British journal of clinical pharmacology最新文献

Aim: Local investigators (LIs) overestimate the objective response rate (ORR) in comparison to Blinded Independent Central Reviewers (BICR) in oncology. In this study, we re-analysed data obtained in the PHEREXA trial (NCT01026142) with the following aims: i) to confirm at the single-patient level the discrepancy observed by analysing aggregated data; ii) to investigate the causes underlying such discrepancy.

Methods: Individual data, available on the VIVLI platform, were analysed. For each patient, the best response was established for LIs and BICR. "Eligible" patients were those with at least one target lesion at screening. The degree of agreement was assessed through the Cohen's Kappa coefficient. Multivariate logistic regression analysis was performed to understand the reasons underlying the discrepancy.

Results: Eligible subjects were 364/452 according to LIs and 371/450 per BICR. We confirmed that LIs overestimate the ORR. We found moderate agreement between the two evaluations (Cohen's κ= 0.48, p < 0.001). The probability of discrepancy increased by 20% with the increasing number of target lesions evaluated. Selection of 8-10 lesions was associated with an increased risk of discrepancy (OR, 5.27; CI 95% = 1.21-24.92; p < 0.03). The evaluation of breast, lung and lymph nodes (only) significantly increased the probability of discrepancy in comparison to the analysis of lymph nodes + organ.

Conclusion: The overestimation of the tumour response by LIs increases with the number of target lesions analysed as well as with specific evaluation sites. Thus, the adoption of the two evaluations appears necessary in uncontrolled trials to provide a better estimate of tumour response.

Aims: The study's aim is to evaluate the pharmacokinetics (PK) and safety of leritrelvir, a novel 3-chymotrypsin-like cysteine protease (3CLpro) inhibitor, in patients with severe renal impairment (RI; n = 7) compared to healthy controls (n = 8).

Methods: This nonrandomized, open-label, parallel-group, single-dose trial included primary PK endpoints (C_max, AUC_0-t, AUC_0-∞, t_1/2) and safety endpoints (AEs, vital signs, laboratory tests). Log-transformed PK parameters were analysed by ANOVA to calculate GMRs (90% confidence intervals [CIs]) for group comparisons, with statistical significance assessed for exposure differences.

Results: PK analysis revealed similar median time-to-peak concentration (T_max) but a reduced elimination half-life (t_1/2) in the RI group (4.20 h vs. 5.09 h). The geometric mean ratios (90% CI) of systemic exposure parameters indicated increases of 30.34% for C_max, 54.19% for AUC_0-t, and 56.83% for AUC_0-∞ in the RI group compared to controls.

Conclusions: Modest PK alterations in severe renal impairment are clinically insignificant given leritrelvir's wide therapeutic index. The drug is well-tolerated (mild-to-moderate, short-duration AEs), and no dose adjustment is needed for patients with renal impairment.

Aim: Tacrolimus monitoring is generally performed in whole blood (WB). Most (>85%) of circulating tacrolimus is bound to red blood cells. During pregnancy, WB monitoring might be suboptimal because of physiological changes including increased plasma volume and decreased haematocrit. Therefore, plasma tacrolimus monitoring might better indicate potential dosage needs in pregnant women.

Methods: This prospective single-centre cohort study aimed to assess and compare tacrolimus WB and plasma concentration-to-dose (C/D) ratios before, during, and after pregnancy in kidney or liver transplant recipients. Linear mixed model analysis was used.

Results: Nine women with 10 pregnancies were included. Based on WB tacrolimus concentrations, the median prescribed dosage significantly increased from 3 pre-pregnancy to 7.5 mg/day (+150%) in the third trimester (p < .001). The correlation between plasma and WB tacrolimus concentrations decreased throughout pregnancy with a correlation coefficient of 0.70 in the first trimester, 0.41 in the second and 0.30 in the third trimester of pregnancy. Median WB tacrolimus C/D ratios significantly decreased from 1.48 pre-pregnancy to 0.58 in the second and third trimester (-61%) (overall time effect p < .001). The effect of time became non-significant after adjusting for haematocrit (p = .40). Median plasma tacrolimus C/D ratios decreased from 0.03 pre-pregnancy to 0.02 in the first trimester (-33%) and remained stable afterward (overall time effect p = 0.33) and was not affected by haematocrit.

