Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):104-118. doi: 10.7417/CT.2023.2477.

ABSTRACT

BACKGROUND: Human breast carcinoma is a complex disease, affecting 1 in 8 women worldwide. The seriousness of the disease increases when the definite cause of the disease remains obscure, thus making prognosis challenging. Researchers are emphasizing on adapting more advanced and targeted therapeutic approaches to address the multifaceted impacts of the disease. Hence, modern multi-omics systems have gained popularity among clinicians, as they offer insights into the genomic, pharmacogenomic, metabolomic, and microbiomic factors, thus allowing researchers to develop targeted and personalized approaches for breast cancer prevention and early detection, and eventually improving patient outcomes.

AIM: The primary focus of this study is to elucidate, through the integration of multi-omics research findings, the inherent molecular origins of diverse subtypes of breast cancer and to evaluate the effectiveness of these findings in reducing breast cancer-related mortalities.

METHODS: Thorough investigation was conducted by reviewing reputable and authoritative medical journals, e-books, and online databases dedicated to cancer research. The Mendelian inheritance in man database (OMIM) was used to scrutinize specific genes and their respective loci associated with the development of different types of breast cancer.

RESULTS: Our present research revealed the holistic picture of sundry molecular, genomic, pharmacogenomic, metabolomic, and microbiomic features of breast cancer. Such findings, like genetic alterations in highly penetrant genes, plus metabolomic and microbiomic signatures of breast cancer, unveil valuable insights and show great potential for multi-omics research in breast oncology.

CONCLUSION: Further research in omics sciences pertaining to breast cancer are at the forefront of shaping precise treatment and bolstering patient survival.

PMID:37994754 | DOI:10.7417/CT.2023.2477

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):68-76. doi: 10.7417/CT.2023.2473.

ABSTRACT

BACKGROUND: Sarcomas are a relatively rare but diverse group of cancers that typically develop in the mesenchymal cells of bones and soft tissues. Occurring in more than 70 subtypes, sarcomas have broad histological presentations, posing significant challenges of prognosis and treatment. Modern multi-omics studies, which include genomics, proteomics, metabolomics, and micro-biomics, are vital to understand the underlying mechanisms of sarcoma development and progression, identify molecular biomarkers for early detection, develop personalized treatment plans, and discover drug resistance mechanisms in sarcomas to upsurge the survival rate.

AIM: This study aims to highlight the genetic risk factors responsible for sarcoma-genesis, and to present a comprehensive review of multi-omics studies about sarcoma.

METHODS: Extensive literature research was undertaken using reliable and authentic medical journals, e-books, and online cancer research databases. Mendelian inheritance in man database (OMIM) was explored to study particular genes and their loci that are responsible to cause various sarcomas.

RESULT: This in-depth research led to the finding out that omics studies provide a more comprehensive understanding of underlying molecular mechanisms of sarcomas. Through genomics, we can reveal genetic alterations that predispose to sarcoma, like mutation in TP53, NF1, and so on. Pharmacogenomics enable us to find molecular targets for specific drugs. Whereas, proteomic and metabolomic studies provide insights into the biological pathways involved in sarcoma development and progression.

CONCLUSION: Future advancements in omics sciences for sarcoma are on the cutting-edge of defining precision treatment plans and improved resilience of sarcoma patients.

PMID:37994750 | DOI:10.7417/CT.2023.2473

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):55-67. doi: 10.7417/CT.2023.2472.

