue this method; group 2 used condoms and elected to switch to COC based on natural estrogen; group 3 used COC based on ethinylestradiol and elected to switch to COC based on natural estrogen. The Spanish Society of Contraception (SEC)-QOL scale assessed health-related QOL. Secondary outcomes included symptoms of premenstrual syndrome, intermenstrual bleeding, duration and intensity of menstrual bleeding, contraception continuation rate, and tolerability. Results: A total of 857 women were enrolled and 785 completed the study. Group 2 (n = 224 completed) had significantly lower SEC-QOL global and dimension scores at baseline and significantly greater increases in SEC-QOL from baseline to 6 months compared with groups 1 (n = 72) and 3 (n = 489). Group 3 reported a similar SEC-QOL score to that of group 1 at baseline but showed significantly greater improvement in SEC-QOL global and psychological scores from baseline to 6 months. Among women receiving COC based on natural estrogen, the contraception continuation rate was 713/780 (91.4%); treatment-related adverse events were reported by 13/780 (1.7%). Conclusions: Improved SEC-QOL after 6 months was found in women who were dissatisfied with their current contraception at baseline and chose to switch to COC based on natural estrogen.
Teresa Cabaleiro, Rosario López-Rodríguez, Manuel Román, Dolores Ochoa, Jesús Novalbos, Alberto Borobia, Antonio Carcas, and Francisco Abad-Santos
Ovid Technologies (Wolters Kluwer Health)
Quetiapine is an atypical antipsychotic used for treatment of schizophrenia. Variability in response to this drug may be associated with pharmacogenetics. The aim of this study was to identify genetic markers related to the pharmacokinetics, pharmacodynamics, and adverse effects of quetiapine. The study population comprised 79 healthy volunteers from two bioequivalence trials who were genotyped to identify polymorphisms in genes encoding enzymes, receptors, and transporters. Quetiapine plasma levels were quantified using high-performance liquid chromatography/mass spectrometry. Prolactin plasma levels were detected by indirect chemiluminescence. Possible adverse effects were recorded throughout the study. Factors with P value of 0.1 or less in the univariate analysis were included in a multiple regression analysis (logistic regression for adverse reactions). The area under the curve and clearance of quetiapine were affected by polymorphisms in CYP1A2 and DRD3, respectively. Men had a lower quetiapine area under the curve compared with women. Prolactin iCmax was higher in volunteers harboring polymorphisms in CYP2C19 and AGT. An association was detected between polymorphisms in CYP1A1 and CYP2C9 and somnolence. Several polymorphisms are responsible for differences in the pharmacokinetics, pharmacodynamics, and safety of quetiapine in healthy individuals.
Teresa Cabaleiro, Dolores Ochoa, Manuel Román, Isabel Moreno, Rosario López-Rodríguez, Jesús Novalbos, and Francisco Abad-Santos
Wiley
Within‐subject coefficient of variation (CVw) plays a decisive role in the determination of sample size in bioequivalence clinical trials. Highly variable drugs may require the participation of a large number of subjects. The aim of this study was to investigate whether gender and polymorphisms in CYP2D6 affect the CVw of risperidone. Two single‐dose, two‐period crossover studies of risperidone (n = 70) were reanalysed to calculate CVw for AUCt and Cmax. Subjects were classified into four different CYP2D6 phenotype groups [poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM)]. The effect of gender was evaluated in EM and IM. CVw was lower in PM (13.3% for AUCt and 10.9% for Cmax) and UM (17.4% and 8.7%) than in EM (28.7% and 34.7%) and IM (33.2% and 27.3%). Variability was slightly lower in women (27.9% for AUCt and 25.7% for Cmax) than in men (33.3% and 37.2%, respectively). Genetic polymorphisms affect within‐subject variability more than gender and could considerably affect sample size calculation. Therefore, subjects participating in bioequivalence trials should be genotyped.
Teresa Cabaleiro, Dolores Ochoa, Rosario López-Rodríguez, Manuel Román, Jesús Novalbos, Carmen Ayuso, and Francisco Abad-Santos
Wiley
To identify genetic markers capable of predicting the pharmacokinetics, pharmacodynamics, and adverse effects of risperidone.
Elba Alonso, María F. Cano-Abad, Ana J. Moreno-Ortega, Jesús Novalbos, Juan Milla, Antonio G. García, and Ana Ruiz-Nuño
Elsevier BV
Teresa Cabaleiro, Rosario López-Rodríguez, Dolores Ochoa, Manuel Román, Jesús Novalbos, and Francisco Abad-Santos
Wiley
The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug‐metabolizing enzymes, transporters, or receptors. The aim of this study was to identify genetic markers predictive of pharmacokinetics, pharmacodynamics, and adverse effects of olanzapine.
