British Journal of Clinical Pharmacology

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ISSN / EISSN : 0306-5251 / 1365-2125
Published by: Wiley (10.1111)
Total articles ≅ 13,110
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, , Rachel Copland, Giorgia De Paoli, Thomas M. MacDonald, , [email protected] Consortium
British Journal of Clinical Pharmacology; doi:10.1111/bcp.15003

Abstract:
Aims The aim of the study was to identify actionable learning points from stakeholders in remote decentralised clinical trials (RDCTs) to inform their future design and conduct. Methods Semi-structured interviews were carried out with a purposive sample of stakeholders, including senior managers, trial managers, technology experts, principal investigators, clinical investigators, research scientists, research nurses, vendors, patient representatives, and project assistants. The interview data were coded using a thematic approach, identifying similarities, differences, and clustering to generate descriptive themes. Further refinement of themes was guided by empirical phenomenology, grounding explanation in the meanings that interviewees gave to their experiences. Results 48 stakeholders were interviewed. Actionable learning points were generated from the thematic analysis. Patient involvement and participant engagement were seen as critical to the success of RDCTs where in-person contact is minimal or non-existent. Involving patients in identifying the research question, creating recruitment materials, apps and websites, and providing ongoing feedback to trial participants, were regarded as facilitating recruitment and engagement. Building strong relationships early with trial partners was thought to support RDCT conduct. Multiple modes of capturing information, including patient-reported outcomes (PROs) and routinely collected data, were felt to contribute to data completeness. However, RDCTs may transfer trial activity burden onto participants and remote-working research staff; therefore, additional support may be needed. Conclusion RDCTs will continue to face challenges in implementing novel technologies. However, maximising patient and partner involvement, reducing participant and staff burden, and simplifying how participants and staff interact with the RDCT may facilitate their implementation.
Helena Edlund, Francesco Bellanti, Huan Liu, , Helen Tomkinson, Joseph Ware, Shringi Sharma, Núria Buil‐Bruna
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14988

Abstract:
This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP-5862 samples from 304 subjects from 12 clinical studies in patients with B-cell malignancies and healthy subjects were analyzed by non-linear mixed-effects modelling. Acalabrutinib PK was characterized by a two-compartment model with first-order elimination. The large variability in absorption was adequately described by transit compartment chain and first-order absorption, with between-occasion variability on the mean transit time and relative bioavailability. The PK of ACP-5862 was characterized by a two-compartment model with first-order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and co-administration of proton pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.
, Deepti Gurdasani, Fu L. Ng, Sandra Soo‐Jin Lee
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14983

Abstract:
Pharmacogenomics is increasingly moving into mainstream clinical practice. Careful consideration must be paid to inclusion of diverse populations in research, translation, and implementation, in the historical and social context of population stratification, to ensure that this leads to improvements in healthcare for all rather than increased health disparities. This review takes a broad and critical approach to the current role of diversity in pharmacogenomics and addresses potential pitfalls in order to raise awareness for prescribers. It also emphasizes evidence gaps and suggests approaches which may minimize negative consequences and promote health equality.
Anne Kathrine Bengaard, Esben Iversen, Thomas Kallemose, Helle Gybel Juul‐Larsen, Line Jee Hartmann Rasmussen, Kim Peder Dalhoff, Ove Andersen, Jesper Eugen‐Olsen,
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14982