ABSTRACT

Colon cancer presents a complex pathophysiological landscape, which poses a significant challenge to the precise prediction of patient prognosis and treatment response. However, the emergence of omics sciences such as genomics, transcriptomics, proteomics, and metabolomics has provided powerful tools to identify molecular alterations and pathways involved in colon cancer development and progression. To address the lack of literature exploring the intersection of omics sciences, precision medicine, and colon cancer, we conducted a comprehensive search in ScienceDirect and PubMed databases. We included systematic reviews, reviews, case studies, clinical studies, and randomized controlled trials that were published between 2015-2023. To refine our search, we excluded abstracts and non-English studies. This review provides a comprehensive summary of the current understanding of the latest developments in precision medicine and omics sciences in the context of colon cancer. Studies have identified molecular subtypes of colon cancer based on genomic and transcrip-tomic profiles, which have implications for prognosis and treatment selection. Furthermore, precision medicine (which involves tailoring treatments, based on the unique molecular characteristics of each patient's tumor) has shown promise in improving outcomes for colon cancer patients. Omics sciences and precision medicine hold great promise for identifying new therapeutic targets and developing more effective treatments for colon cancer. Although not strictly designed as a systematic review, this review provides a readily accessible and up-to-date summary of the latest developments in the field, highlighting the challenges and opportunities for future research.

PMID:37994749 | DOI:10.7417/CT.2023.2472

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):37-45. doi: 10.7417/CT.2023.2470.

ABSTRACT

Lung cancer is a complex disease, with a wide range of genetic alterations and clinical presentations. Understanding the natural and clinical history of the disease is crucial for developing effective diagnostic and treatment strategies. Omics approaches, such as genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools for understanding the molecular mechanisms underlying lung cancer and for identifying novel biomarkers and therapeutic targets. These approaches enable researchers to examine the entire genome, transcriptome, proteome, or metabolome of a cell or tissue, providing a comprehensive view of the biological processes involved in lung cancer development and progression. Targeted therapies that address specific genetic mutations and pathways hold promise for improving the diagnosis and treatment of this disease.

PMID:37994747 | DOI:10.7417/CT.2023.2470

J Infect. 2023 Nov 20:S0163-4453(23)00562-5. doi: 10.1016/j.jinf.2023.11.008. Online ahead of print.

NO ABSTRACT

PMID:37992877 | DOI:10.1016/j.jinf.2023.11.008

Xenobiotica. 2023 Nov 22:1-35. doi: 10.1080/00498254.2023.2287168. Online ahead of print.

ABSTRACT

1. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of MPA, and optimize the dosage for adult kidney transplant recipients.2. One-hundred and four adult renal transplant patients were enrolled. The PPK model was established using the Phoenix® NMLE software and the stepwise methods were filtered for significant covariates. Monte Carlo simulations were performed to optimize the dosage regimen.3. A two-compartment model with first-order absorption and elimination (including lag time) provided a more accurate description of MPA pharmacokinetics. Serum albumin (ALB) significantly affected the central apparent clearance (CL/F), whereas post-transplant time and creatinine clearance were associated with a central apparent volume of distribution (V/F). The estimated population values obtained by the final model were 17.5 L/h and 93.97 L for CL/F and V/F, respectively. Simulation results revealed that larger mycophenolate mofetil doses are required as the ALB concentration decreases. This study established a PPK model of MPA and validated it using various methods. ALB significantly affected CL/F and recommended optimal dose strategies were given based on the final model. These results provide a reference for the personalized therapy of MPA for kidney transplant patients.

PMID:37991412 | DOI:10.1080/00498254.2023.2287168

J Chin Med Assoc. 2023 Nov 22. doi: 10.1097/JCMA.0000000000001026. Online ahead of print.

ABSTRACT

BACKGROUND: Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a common cancer treatment. However, the pharmacologic characteristics of VEGF-TKIs may influence cardiovascular risks. The relative risks of major adverse cardiovascular events (MACEs) associated with VEGF-TKIs are poorly understood.

METHODS: We searched PubMed, Embase, and ClinicalTrials.gov from inception until August 31, 2021, for phase II/III randomized controlled trials of 11 VEGF-TKIs (axitinib, cabozantinib, lenvatinib, pazopanib, ponatinib, ripretinib, regorafenib, sorafenib, sunitinib, tivozanib, and vandetanib). The endpoints were heart failure, thromboembolism, and cardiovascular death. The Mantel-Haenszel method was used to calculate the risk of VEGF-TKI among users by comparing to nonusers. Pairwise meta-analyses with a random-effects model was used to estimate the risks of the various VEGF-TKIs. We estimated ranked probability with a P-score and assessed credibility by employing the Confidence in Network Meta-Analysis framework.

