British journal of clinical pharmacology最新文献

We report individualized off-label monthly use of a high dose of long-acting intramuscular cabotegravir/rilpivirine (CAB/RPV = 600 mg/900 mg) co-administered preconceptionally and throughout pregnancy with subcutaneous lenacapavir to a young woman with perinatally acquired HIV, multiple comorbidities, and class III obesity. Therapeutic drug monitoring for CAB and RPV was performed throughout the pregnancy and postpartum. At 7 weeks gestation, the plasma CAB and RPV C_troughs were 16 (2.58 mg/L) and 9 (0.11 mg/L) times above the respective protein adjusted (PA)-IC₉₀. From 7 to 32 weeks of gestation, plasma CAB and RPV C_troughs decreased to 1.28 and to 0.08 mg/L, respectively, but remained above PA-IC₉₀ for both drugs. After receiving one monthly high-dose CAB/RPV injection after delivery at 7 weeks postpartum, the plasma CAB and RPV C_troughs were 4.02 and 0.19 mg/L, 56% and 73% higher than at 7 weeks of gestation. Despite a decrease in cabotegravir (50%) and rilpivirine (27%) concentrations between first and third trimesters, plasma exposures remained above therapeutic thresholds and viral load <20 copies/mL was maintained throughout pregnancy. Higher CAB and RPV exposures did not result in adverse maternal, pregnancy or infant safety outcomes. At 7 weeks postpartum, CAB/RPV was switched to standard bimonthly dosing. At 33 weeks postpartum, the patient remained undetectable on standard CAB/RPV bimonthly dose, although subsequent pregnancies might require long-acting CAB/RPV dosing adjustments. Our case of empiric use of high-dose CAB/RPV with monthly injections and therapeutic drug monitoring during pregnancy in a complex patient with class III obesity provides novel insights into pharmacokinetics of long-acting CAB/RPV.

Bariatric surgery alters gastrointestinal anatomy and physiology, which likely impacts upon oral medication absorption. Drug- and alcohol-related deaths in this population are being increasingly reported; however, toxicological detail is lacking. Using data reported to the National Programme on Substance Use Mortality, we identified 18 deaths in people who had previously undergone bariatric surgery. Opioids were detected in almost all cases and were frequently implicated in causing death. Multiple medications were detected at post-mortem in every case and often included medications that the deceased was not actively prescribed. Mental health conditions and chronic pain were commonly listed comorbidities and one-third of deaths were deemed suicide. Illicit drug and alcohol use was rare, highlighting a distinct vulnerability to prescription medication harms. Our findings emphasize a need to understand how bariatric surgery alters pharmacokinetics and for integrated, multidisciplinary aftercare, therapeutic drug monitoring and tailored education of safe medication use in bariatric surgery patients.

Aims: Cannabidiol (CBD), the main non-intoxicating compound from the cannabis plant, is regularly used by patients with chronic pain who also take analgesics. CBD has previously been shown to inhibit CYP-mediated drug metabolism. This study aimed to characterize the potential pharmacokinetic interaction of CBD with amitriptyline and tramadol, two commonly used analgesics.

Methods: This was an open-label, fixed-sequence, 2-way crossover study in 13 healthy participants. On Day 1, 25 mg amitriptyline and 50 mg tramadol were co-administered orally in a fasted condition, followed by a 7-day washout period. On Day 8, 30 mg CBD was administered orally 1 h prior to amitriptyline and tramadol. Pharmacokinetic sampling was performed for CBD, amitriptyline, tramadol and their respective active metabolites nortriptyline and O-desmethyltramadol for up to 24 h post-dose. The areas under the curve (AUCs) were compared between visits using a mixed effects model.

Results: Twelve participants (4M/8F) completed the study; one participant (M) dropped out for personal reasons. CBD significantly increased the AUC_0-24h (least square means [LSM] ratio 1.13, 95% CI: 1.01, 1.26, p = 0.033) and the C_max (LSM ratio 1.17, 95% CI: 1.01, 1.36, p = 0.041) of amitriptyline. CBD did not significantly change the AUC_0-24h and C_max of nortriptyline and tramadol, and the C_max of O-desmethyltramadol.

Conclusions: A single dose of 30 mg CBD significantly influenced the metabolism of amitriptyline in healthy volunteers. In patients, CBD-induced drug interactions may be more pronounced in chronic dosing and dependent upon prandial status.

Introduction: In recent years, the treatment of spinal muscular atrophy (SMA), a rare disease, has significantly progressed, improving patients' survival and overall quality of life. However, current SMA treatments are expensive, and some (nusinersen) are very inconvenient for patients. There is reason to believe that there are economic benefits of switching patients from nusinersen to risdiplam, especially because real-world analysis has shown non-inferiority in clinical outcomes along with a favourable safety profile of switching.

Aim: To conduct the cost-utility analysis of switching from nusinersen to risdiplam.

Methods: A discrete event simulation model was created for three different groups of patients with SMA (types 1-3), comparing the cost-utility of nusinersen to the risdiplam switch and continuing nusinersen therapy. Analysis was conducted from the perspective of the Croatian Health Insurance Fund for the time horizon of 80 years. A deterministic, one-way, one-factor sensitivity analysis was carried out using the Monte Carlo simulation.