Abstract:
Aim To investigate whether the association between levels of medication use (including polypharmacy and potentially inappropriate medications [PIMs]) and health outcomes such as readmission and mortality is dependent on baseline suPAR. Methods This registry-based cohort study included medical patients admitted to the emergency department (ED) at Copenhagen University Hospital Hvidovre, Denmark. Patients were grouped according to their admission suPAR levels: low (0-3 ng/mL), intermediate (3-6 ng/mL), or high (>6 ng/mL). Hyper-polypharmacy was defined as ≥10 prescribed medications. PIMs were identified based on the European Union (EU)(7)-PIM list, and data on admissions and mortality were obtained from national registries. Risk of 90-day readmission and mortality was assessed by Cox regression analysis adjusted for sex, age and Charlson Comorbidity Index. Results were reported as hazard ratios (HRs) within 90 days of index discharge. Results In total, 26,291 patients (median age 57.3 years; 52.7% female) were included. Risk of 90-day readmission and mortality increased significantly for patients with higher suPAR or higher number of medications. Among patients with low suPAR, patients with ≥10 prescribed medications had a HR of 2.41 (95% CI = 2.09-2.78) for 90-day readmission and 8.46 (95% CI = 2.53-28.28) for 90-day mortality compared to patients with 0 medications. Patients with high suPAR generally had high risk of readmission and mortality, and the impact of medication use was less pronounced in this group. Similar, but weaker, association patterns were observed between suPAR and PIMs. Conclusion The association between levels of medication use and health outcomes is dependent on baseline suPAR.
Pannaphak Hirunsatitpron, Nutthiya Hanprasertpong, Kajohnsak Noppakun, Dumnoensun Pruksakorn, Supanimit Teekachunhatean,
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14979

Abstract:
Aim Mycophenolic acid (MPA) is an immunosuppressive drug commonly used for prophylaxis of graft rejection in solid organ transplant recipients. The main concern with the prolonged use of immunosuppressive drugs is the risk of developing cancer. However, it remains unclear whether the immunosuppressive regimens containing MPA confer an increased degree of cancer risk. The present study aimed to determine the association between MPA exposure and the incidence of cancer in solid organ transplant recipients. Methods A systematic search was performed on PubMed, EMBASE, and Cochrane Library. Relevant articles that have the findings on the incidence (or event) of cancer in cohorts with and without MPA exposure were retrieved for data extraction. A meta-analysis was conducted by means of the random-effects model, and the relative risk (RR) and its 95% confidence interval (95%CI) was used as a summary effect measure. Results A total of 39 studies were eligible for inclusion, with 32 studies that enabled meta-analysis. MPA exposure was significantly associated with a lower risk of cancer when compared to azathioprine exposure (RR = 0.66, 95%CI = 0.53-0.81, p <0.001) or no exposure to any additional treatments (RR = 0.85, 95%CI = 0.73-0.99, p = 0.04). No significant difference in cancer risk for the comparison between MPA exposure and mTOR inhibitor exposure (RR = 1.54, 95%CI = 0.96-2.46, p = 0.07). Conclusions MPA exposure was not associated with an increased risk of cancer and may even be associated with a lower risk of cancer when compared to azathioprine or no treatment.
, Edward J. Fuchs, Sarah Lee, Valeriu Damian, Paul Galette, Robert Janiczek, Katarzyna J. Macura, Michael A. Jacobs, Ethel D. Weld, Meiyappan Solaiyappan, et al.
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14977

Abstract:
Aim Cabotegravir long-acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection. Methods Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic-guided injection targeting the gluteal muscles. MRI was performed to determine injection-site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue, and combined IM/SC compartments and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3, and 8. Linear regression analysis examined correlations between MRI-derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (Cmax) and partial area under the concentration-time curve (AUC) through Weeks 4 and 8. Results Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n=2), combined IM/SC compartments (n=4), SC compartment (n=1), and retroperitoneal cavity (n=1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, Cmax, and partial AUC through Weeks 4 and 8. Conclusion MRI clearly delineated cabotegravir LA injection-site location and depot kinetics in healthy adults. Although injection-site variability was observed, drug depot surface area correlated with both plasma Cmax and partial AUC independently of anatomical distribution.
, R. M. V. de Melo, T. T. Viana, A. G. Q. de Jesus, T. C. da Silva, V. M. da Silva, W. N. de Carvalho, D. N. V. da Silva, L. C. S. Passos
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14978