RESULTS: We identified 69 trials involving 30 180 patients with cancer. The highest risk of MACEs was associated with high-potency tivazonib (odds ratio [OR] 3.34), lenvatinib (OR 3.26), and axitinib (OR: 2.04), followed by low-potency pazopanib (OR: 1.79), sorafenib (OR: 1.77), and sunitinib (OR: 1.66). The risk of heart failure significantly increased in association with less selective sorafenib (OR: 3.53), pazopanib (OR: 3.10), and sunitinib (OR: 2.65). The risk of thromboembolism significantly increased in association with nonselective lenvatinib (OR: 3.12), sorafenib (OR: 1.54), and sunitinib (OR: 1.53). Higher potency (tivozanib, axitinib) and lower selectivity (sorafenib, vandetanib, pazopanib, sunitinib) were associated with a higher probability of heart failure. Low selectivity (lenvatinib, cabozantinib, sorafenib, sunitinib) was associated with a higher probability of thromboembolism.

CONCLUSION: Higher-potency and lower-selectivity VEGF-TKIs may influence the risks of MACEs, heart failure, and thromboembolism. These findings may facilitate evidence-based decision-making in clinical practice.

PMID:37991373 | DOI:10.1097/JCMA.0000000000001026

Clin Transl Sci. 2023 Nov 22. doi: 10.1111/cts.13672. Online ahead of print.

ABSTRACT

Clinical implementation of pharmacogenomic (PGx)-guided prescribing in oncology lags behind research evidence generation. We aimed to identify healthcare professionals' (HCPs) and consumers' knowledge, attitudes, perspectives, and education needs to inform strategies for implementation of scalable and sustainable oncology PGx programs. Systematic review of original articles indexed in EMBASE, EMCARE, MEDLINE, and PsycInfo from January 2012 until June 2022, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and using the Mixed Methods Appraisal Tool. PROSPERO registration number CRD42022352348. Of 1442 identified studies; 23 met inclusion criteria with 87% assessed high quality. Of these, 52% reported on HCPs, 35% on consumers, and 13% on both HCPs and consumers. Most were conducted in the United States (70%) and included multiple cancer types (74%). Across studies, HCPs and consumers mostly perceived value in PGx, however, both groups reported barriers to utilization, including cost, lack of consistent recommendations across guidelines, and limited knowledge among HCPs; test accuracy, clear testing benefits, and genomic information confidentiality among consumers. HCPs and consumers value and want to engage in PGx strategies in oncology care, however, are inhibited by unmet needs and practice and knowledge gaps. Implementation strategies aimed at addressing these issues may best support increased PGx uptake in oncology practice.

PMID:37991131 | DOI:10.1111/cts.13672

Obes Pillars. 2023 Feb 21;5:100059. doi: 10.1016/j.obpill.2023.100059. eCollection 2023 Mar.

ABSTRACT

BACKGROUND: Once thought to be primarily a result of lifestyle, it is now known that obesity has significant genetic components. Dozens of genes have been linked to obesity, and office-based genetic testing for obesity-associated genes is now readily available. As both pharmacotherapy and genetic testing for obesity become more accessible, pharmacogenetic personalization is becoming a reality. In this case report, a patient with a PLXNA4 polymorphism had a superior weight loss response to phentermine/topiramate therapy than has previously been reported in the literature. Thus, variants in PLXNA4 may provide a genetic basis for this patient's superior response to weight loss pharmacotherapy and cardiovascular risk factor reduction.

METHODS: In this case study, office-based genetic testing was utilized to identify the presence of variants in nearly 80 genes that have been linked to obesity in a patient who had hyper-responsive weight loss results on phentermine/topiramate pharmacotherapy.

RESULTS: A variant of the PLXNA4 gene, which has known pathogenic variants linked to genetic obesity syndromes, was identified in this patient who had a superior weight loss response to phentermine/topiramate pharmacotherapy.