Conclusion: Our findings suggest that increasing dosages targeting WB tacrolimus concentrations may not be necessary during pregnancy based on plasma tacrolimus concentrations. However, larger studies are needed to confirm the findings.

Aims: The serum creatinine-to-cystatin C ratio (Cr/Cys-C) has recently garnered interest as a simpler surrogate marker for sarcopenia assessment. However, the reported Cr/Cys-C thresholds vary in different disease states, and Cr/Cys-C is yet to be established as a reliable diagnostic marker. This study aimed to identify a Cr/Cys-C threshold at which Cys-C-based estimated glomerular filtration rate (eGFRcys) provides more accurate renal function assessment than Cr-based eGFR (eGFRcr) for informing drug dosing strategies in sarcopenia.

Methods: This retrospective study included 172 patients who had been receiving a consistent dose of oral magnesium oxide for at least one week and had undergone same-day measurements of serum Cr, Cys-C and magnesium (Mg). Based on previously reported Cr/Cys-C thresholds (< 0.887, < 0.80 and < 0.67), patients were stratified into sarcopenia and non-sarcopenia cohorts.

Results: In all subjects, eGFRcr and eGFRcys each demonstrated a significant negative correlation with serum Mg level. At Cr/Cys-C thresholds of < 0.80 and < 0.67, serum Mg level showed a significant inverse correlation with eGFRcys in both sarcopenia and non-sarcopenia cohorts, but did not correlate significantly with eGFRcr in the sarcopenia cohort. ROC analysis identified an optimal Cr/Cys-C cutoff of 0.82 at which serum Mg level correlates significantly with eGFRcys but not with eGFRcr, yielding a sensitivity of 100% and specificity of 69.23%.

Conclusion: These findings suggest that at Cr/Cys-C below 0.82, the accuracy of eGFRcr in assessing renal function may be compromised, and eGFRcys should be used in such cases.

Aims: Valproic acid is an inhibitor of histone deacetylases (HDACs) and is used for the treatment of epileptic seizures. The drug (sodium valproate) has antihypertensive effects, and HDACs modulate renal Na⁺-transporting ATPases. The aim was to investigate whether valproate could be repositioned as an adjunctive drug for the prevention of acute kidney injury (AKI).

Methods: AKI due to ischemia followed by reperfusion (I/R) was induced by clamping of the renal arteries in rats that had received valproate or a vehicle for 20 days. Plasma creatinine and urea concentrations, and glomerular filtration rate (colorimetrically); plasma and urinary Na⁺ and K⁺ concentrations, and urinary excretion of Na⁺ and K⁺ (spectrophotometrically); proximal tubules (Na⁺+K⁺)ATPase activity (release of P_i from ATP); and blood pressure (pletismography) were measured 48 h later.

Results: AKI increases plasma creatinine and returns to baseline values observed in non-operated animals when I/R rats are pretreated with valproate. Its decrease in urine is significantly prevented by valproate administration. The elevated plasma urea concentration is significantly reduced. Urinary excretion of Na⁺ and K⁺ decreases in I/R, but while the former is recovered by valproate, this does not occur with K⁺. The plasma levels of both ions remain ~10% below those of Sham controls. The decrease in (Na⁺+K⁺)ATPase activity in I/R rats is totally prevented by valproate. The AKI-provoked hypertension is prevented by valproate.

Conclusions: Valproate has pharmacological properties that point to its potential repositioning as an adjuvant in improving several outcomes in AKI and potentially avoiding progression to chronic kidney disease.