Abstract:
Chagas cardiomyopathy is the most prevalent non-ischemic cardiomyopathy in Latin America, with high morbidity and mortality even today. Treatment of these patients is based on the use of medications for heart failure. This study evaluated a case series of patients with Chagas heart disease who used sacubitril/valsartan at a referral hospital for this disease in Brazil. After six months, there was a symptomatic improvement in these individuals assessed by the NYHA functional class, with a 44.3% reduction in the absolute number of patients classified as III-IV in the period (p 0.035), but without changes in the parameters on the echocardiogram for reverse ventricular remodeling. There was a high mortality rate and number of hospitalizations. These results emphasize the importance of studying the use of sacubitril/valsartan in Chagas heart disease to better describe its effectiveness considering the peculiarities of these individuals.
, Markovits Noa, Margalit Ofer, Halpern Naama, Boursi Ben, Shmueli Einat
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14974

Abstract:
Oxaliplatin is a common chemotherapy agent that is used in the treatment of multiple solid malignancies. Immune-mediated thrombocytopenia is a rare and potentially life-threatening adverse effect of oxaliplatin that is characterized by severe thrombocytopenia which may be accompanied by overt bleeding. This adverse effect is most likely mediated via anti-platelet antibodies that become reactive in the presence of oxaliplatin. Due to its rarity and severity, information is scarce regarding the effect of desensitization or attempts at rechallenge after prolonged withdrawal of oxaliplatin. This short report describes three cases of oxaliplatin immune-mediated thrombocytopenia, including a case occurring under desensitization protocol and a case of recurrence after a prolonged withdrawal. All three patients are female, have prolonged exposures to oxaliplatin and were all treated for metastatic colorectal cancer. Physicians should be aware of oxaliplatin immune-mediated thrombocytopenia as symptoms may appear rapidly. Oxaliplatin should be permanently discontinued for patients experiencing this adverse effect, as recurrence is highly likely even in the setting of desensitization.
Wei Yin, Fahimeh Mamashli, Derek L. Buhl, Polyna Khudyakov, Dmitri Volfson, Ferenc Martenyi, Hakop Gevorkyan, Laura Rosen,
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14975

Abstract:
AIMS TAK-071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071. METHODS TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, ECG, and EEG evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate its pharmacokinetics (PK), relative bioavailability and food effect. RESULTS TAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Co-administration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition. CONCLUSIONS PK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted.
, Guodong Kang, Ran Hu, Lei Zhang, Jing Yu, Zhiguo Wang, Fenyang Tang
British Journal of Clinical Pharmacology; doi:10.1111/bcp.14976

Abstract:
AIMS The bivalent oral poliovirus vaccine (bOPV; types 1 and 3) replaced the trivalent OPV (tOPV; types 1, 2 and 3) globally in April, 2016. A routine schedule of 1 dose of inactivated poliovirus vaccine (IPV) and a subsequent 3 doses of bOPV was implemented in Jiangsu simultaneously. The schedule was changed to “2 IPV+2 bOPV” on September 1, 2019. Although OPV type 2 has been removed, challenges persist because of adverse events following immunization (AEFIs) with bOPV. Therefore, we analysed and evaluated the safety profile of bOPV administered in children based on passive postmarketing AEFI surveillance. METHODS We collected all bOPV-related AEFI reports in Jiangsu from the Chinese National AEFI Information System (CNAEFIS) between May 2016 and April 2020. We obtained the administered doses of bOPV from the Jiangsu Provincial Electronic Immunization Registries System. A descriptive analysis was performed. RESULTS In total, 2,084 bOPV-related AEFIs were retrieved from the CNAEFIS. The overall reporting rate was 24.16 per 100,000 doses. Most AEFIs were nonserious. The most frequently reported symptoms were fever, rash and gastrointestinal disorders. Only 1.34% of AEFIs were serious, in which thrombocytopenic purpura accounted for the largest category. Seventeen serious adverse events, including two vaccine-associated paralytic poliomyelitis (VAPP) cases, were considered to be related to bOPV vaccination. The rate of VAPP was 0.2 per million doses. CONCLUSION AEFI analysis showed that bOPV was well tolerated. The events most frequently reported were nonserious. However, bOPV can still cause VAPP. Attention should be given to risks related to bOPV.
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