CONCLUSION: Due to overlapping molecular pathways, it is possible that PLXNA4 variants convey a superior weight-loss response and therefore superior cardiovascular risk factor reduction phentermine/topiramate therapy. Further studies are needed to examine the relationship between PLXNA4 variants and weight loss with phentermine/topiramate pharmacotherapy.

PMID:37990741 | PMC:PMC10662083 | DOI:10.1016/j.obpill.2023.100059

Psychophysiology. 2023 Nov 21:e14481. doi: 10.1111/psyp.14481. Online ahead of print.

ABSTRACT

Establishing quantifiable biological markers associated with anxiety will increase the objectivity of phenotyping and enhance genetic research of anxiety disorders. Heart rate variability (HRV) is a physiological measure reflecting the dynamic relationship between the sympathetic and parasympathetic nervous systems, and is a promising target for further investigation. This review summarizes evidence evaluating HRV as a potential physiological biomarker of anxiety disorders by highlighting literature related to anxiety and HRV combined with investigations of endophenotypes, neuroimaging, treatment response, and genetics. Deficient HRV shows promise as an endophenotype of pathological anxiety and may serve as a noninvasive index of prefrontal cortical control over the amygdala, and potentially aid with treatment outcome prediction. We propose that the genetics of HRV can be used to enhance the understanding of the genetics of pathological anxiety for etiological investigations and treatment prediction. Given the anxiety-HRV link, strategies are offered to advance genetic analytical approaches, including the use of polygenic methods, wearable devices, and pharmacogenetic study designs. Overall, HRV shows promising support as a physiological biomarker of pathological anxiety, potentially in a transdiagnostic manner, with the heart-brain entwinement providing a novel approach to advance anxiety treatment development.

PMID:37990619 | DOI:10.1111/psyp.14481

Anim Genet. 2023 Nov 22. doi: 10.1111/age.13376. Online ahead of print.

ABSTRACT

The recent advances in high-throughput next-generation sequencing technologies have heralded the arrival of the Big Data era. As a result, the use of pharmacogenetics in drug discovery and individualized drug therapy has transformed the field of precision medicine. This paradigm shift in drug development programs has effectively reshaped the old drug development practices, which were primarily concerned with the physiological status of patients for drug development. Pharmacogenomics bridges the gap between pharmacodynamics and pharmacokinetics, advancing current diagnostic and treatment strategies and enabling personalized and targeted drug therapy. The primary goals of pharmacogenetic studies are to improve drug efficacy and minimize toxicities, to identify novel drug targets, to estimate drug dosage for personalized medicine, and to incorporate it as a routine diagnostic for disease susceptibility. Although pharmacogenetics has numerous applications in individualized drug therapy and drug development, it is in its infancy in veterinary medicine. The objective of this review is to present an overview of historical landmarks, current developments in various animal species, challenges and future perspectives of genomics in drug development and dosage optimization for individualized medicine in veterinary subjects.

PMID:37990577 | DOI:10.1111/age.13376

Pharmacy (Basel). 2023 Nov 19;11(6):180. doi: 10.3390/pharmacy11060180.

ABSTRACT

The field of pharmacogenomics is at the forefront of a healthcare revolution, promising to usher in a new era of precision medicine [...].

PMID:37987390 | DOI:10.3390/pharmacy11060180

Pharmacy (Basel). 2023 Nov 17;11(6):178. doi: 10.3390/pharmacy11060178.

ABSTRACT

(1) Background: This retrospective analysis utilizing electronic medical record (EMR) data from a tertiary integrated health system sought to identify patients and prescribers who would benefit from pharmacogenomic (PGx) testing based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. (2) Methods: EMR data from a clinical research data warehouse were analyzed from 845,518 patients that had an encounter between 2015 and 2019 at an academic medical center. Data were collected for 42 commercially available drugs with 52 evidence-based PGx guidelines from CPIC. Provider data were obtained through the EMR linked by specialty via national provider identification (NPI) number. (3) Results: A total of 845,518 patients had an encounter in the extraction period with 590,526 medication orders processed. A total of 335,849 (56.9%) patients had medication orders represented by CPIC drugs prescribed by 2803 providers, representing 239 distinct medications. (4) Conclusions: The results from this study show that over half of patients were prescribed a CPIC actionable medication from a variety of prescriber specialties. Understanding the magnitude of patients that may benefit from PGx testing, will enable the development of preemptive testing processes, physician support strategies, and pharmacist workflows to optimize outcomes should a PGx service be implemented.

