Risk Of Therapy Failure Research Articles

Bioavailability of Orally Administered Drugs in Critically Ill Patients

Critically ill patients managed in the Intensive Care Unit (ICU) suffer from several pathophysiological alterations due to critical illness resulting in potential changes in the pharmacokinetics of drugs including systemic absorption. Nevertheless, these patients are still given some medications in unadjusted doses thereby putting the patients at a risk for therapy failure. The objective for this study was to summarize the available evidence regarding oral drug absorption in the ICU. A literature search of the databases MEDLINE, EMBASE, and PubMed was conducted on (February 24, 2020). Articles discussing the rate and/or extent of orally administered drugs in critically ill patients were included. A total of 58 studies were found: 17 interventional studies, 33 observational studies (30 prospective, 3 retrospective) and 8 case reports. A total of 43 articles reported altered drug absorption in critically ill patients suggesting the need for alternative measures to facilitate treatment success. The absorption of orally administered drugs may be altered in critically ill patients. Measures for altered drug absorption in critically ill patients were suggested such as holding tube feeding before and after medication administration, increasing doses of orally administrated drugs and using alternate routes of administration.

The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study.

Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug‐metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1‐OH‐midazolam (OHM) and 1‐OH‐midazolam‐glucuronide (OHMG) after oral administration are largely unknown for the entire pediatric age span. We aimed to fill these knowledge gaps with a pediatric [14C]midazolam microtracer population pharmacokinetic study. Forty‐six stable, critically ill children (median age 9.8 (range 0.3–276.4) weeks) received a single oral [14C]midazolam microtracer (58 (40–67) Bq/kg) when they received a therapeutic continuous intravenous midazolam infusion and had an arterial line in place enabling blood sampling. For midazolam, in a one‐compartment model, bodyweight was a significant predictor for clearance (0.98 L/hour) and volume of distribution (8.7 L) (values for a typical individual of 5 kg). The typical oral bioavailability in the population was 66% (range 25–85%). The exposures of OHM and OHMG were highest for the youngest age groups and significantly decreased with postnatal age. The oral bioavailability of midazolam, largely reflective of intestinal and hepatic CYP3A activity, was on average lower than the reported 49–92% for preterm neonates, and higher than the reported 21% for children> 1 year of age and 30% for adults. As midazolam oral bioavailability varied widely, systemic exposure of other CYP3A–substrate drugs after oral dosing in this population may also be unpredictable, with risk of therapy failure or toxicity.

The Diabetes-Tuberculosis Co-Epidemic: The Interaction between Individual and Socio-Economic Risk Factors

Abstract Worldwide, tuberculosis (TB) is a major cause of morbi-mortality, about 30% of the population having a Mycobacterium tuberculosis infection. Patients with diabetes mellitus (DM) have a threefold increased risk of developing the disease. The prevalence of DM is rapidly increasing, especially in countries with low and middle income, where TB incidence is also increased, thus baffling the efforts for TB control. The DM-TB co-epidemic is more frequent in married, older men, with reduced level of education, low income, without a steady job, with lifestyle habits such as alcohol consumption, smoking, sedentarism, living in an urban environment, in crowded areas, in insanitary conditions. These patients have a higher body mass index (BMI) compared with those without DM and frequently present family history of TB, family history of DM, longer duration of DM and reduced glycemic control. TB associated with DM is usually asymptomatic, more contagious, multidrug resistant and is significantly associated with an increased risk of therapy failure, relapse and even death. Thus, the DM-TB comorbidity represents a threat to public health and requires the implementation of urgent measures in order to both prevent and manage the two diseases.

Abstract 3158: Prostate cancer derived biomarkers within platelets have the ability to predict therapeutic response in castration resistant patients

Abstract Background: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. In this article a novel platform for circulating biomarker analysis has been used to follow cancer-derived transcripts implicated in therapy resistance. Method: The platelet population of blood samples and QRT-PCR were used to identify selected biomarkers in CRPC patient's prior chemo- or androgen synthesis (AS)-directed therapies. The association between biomarker statuses (positive vs. negative) and therapy response, progression-free survival (PFS) and overall survival (OS) was examined. Results: 40 patients received either docetaxel (n = 17) or AS-directed (n = 23) therapy, with a therapy response rate of 29% respectively 48%. The cancer-associated biomarkers were present within the platelet fraction. Analyzing these biomarkers in the chemotherapy group were associated with a short OS (p = 0.025). In the AS-directed group, the biomarkers were associated with shorter PFS (p = 0.015), and with an increased risk of therapy failure (HR: 5,5; p = 0,023), as well as short OS (p = 0.012). Conclusions: Analyzing circulating biomarkers in the platelet population enables us to predict who will benefit from AS-directed therapy with high accuracy, and platelet based analysis of cancer derived biomarkers may be used in treatment stratification of patients scheduled for AS-directed therapies. Citation Format: Lee-Ann Tjon-Kon-Fat, Marie Lundholm, Thomas Wurdinger, Camilla Thellenberg-Karlsson, Anders Widmark, Pernilla Wikström, Jonas Nilsson. Prostate cancer derived biomarkers within platelets have the ability to predict therapeutic response in castration resistant patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3158.

Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease.

The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in patients with IBD during regular thiopurine therapy. Clinical effectiveness and tolerability of weight-based thiopurine therapy were determined in all patients with IBD displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 and 2012, as part of standard clinical follow-up after initiation of conventional thiopurine therapy. Forty-one (84%) of 49 included patients with IBD discontinued thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 weeks (range, 7-155). The majority of patients with a skewed metabolism discontinued thiopurines because of adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/8 × 10 RBC (range, 46-419), median 6-MMPR level was 11,020 pmol/8 × 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01). This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.

P344 Short and medium term efficacy of adalimumab in ulcerative colitis – a multicentre, prospective observational study

are particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in IBD patients. Methods: Clinical effectiveness and tolerability of regular weight-based thiopurine therapy were determined in all IBD patients displaying a skewed metabolism [ratio 6-MMPR/ 6-thioguaninenucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 2012, being part of standard clinical follow-up after initiation of conventional thiopurines. Results: Fourty-one (84%) out of 49 included IBD patients discontinued thiopurines (55% female, 53% with Crohn’s disease and 47% with ulcerative colitis) with a median duration of 14 weeks (IQR 10 29). The majority of patients discontinued thiopurines due to adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was thiopurine induced hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/10e8RBC (IQR 113 218 pmol/10e8RBC), median 6-MMPR level was 11020 pmol/10e8RBC (IQR 721

The magnitude of intentional non-adherence to antiretroviral therapy among patients attending HIV care and treatment clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania

Background: Suppression of viral replication is the goal of antiretroviral therapy. It is one of the most important factors influencing long-term prognosis of HIV infection. Non-adherence increases the risk of viral mutations which can result in crossresistance and thus the risk for therapy failure. Objectives: To determine the magnitude of intentional nonadherence to antiretroviral therapy among patients receiving antiretroviral therapy comprised of two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor at the HIV care and treatment clinic (CTC) of Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania. Method: A total of 250 patients were recruited between July 2007 and January 2008 at the HIV CTC of MNH. A structured questionnaire was used for interviewing the patients in order to assess intentional non-adherence through recall, as well as the presence of solicited antiretroviral drugs (ARVs) related side effects during the past 3, 7 and 30 days respectively, since ARV initiation. In addition, clinical (weight changes and incident opportunistic illnesses) as well as immunological (CD4 count) progress in the past 2 years was ascertained through review of patients’ clinical documents. Results: About half (45.6%) of the patients reported to have experienced the side effects associated with ARVs. Most patients (70.1%) experienced peripheral neuropathy. Other side effectsreported included; skin itching/rashes (19.6%), breast enlargement (10.3%), abdominal pain (7.5%), dizziness (5.6%), lipodystrophy (4.7%), vomiting (3.7%), poor vision (2.8%), nausea (1.9%), and headache (1.9%). A total of 18 (7.2 %) patients reported to have ever missed taking their medications. Four patients (1.6%) reported to have skipped their medication in the past 3 days; two (0.8%) in the past 7 days; and twelve (4.8%) in the past 30 days. Only 3 (1.2%) patients admitted to have intentionally skipped their doses due to the side effects they experienced while taking ARVs. The median CD4 count and mean body weight increased from 206 cells/μL and 62 kg to 311 cells/ μL and 65 kg, respectively, during a period of previous 24 months. Conclusion: ARV related side effects were common among patients attending the MNH CTC, but these did not result into significant intentional non-adherence. It is however recommended that a more comprehensive study involving a larger number of patients at different ART providing sites in the country be conducted so as to make a more comprehensive conclusion on this subject. Studies involving self-reported adherence and plasma ARVs concentration measurement area are also necessary in order to make a good correlation of adherence self-reporting and the actual amount of thedrug in the blood.Key words: Intentional non-adherence, ARVs, CD4, Weight change, HIV, Antiretroviral therapy

