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Background:Baricitinib (BARI) and tofacitinib (TOFA) are Janus kinase inhibitors (JAKi) approved for treating rheumatoid arthritis (RA). Phase II clinical trials have shown a significant dose-response relationship for JAKi. However, there’s a lack of studies analyzing the correlation between blood drug levels and clinical response in RA [1].Objectives:To evaluate the precision of drug plasma levels in discerning the clinical disease status of RA patients receiving BARI and TOFA.Methods:Multicenter, non-interventional prospective study involving RA patients receiving BARI or TOFA, according to clinical judgment. Patients were enrolled during their first follow-up visit after initiating JAKi treatment (at 12-16 weeks). The primary endpoints was to determine the accuracy of drug plasma levels in discerning clinical disease status based on the Clinical Disease Activity Index (CDAI). BARI and TOFA levels were determined simultaneously by liquid chromatography tandem mass spectrometry (LC-MS/MS)[2]. C max (after 45min of drug administration) and C min (just before drug intake) was analysed in each patient.Results:Fourty-nine patients (84% female, 86% seropositive (RF and/or ACPA), mean age 54 ± 12.9 years and mean RA duration 10±8.4 years) were included: 44 received BARI and 5 TOFA. The mean number of previously administered biological DMARDs was 1.1±1.5. Three patients had received previous treatment with another JAKi. The mean DAS28 and CDAI at JAKi initiation were 4.63±1.25 and 21.6±9.0, respectively. At the 12–16-week visit, 37 patients (75.5%) achieved remission or low disease activity according to CDAI, with a mean DAS28 and CDAI of 2.62±1.25 and 8.0±7.2, respectively (Table 1). Table 2 summarizes the mean drug plasma levels according to CDAI score. Drug plasma levels (both Cmax and Cmin) showed similar results in patients with different disease activity statuts according to CDAI, without significant differences. However, the two patients treated with BARI and high disease activity showed the lower drug levels, although the difference was not significant.Conclusion:In this preliminary study, no clear dose-response relationship was found between plasma JAKi levels and disease activity in RA. However further studies including patients with moderate/high disease activity are needed to assess the potential usefulness of evaluating plasma drug levels as indicator of the clinical status of RA patients undergoing treatment with BARI and TOFA.REFERENCES:[1] Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum 2012;64:970-81.[2] Koller D, Vaitsekhovich V, Mba C, Steegmann JL, Zubiaur P, Abad-Santos F, et al. Effective quantification of 11 tyrosine kinase inhibitors and caffeine in human plasma by validated LC-MS/MS method with potent phospholipids clean-up procedure. Application to therapeutic drug monitoring. Talanta 2020;208:120450.Acknowledgements:NIL.Disclosure of Interests:Beatriz Frade-Sosa received support for attending meetings and/or speaker honoraria from Pfizer, AbbVie, Lilly, BMS, Galápagos, Sandoz and GSK., Chafik Alejandro Chacur: None declared, Jose Inciarte-Mundo Current employee at Astrazeneca., Cristina Valero: None declared, Marta Novella-Navarro: None declared, Helena Borrell Paños: None declared, Águeda Prior-Español: None declared, Eduard Graell: None declared, Pablo Zubiaur: None declared, Gonzalo Villapalos: None declared, Nuria Sapena: None declared, Lola Tobalina: None declared, Antonio Gómez-Centeno: None declared, Lourdes Mateo: None declared, Alejandro Balsa: None declared, Sara Marsal Barril: None declared, Rosario Garcia-Vicuña: None declared, Raimon Sanmarti: None declared.

Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Despite being more effective than monotherapies, they produce frequent adverse drug reactions (ADRs). Institutions such as Food and Drug Administration and European Medicines Agency recommend precaution with CYP2D6 poor metabolizers (PMs) that receive CYP3A4 inhibitors and tamsulosin. However, no specific pharmacogenetic guideline exists for tamsulosin. Furthermore, to date, no pharmacogenetic information is available for dutasteride. Henceforth, we studied the pharmacokinetics and safety of dutasteride/tamsulosin 0.5 mg/0.4 mg capsules according to 76 polymorphisms in 17 candidate pharmacogenes. The study population comprised 79 healthy male volunteers enrolled in three bioequivalence, phase-I, crossover, open, randomized clinical trials with different study designs: the first was single dose in fed state, the second was a single dose in fasting state, and the third was a multiple dose. As key findings, CYP2D6 PMs (i.e., *4/*4 and *4/*5 subjects) and intermediate metabolizers (IMs) (i.e., *1/*4, *1/*5, *4/*15 individuals) presented higher AUC ( p = 0.004), higher t 1/2 ( p = 0.008), and lower Cl/F ( p = 0.006) when compared with NMs (*1/*1 individuals) and UMs (1/*1 × 2 individuals) after multiple testing correction. Moreover, fed volunteers showed significantly higher t max than fasting individuals. Nominally significant associations were observed between dutasteride exposure and CYP3A4 and CYP3A5 genotype and between tamsulosin and ABCG2 , CYP3A5 , and SLC22A1 genotypes. No association between the occurrence of adverse drug reactions and genotype was observed. Nonetheless, higher incidence of adverse events was found in a multiple-dose clinical trial. Based on our results, we suggest that dose adjustments for PMs and UMs could be considered to ensure drug safety and effectiveness, respectively. Further studies are warranted to confirm other pharmacogenetic associations.

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

The characteristics of the host are crucial in the final outcome of COVID-19. Herein, the influence of genetic and clinical variants in COVID-19 severity was investigated in a total of 1350 patients. Twenty-one single nucleotide polymorphisms of genes involved in SARS-CoV-2 sensing as Toll-like-Receptor 7, antiviral immunity as the type I interferon signalling pathway ( TYK2, STAT1, STAT4, OAS1, SOCS ) and the vasoactive intestinal peptide and its receptors ( VIP/VIPR1,2 ) were studied. To analyse the association between polymorphisms and severity, a model adjusted by age, sex and different comorbidities was generated by ordinal logistic regression. The genotypes rs8108236-AA (OR 0.12 [95% CI 0.02–0.53]; p  = 0.007) and rs280519-AG (OR 0.74 [95% CI 0.56–0.99]; p  = 0.03) in TYK2 , and rs688136-CC (OR 0.7 [95% CI 0.5–0.99]; p  = 0.046) in VIP, were associated with lower severity; in contrast, rs3853839-GG in TLR7 (OR 1.44 [95% CI 1.07–1.94]; p  = 0.016), rs280500-AG (OR 1.33 [95% CI 0.97–1.82]; p  = 0.078) in TYK2 and rs1131454-AA in OAS1 (OR 1.29 [95% CI 0.95–1.75]; p  = 0.110) were associated with higher severity. Therefore, these variants could influence the risk of severe COVID-19.