PMID:37987388 | DOI:10.3390/pharmacy11060178

Pharmacy (Basel). 2023 Oct 26;11(6):170. doi: 10.3390/pharmacy11060170.

ABSTRACT

This study assesses the readiness and willingness of community pharmacists in England to deliver the pharmacogenomic (PG) testing service. A survey covering demographics and four key themes including awareness and training, general views and experience, barriers, willingness, and confidence was distributed to community pharmacies in the boroughs of Croydon and Sutton in South London. A total of 51 pharmacists responded to the survey. The study revealed that most respondents had a limited familiarity or understanding of pharmacogenomics (n = 32, 63%). Moreover, on average, around 60% of participants were unable to accurately identify drugs that currently have or could have potentials for PG testing. They indicated that their pharmacogenomic education and training is inadequate, with only 2/51 pharmacists reported receiving relevant training. Time constraints, shortage of staff and lack of knowledge were identified as barriers that could hinder the implementation of PG. Over 60% of respondents expressed willingness to provide PG testing service after receiving adequate training. The study found that currently not all community pharmacists are prepared to provide PG testing services, with newly qualified pharmacists appearing to have an upper hand when it comes to understanding the subject. Therefore, consistent, and uniform training is required to allow community pharmacists with all years of experience to equally contribute to the implementation of PG testing.

PMID:37987380 | DOI:10.3390/pharmacy11060170

Hematol Rep. 2023 Nov 20;15(4):634-650. doi: 10.3390/hematolrep15040065.

ABSTRACT

Methotrexate (MTX), a structurally related substance to folic acid, is an important chemotherapeutic agent used for decades in the treatment of pediatric acute lymphoblastic leukemia (ALL) and other types of cancer as non-Hodgkin lymphomas and osteosarcomas. Despite the successful outcomes observed, the primary drawback is the variability in the pharmacokinetics and pharmacodynamics between patients. The main adverse events related to its use are nephrotoxicity, mucositis, and myelosuppression, especially when used in high doses. The potential adverse reactions and toxicities associated with MTX are a cause for concern and may lead to dose reduction or treatment interruption. Genetic variants in MTX transport genes have been linked to toxicity. Pharmacogenetic studies conducted in the past focused on single nucleotide polymorphisms (SNPs) in the coding and 5'-regulatory regions of genes. Recent studies have demonstrated a significant role of microRNAs (miRNAs) in the transport and metabolism of drugs and in the regulation of target genes. In the last few years, the number of annotated miRNAs has continually risen, in addition to the studies of miRNA polymorphisms and MTX toxicity. Therefore, the objective of the present study is to investigate the role of miRNA variants related to MTX adverse effects.

PMID:37987321 | DOI:10.3390/hematolrep15040065

J Gene Med. 2023 Nov 20:e3634. doi: 10.1002/jgm.3634. Online ahead of print.

ABSTRACT

BACKGROUND: Clopidogrel is an antiplatelet drug widely prescribed to prevent atherothrombotic events in coronary artery disease patients. However, there is evidence to suggest that the effectiveness of clopidogrel varies owing to genetic diversity in CYP2C19. This heterogeneity in South Asians, who are also known to have high risk of cardiac events than other population groups, highlights the importance of investigating CYP2C19 variants to estimate the risk proportion in the groups.

METHODS: Given the high prevalence and genetic heterogeneity, the population-based case control was conducted in a cohort of 1191 subjects comprising 645 acute coronary syndrome (ACS) cases (unstable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction) and 546 healthy controls of South Asian Indian origin. The metabolization status of CYP2C19 was assessed using *2, *3 and *17 variants in the stated cohorts to determine the prevalence of metabolization and its association with phenotypes.