Rosario López-Rodríguez, Teresa Cabaleiro, Dolores Ochoa, Manuel Román, Alberto M Borobia, Antonio J Carcas, Carmen Ayuso, Jesús Novalbos, and Francisco Abad-Santos
Future Medicine Ltd
Aim: Clinical trials with healthy volunteers are a useful model for evaluating safety and tolerability, without the interference of concomitant diseases and drugs. The present study aims to improve our understanding of antipsychotic-related adverse reactions (ARs) and their possible association with common genetic variants of pharmacodynamic proteins such as neurotransmitter receptors/transporters. Materials & methods: A total of eight polymorphisms located in seven pharmacodynamic-related genes (SCL6A4, MDR1, 5HT2A, DRD2, DRD3, COMT and GRIN2B) were genotyped in a cohort of 211 healthy volunteers who received a single dose of risperidone (1 mg), olanzapine (5 mg) or quetiapine (25 mg). Results: Interestingly, a significant association was found between the incidence of neurological ARs and specific polymorphisms in key genes (DRD2 and SCL6A4). Conclusion: Genetic variants in pharmacodynamic genes could represent valuable markers of AR risk and antipsychotic safety. Original submitted 7 February 2013; Revision submitted 3 June 2013
Teresa Cabaleiro, Manuel Román, Dolores Ochoa, María Talegón, Rocío Prieto-Pérez, Aneta Wojnicz, Rosario López-Rodríguez, Jesús Novalbos, and Francisco Abad-Santos
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan Cmax than men (590.5 ± 75.8 ng/ml versus 282.1 ± 30.8 ng/ml; P ≤ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (P ≤ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg; P ≤ 0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg; P ≤ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.
Manuel Román, Teresa Cabaleiro, Dolores Ochoa, Jesús Novalbos, María Chaparro, Javier P. Gisbert, and Francisco Abad-Santos
Elsevier BV
Rosario López-Rodríguez, Manuel Román, Jesús Novalbos, Maria Laura Pelegrina, Dolores Ochoa, and Francisco Abad-Santos
Ovid Technologies (Wolters Kluwer Health)
Hyperprolactinemia mediated by antagonism of dopaminergic neurotransmission in the pituitary gland is a common adverse effect of antipsychotics. Recent studies have suggested that polymorphisms of dopamine receptors can affect the therapeutic response to antipsychotics. Thus, our aim was to evaluate whether 2 such polymorphisms (DRD2 Taq1A and DRD3 Ser9Gly) modulate prolactin release in healthy volunteers (n = 119) receiving a single dose of quetiapine (25 mg, n = 26), olanzapine (5 mg, n = 57), or risperidone (1 mg, n = 36). The increases in maximum concentration and in area under the curve were calculated from plasma prolactin levels after subtraction of pretreatment levels. Multiple regression analyses revealed that prolactin increases in maximum concentration and in area under the curve depended on drug (quetiapine < olanzapine < risperidone; P < 0.001), sex (women > men; P < 0.001), and Taq1A polymorphism (A1+ > A2/A2; P < 0.05). Analysis of the individual drugs revealed that prolactin secretion was modulated by sex and Taq1A polymorphism in olanzapine and risperidone (P < 0.05); however, these factors were not linked to prolactin secretion in quetiapine.