Aims: The study aims to develop a physiologically-based pharmacokinetic (PBPK) model to quantitatively evaluate the role of ATP-binding cassette sub-family B member 1 (ABCB1) and ATP-binding cassette super-family G member 2 (ABCG2) in the drug-drug interaction (DDI) between rifampin and linezolid and to predict the impact of high-dose rifampin on linezolid pharmacokinetics (PK).

Methods: We developed a PBPK model of linezolid and verified this using published clinical PK data. The built-in PK-SIM PBPK model for rifampin was used as a perpetrator model, which incorporate ABCB1 and ABCG2 transporter activity, along with inhibition and induction kinetic parameters. Using the developed PBPK models, linezolid PK was predicted when co-administered with rifampin and verified using published data. Based on the developed DDI model, linezolid exposure when co-administered with high-dose rifampin at steady state was predicted.

Results: The developed linezolid PBPK model had acceptable predictive performance for 36 different PK arms from 13 individual clinical studies. The PBPK-predicted DDI effect of standard dose rifampin on linezolid, with AUC and C_max ratios of 0.77 and 0.87, respectively, aligned well with observed DDI ratio. PBPK simulations indicated that both ABCG2 and ABCB1 contributed to the DDI between linezolid and rifampin, with ABCB1 playing the major role in the interaction. Increasing the daily dose of rifampin from 10 mg/kg to 20-40 mg/kg resulted in a similar linezolid exposure.

Conclusions: Our study suggested that ABCB1 is the primary transporter responsible for the interaction between rifampin and linezolid. The DDI effect of high-dose rifampin on linezolid plasma exposure is similar to that of standard-dose rifampin.

Aims: Amoxicillin, a widely used β-lactam antibiotic, requires improved pharmacokinetic characterization during breastfeeding. This study used a population pharmacokinetic (PopPK) approach to model amoxicillin concentrations in breast milk, identify variability sources and estimate infant exposure, applying worst-case scenarios.

Methods: Breastfeeding mothers receiving amoxicillin for at least 2 days were enrolled. At steady state, three (nearly) paired blood and milk samples were collected between two doses: 15-30 min, 1-2 h and 3-4 h post-dose. Samples were analysed using LC-MS/MS. PopPK modelling was performed with Monolix. Milk-to-plasma (M/P) concentrations ratios and relative infant dose (RID) were evaluated. RID was calculated relative to both adult and paediatric dosing regimens. Monte Carlo simulations estimated infant exposure at high maternal doses (6 g/day).

Results: Twenty-five mother-infant pairs were included. All plasma and milk samples (n = 75/matrix) contained quantifiable amoxicillin. A two-compartment model described the data, with drug transfer from plasma to milk and elimination from milk. Simulated M/P concentrations ratios were 4.1%-5.4%, while observed values ranged from 4.5% to 9.6%. RID based on adult or paediatric dosages remained <0.4%, regardless of measured or simulated concentrations. No adverse effects were reported in breastfed infants.

Conclusions: These findings support the low transfer of amoxicillin into breast milk and align with the absence of adverse effects in breastfed infants, reinforcing its safety during lactation.

Aim: Elexacaftor/tezacaftor/ivacaftor (ETI) has markedly improved cystic fibrosis (CF) outcomes. However, its long-term impact on nutrition, metabolism and liver health remains underexplored. We assessed 30-month changes in pulmonary, nutritional, metabolic and inflammatory markers in people with CF (PwCF) homozygous for F508del.

Methods: We retrospectively analysed 112 PwCF (median age-31 years) treated with ETI from July 2021 to December 2024. Clinical, spirometric and biochemical data were collected at baseline and at 6, 12, 24 and 30 months.