RESULTS: The results suggest a possible genetic association between studied CYP2C19 polymorphisms and ACS, since there was a higher proportion of intermediate and poor metabolizers present in the studied cohorts. The association analyses revealed that the *2 allele of CYP2C19 confers a significant risk for ACS, while the *17 allele provides protection.

CONCLUSIONS: These findings contribute to the understanding of CYP2C19 genetic variants and their impact on clopidogrel response in South Asian Indians. Additionally, they underline the significance of assessing CYP2C19 variations in patients receiving clopidogrel therapy in order to improve therapeutic outcomes.

PMID:37985132 | DOI:10.1002/jgm.3634

Carbohydr Polym. 2024 Jan 15;324:121536. doi: 10.1016/j.carbpol.2023.121536. Epub 2023 Nov 4.

ABSTRACT

Scaffolds grafting combined with local delivery of antibiotics at the injury site may promote bone regeneration along with prevention of infections. In this work, a processing strategy combining the 3D-printing of polysaccharide-based inks with supercritical (sc)CO2 technology was employed to manufacture drug-loaded, nanostructured, and personalized-to-patient aerogels for the first time. Methylcellulose (MC) was employed as graft matrix endowed with nanohydroxyapatite (nHA) to confer bioactivity as required in bone tissue engineering (BTE). MC-nHA aerogels were obtained through the 3D-printing of hydrogel-based scaffolds followed by scCO2 drying. Aerogels were loaded with vancomycin (VAN), an antibiotic employed in the management of bone infections. Textural properties and printing fidelity of scaffolds were studied as well as VAN release, long-term bioactivity, and pre-osteoblasts mineralization. In vitro cell studies and in vivo Artemia salina tests were carried out to evaluate the potential toxicity of the antibiotic-loaded aerogels. Aerogels efficacy in inhibiting bacterial growth was assessed by antimicrobial tests with Staphylococcus aureus. Textural stability of the aerogels after 7 months of storage was also evaluated. Obtained results showed that the scaffolds promoted the intended two-in-one effect (bone repair and infection management simultaneously) in a personalized way, regulating formulation design, drug dose, and porosity.

PMID:37985110 | DOI:10.1016/j.carbpol.2023.121536

Clin Pharmacol Ther. 2023 Nov 20. doi: 10.1002/cpt.3094. Online ahead of print.

NO ABSTRACT

PMID:37984075 | DOI:10.1002/cpt.3094

Pharmacol Res Perspect. 2023 Dec;11(6):e01154. doi: 10.1002/prp2.1154.

ABSTRACT

UDP-glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that play important roles in the detoxification of endogenous and exogenous substrates. The 22 human UGTs belong to four families (UGT1, UGT2, UGT3, and UGT8) and differ in their expression, substrate specificity, UDP-sugar preference, and physiological functions. Differential expression/activity of the UGTs contributes to interperson variability in drug responses and toxicity, hormone homeostasis, and disease/cancer risks. However, in normal tissues, the tissue-specific expression profiles and transcriptional regulation of the UGTs are still not fully understood. In this study, we comprehensively analyzed the transcriptome of 22 UGTs in 54 human tissues/regions using RNAseq data from GTEx. We then validated the findings in the liver and small intestine samples using real-time PCR. Our results showed large interindividual variability across tissues in the expression of each UGT and the overall composition of UGT pools, consisting of different UGTs and their splice isoforms. Our results also revealed coexpression of the UGTs, Cytochrome P450s, and many transcription factors in the liver, suggesting potential coregulation or functional coordination. Our results provide the groundwork for future studies to detail further the regulation of the expression and activity of the UGTs.

PMID:37983911 | DOI:10.1002/prp2.1154

Clin Infect Dis. 2023 Nov 20:ciad700. doi: 10.1093/cid/ciad700. Online ahead of print.

ABSTRACT

BACKGROUND: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin.

METHODS: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg BID with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L.

RESULTS: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, while 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia.

CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.

PMID:37982585 | DOI:10.1093/cid/ciad700