A. Lamana, A. Ortiz, J. Álvaro-Gracia, Belén Díaz-Sánchez, J. Novalbos, R. García-Vicuña and I. González-Álvaro
As interleukin-15 (IL-15) has been implicated in the pathophysiology of rheumatoid arthritis, we analysed the serum IL-15 (sIL-15) levels in healthy subjects and patients with early arthritis to establish a cut-off point that might serve to define elevated sIL-15. This is an initial step to determine whether sIL-15 has the potential for use as a biomarker for patients with early arthritis. The IL-15 concentration was measured in serum obtained from 161 healthy controls and from 174 patients with early arthritis, and the relationship between the expression of the two IL-15 mRNA variants and the sIL-15 levels was also assessed. In healthy controls, the median sIL-15 value was 0.83 [interquartile range (IQR) 0-8.68] pg/mL; there was no significant difference in the sIL-15 values according to gender [median level in males was 1.99 (IQR: 0-8.68) pg/mL and in females 0.50 (0-8.25) pg/mL: p = 0.821]. Moreover, sIL-15 levels did not correlate with age (r = 0.033, p = 0.685), and they did not display a clear circadian rhythm in healthy donors, with the median values for IL-15 close to zero at each time tested. In the light of these findings, we considered that sIL-15 was elevated if its concentration was above 20 pg/mL, since this cut-off point corresponded to the 90th percentile for this healthy population. We found that 30% of the patients with early arthritis had sIL-15 values > 20 pg/mL. The levels of sIL-15 did not correlate with disease duration in early arthritis patients, nor did they fluctuate with changes in disease activity over the follow-up period. In addition, the high level of sIL15 in patients was not associated with alterations in the alternative splicing of the IL-15 mRNA, favouring the variant that produces the protein with a long signal peptide for secretion. Serum IL-15 levels were increased in a subpopulation of patients with early arthritis, indicating that this measure may serve as a biomarker for this condition. Further studies will be necessary to determine whether the clinical evolution or response to treatment of patients with high sIL-15 levels differs.
Jesús Novalbos, Rosario López-Rodríguez, Manuel Román, Sonia Gallego-Sandín, Dolores Ochoa, and Francisco Abad-Santos
Ovid Technologies (Wolters Kluwer Health)
The objective of this study was to analyze the relationship between CYP2D6 genotype and pharmacokinetics and pharmacodynamics of risperidone. Seventy-one healthy volunteers (36 women and 35 men) received a 1-mg single oral dose of risperidone. Six major CYP2D6 polymorphisms (CYP2D6*3, *4, *5, *6, *7, and *9) and the duplication were detected. Subjects were classified into 4 phenotypic groups: 6 ultrarapid (UMs), 34 extensive (EMs), 25 intermediate (IMs), and 6 poor metabolizers (PMs). There was a clear relationship between the number of active alleles and the pharmacokinetic parameters for risperidone and 9-hydroxyrisperidone, but there were no differences for total active moiety. Area under the curve and half-life of risperidone were significantly higher in PMs and IMs compared with EMs and UMs, which showed higher area under the curve of 9-hydroxyrisperidone. Risperidone produced a small decrease in blood pressure, a mild increase in QTc and a quick increase in prolactin, without significant differences between groups. Surprisingly, the incidence of adverse reactions was lower in PMs (50%) than in other subjects (78%). In conclusion, metabolism of risperidone depends on the number of active CYP2D6 alleles. So, PM subjects show higher concentrations of risperidone and very low concentrations of 9-hydroxyrisperidone. On the contrary, EM and UM subjects show low concentrations of risperidone and high concentrations of 9-hydroxyrisperidone. However, no major pharmacodynamic differences are observed between CYP2D6 genotypes, presumably because of the similar pharmacological activity of parent drug and metabolite.
Alberto M. Borobia, Jesús Novalbos, Pedro Guerra-López, Rosario López-Rodríguez, Beatriz Tabares, Vanesa Rodríguez, Francisco Abad-Santos, and Antonio J. Carcas
Elsevier BV
A PEIRO, J NOVALBOS, P ZAPATER, R MOREU, R LOPEZRODRIGUEZ, V RODRIGUEZ, F ABADSANTOS, and J HORGA
Elsevier BV
R LOPEZRODRIGUEZ, J NOVALBOS, S GALLEGOSANDIN, M ROMANMARTINEZ, J TORRADO, J GISBERT, and F ABADSANTOS
Elsevier BV
J. Adan-Manes, J. Novalbos, R. Lopez-Rodriguez, J. L. Ayuso-Mateos, and F. Abad-Santos
Hindawi Limited
Serotonin syndrome, which occurs as a result of enhanced serotonin concentration in the central nervous system, is a well‐known adverse effect of serotonin‐active medications. The concomitant use of antidepressant drugs associated with lithium as a co‐adjuvant seems to increase the risk of this adverse reaction. We report a case of the serotonin syndrome during treatment with lithium and venlafaxine, an antidepressant with a dual selective re‐uptake inhibition mechanism, and review the literature for similar cases. A 71‐year‐old woman developed serotonin syndrome while receiving treatment with moderate doses of lithium and venlafaxine for refractory depression. She had been taking higher doses of venlafaxine during the previous months with no significant secondary effects. Use of the Naranjo adverse drug reaction probability algorithm indicated a probable relationship between serotonin syndrome and treatment with lithium and venlafaxine.
Publications
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