Results: ETI produced sustained lung function gains (percent predicted FEV₁ + 15 points at 24 months, p < 0.001), BMI increase (+1.7 kg/m² in year-one, p < 0.001) and marked C-reactive protein reduction (-80% at 6 months), with an 85% decrease in pulmonary exacerbations. Nutritional recovery shifted BMI distribution: underweight prevalence declined from 12.5% to 1.8%, while overweight rose from 15.2% to 27.7%. Adolescents improved in weight-for-age Z-scores (+0.42, p = 0.01). Total and LDL cholesterol increased but remained within reference ranges; HDL, triglycerides and glycaemic control stayed stable, with no new cystic fibrosis-related diabetes (CFRD). Vitamin D improved; vitamin B12 fluctuated with supplementation. Mild, transient transaminase elevations occurred in 4.5% of PwCF, with no fibrosis progression (APRI/FIB-4 below risk thresholds).

Conclusion: ETI provides durable multisystem benefits, preserving lung function and improving nutritional and metabolic profiles. However, the shift towards overweight/obesity and biochemical signs of hepatic stress suggests evolving cardiometabolic risks. These findings support early ETI initiation and reinforce the need for ongoing monitoring of nutrition, lipid profile and liver function, together with updated CF care strategies to mitigate long-term cardiometabolic complications.

Aims: Chemical Adherence Testing (CAT) is gaining prominence as a reliable and valid clinical method to detect whether antihypertensive agents are being taken as prescribed. This study aimed to explore clinicians' attitudes and perspectives on the clinical use of CAT.

Methods: Clinicians involved in hypertension care were recruited through purposive and snowball sampling (N = 9). Participants represented general practice, cardiology, geriatric medicine, clinical pharmacology, nephrology and internal medicine. Semi-structured interviews were carried out, and transcripts were analysed using reflexive thematic analysis with an inductive, constructivist approach. Theme development was peer-reviewed by a health psychologist and clinical pharmacologist to enhance reflexivity.

Results: Three themes were developed: (1) The impactful weight of new evidence- CAT was perceived as a valuable, more objective tool for checking for non-adherence and informing treatment, especially in cases of suspected treatment-resistant hypertension; (2) CAT meets clinical reality- participants highlighted practical barriers such as test availability, workflow disruption, staffing needs and costs that could impact implementation in an overburdened healthcare system; (3) The human side of CAT- while CAT supported discussions around adherence, clinicians highlighted the need for trust, consent and sensitive communication to avoid perceptions of policing or blame.

Conclusion: Clinicians viewed CAT as a promising tool for improving diagnostic clarity and prompting adherence discussions. However, concerns about logistical feasibility, ethical use and potential strain on patient relationships were evident. Successful implementation requires clinician training, clear communication and system-level support to ensure CAT is integrated in an ethical, patient-centred way that preserves trust and supports collaborative care.

Aims: Prescribing is a complex, essential skill that doctors must acquire to practice medicine safely and effectively. The British Pharmacological Society has historically provided a core curriculum to guide clinical pharmacology and prescribing education in UK medical schools. This study aimed to update the 2012 curriculum to reflect contemporary practice, regulatory requirements and the evolving needs of medical education.

Methods: A modified Delphi was undertaken. A steering committee of six clinical and educational experts reviewed the previous curriculum and oversaw the process. Forty experts, comprising clinical and academic pharmacologists, medical educators and pharmacists from across the UK, participated in three Delphi rounds. Round 1 involved item-level review of existing learning outcomes; Round 2 incorporated feedback and new proposals; Round 3 convened expert panels to resolve outstanding disagreements. Consensus was defined as ≥75% agreement.

Results: The updated curriculum comprises four sections: (I) Principles of Clinical Pharmacology, (II) Drugs, (III) Therapeutics and (IV) Prescribing and related skills. Key changes include consistent application of clearly defined command verbs, updates to reflect current practice and a reduction in learning outcomes (226 to 205), particularly in Section I. The core drug list remained stable, with minor revisions and reorganization.

Conclusion: This updated British Pharmacological Society curriculum provides a robust, evidence-based framework for clinical pharmacology and prescribing education. Its structured approach supports curriculum design, mapping and quality assurance, while alignment with national assessments and regulatory expectations ensures relevance for undergraduate education and early clinical practice. It aims to enhance safe, effective and responsible prescribing by future doctors.