UDP-Glucuronosyltransferase (UGT) Polymorphisms Affect Atorvastatin Lactonization In Vitro and In Vivo

The response to statins shows large interpatient variability. Atorvastatin delta-lactone is pharmacologically inactive but has been associated with toxicity. We investigated the role of UDP-glucuronosyltransferases (UGTs) in atorvastatin lactonization. In human liver microsomes, lactonization was correlated with UGT1A3 (r(s) = 0.61, P < 0.0001) but not with UGT1A1. Surprisingly, lactone formation was significantly higher in carriers of UGT1A1*28, an allele that is associated with lower UGT1A1 expression. We show that this inverse correlation is due to extensive linkage disequilibrium in the UGT1A locus and that several UGT1A3 haplotypes are associated with strong increases in UGT1A3 expression in vitro. Analyses of the pharmacokinetic parameters of atorvastatin and metabolites in genotyped volunteers confirmed that there is an increase in atorvastatin lactonization in carriers of UGT1A3*2 in vivo. The potential of UGT genotyping to identify patients who are at increased risk for failure of therapy and/or adverse effects of statins warrants further investigation.

Clinical and cytogenetic features of a population‐based consecutive series of 285 pediatric T‐cell acute lymphoblastic leukemias: Rare T‐cell receptor gene rearrangements are associated with poor outcome

Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias (T-ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T-ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T-cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 x 10(9)/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5-year event-free survival (EFS) and overall survival for all patients were 0.61 (+/-0.03) and 0.67 (+/-0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of > or =200 x 10(9)/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T-ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results.

HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review

To assess the efficacy of ritonavir-boosted protease inhibitor monotherapy. Systematic review of all protease inhibitor-monotherapy studies published in peer-reviewed journals or presented at conferences to date. Data of randomized controlled trials were pooled to yield common odds ratios. Twenty-two protease inhibitor-monotherapy studies were identified. In the intent-to-treat analysis, 395 out of 582 (67.9%) patients had undetectable HIV-RNA at the end of follow-up. In the six randomized controlled trials (all lopinavir/ritonavir monotherapy), the risk of therapy failure was greater on monotherapy: 121 out of 364 (33.2%) patients on monotherapy against 64 out of 280 (22.9%) patients on HAART [pooled odds ratio 1.48 (95% confidence interval 1.02-2.13, P = 0.037)]. Regarding patients with successfully resuppressed HIV-RNA upon (re-)introducing nucleoside reverse transcriptase inhibitors (NRTIs) as nonfailures, the risk of therapy failure was comparable: 98 out of 364 (26.9%) against 64 out of 280 (22.9%) patients [odds ratio 1.05 (95% confidence interval 0.72-1.53, P = 0.81)]. The overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to HAART. The efficacy improves in patients started on monotherapy after suppressed HIV-RNA for at least 6 months. Ten percent of patients have viral rebound with HIV-RNA levels between 50 and 500 copies/ml. Possible explanations are lack of HIV suppression in particular cells or compartments, alternative resistance mechanisms, and nonadherence. Once proven that reintroduction of NRTIs, in patients with loss of viral suppression, is safe and effective, a broader use of simplification of HAART to protease inhibitor monotherapy might be justified. This review supports that the majority of patients with prolonged viral suppression on HAART can successfully be treated with protease inhibitor monotherapy. Arguments for this strategy are NRTI/NNRTI side effects, NRTI/NNRTI resistance, and costs.

Spread of Klebsiella pneumoniae producing SHV-5 beta-lactamase among hospitalized patients.

The first outbreak of infections caused by an SHV-5 producing strain of Klebsiella pneumoniae is reported. Within a period of 1 year and 9 months, multiresistant K. pneumoniae strains caused severe infections, mostly of the lower respiratory tract, in 22 patients. The strains were resistant to penicillins, third-generation cephalosporins, aztreonam, chloramphenicol, tetracycline and co-trimoxazole. The resistance determinants were transferable to Escherichia coli. All isolates produced a beta-lactamase with a pI of 8.2. Ceftazidime was hydrolyzed at this band. These characteristics, together with the resistance phenotype, are identical to those of a reference strain producing the beta-lactamase SHV-5. The K. pneumoniae strains of all patients were identical in their capsular serotype (K1), plasmid pattern and plasmid fingerprint after digestion with Dra I restriction endonuclease. We conclude that this outbreak was caused by the spread of one clone of K. pneumoniae producing SHV-5 beta-lactamase among patients of different wards. Our results indicate a real risk for failure of therapy by third-generation cephalosporins in intensive care patients due to SHV-5 producing pathogens.