Results: The incremental cost-effectiveness ratio of nusinersen to risdiplam switch versus staying on nusinersen was EUR-136930 ± 82 336 for type 1 SMA (i.e. the switch dominated), for type 2 SMA it was EUR 2681860 ± 321 859, and for type 3 SMA it was EUR 2576667 ± 676 078. For all three types of SMA, switching to risdiplam showed positive net monetary benefit (type 1: EUR 35449 ± 17 113; type 2: EUR 799264 ± 30 765; type 3: EUR 767498 ± 7283). Market forces may substantially impact pricing dynamics; therefore, these results should be interpreted with consideration of inherent uncertainties.

Conclusion: The cost-effectiveness of switching from nusinersen to risdiplam is evident across all SMA types. Further research on the long-term impact of switching treatments in SMA is essential to address uncertainties and optimize cost-effective therapeutic strategies.

Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have well-documented cardiovascular benefits. However, the cardiovascular benefits of early SGLT2i use in diabetics experiencing acute myocardial infarction (MI) remain unclear.

Methods: To evaluate the cardiovascular effects of early initiation of SGLT2i in diabetics experiencing acute MI, this study emulated a target trial using data from Taiwan's Health Research Data Integration Service of the National Health Insurance Administration. This study analysed cardiovascular composite outcomes, including hospitalization for heart failure (HHF), MI re-hospitalization, ischaemic stroke, cardiovascular mortality, and individual outcomes. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazard models.

Results: Among 36,103 diabetic patients experiencing acute MI, SGLT2i administration within 14 days after acute MI (N = 2,149) reduced cardiovascular composite risks relative to dipeptidyl peptidase-4 inhibitors (DPP4i) (N = 10,802, HR = 0.89, 95% CI: 0.82-0.96, p = 0.0017). Compared to DPP4i, SGLT2i significantly reduced HHF (HR = 0.86, 0.79-0.95), MI re-hospitalization (HR = 0.70, 0.62-0.80), and cardiovascular mortality (HR = 0.65, 0.54-0.79) risks, but not ischaemic stroke. Sensitivity analysis confirmed the robust therapeutic efficacy of SGLT2i, and Subgroup analyses suggested that the therapeutic efficacy of SGLT2i may be affected by chronic kidney disease, age, and percutaneous coronary intervention. The cardiovascular benefits were consistent across patients without heart failure and new SGLT2i users. Exploratory analyses revealed comparable results between SGLT2i and glucagon-like peptide-1 receptor agonists.

Conclusions: Early SGLT2i use in diabetics experiencing acute MI reduced cardiovascular risk, supporting its potential therapeutic use.

Aim: Angiotensin-Converting Enzyme inhibitors/Angiotensin II Receptor Blockers (ACEi/ARB) therapy is recommended to improve outcomes after acute kidney injury (AKI). However, data on their effects in very old adults after AKI remain limited.

Methods: This cohort study utilized data from TriNetX, including adults aged ≥85 years who underwent dialysis during hospitalization and discontinued dialysis upon discharge between 2012 and 2022. Patients initiating ACEi/ARB within 90 days post-discharge were identified and propensity score-matched (1:1) with controls. Outcomes, including mortality, major adverse kidney events (MAKE) and major adverse cardiovascular events (MACE), were analysed using Cox proportional hazards models in an emulated target trial analysis.

Results: Among 88 024 patients, 3637 ACEi/ARB users were matched to 3637 controls, with a mean follow-up of 9.02 months. ACEi/ARB use was associated with a significantly lower risk of all-cause mortality (aHR = 0.64; p < 0.01) and MAKE (aHR = 0.63; p < 0.01). No significant difference was observed in MACE between groups (aHR = 0.94; p = 0.49). The observed protective effect of ACEi/ARB on MAKE was more pronounced in patients with hypertension. ACEi/ARB use was associated with a higher risk of hypotension (aHR = 1.38; p < 0.01) and hyperkalaemia (aHR = 1.69; p < 0.01).

Conclusion: Among very old adults after dialysis for AKI, the ACEi/ARB therapy was significantly associated with lower risks of all-cause mortality and MAKE, but with a significantly increased risk of hypotension and hyperkalaemia. These findings support the cautious use of ACEi/ARB in this high-risk population.

Aims: Endothelin A (ET_A) receptor antagonists may reduce cirrhosis-associated portal hypertension (PH). They are associated with fluid retention, which might be mitigated by sodium-glucose co-transporter 2 inhibitors (SGLT2is). Efficacy, safety and tolerability of combining the selective ET_A receptor antagonist zibotentan and the selective SGLT2i dapagliflozin were investigated.

Methods: Patients with compensated cirrhosis (Child-Pugh A) were randomized 1:1 to zibotentan 2.5 mg plus dapagliflozin 10 mg (zibo/dapa) or placebo in a 6-week parallel, double-blind Phase II study. The absolute change in hepatic venous pressure gradient (HVPG) from baseline to week 6 was evaluated in the full analysis set using analysis of covariance.

Results: In 28 participants (n = 14 per group), median age was 64 years (range: 37-78), common causes of cirrhosis were metabolic dysfunction-associated steatotic (46%) or alcohol-associated liver disease (39%), and 46% were receiving stable doses of non-selective beta-blockers. Baseline HVPG was 6.5-19 mmHg, and 16/28 had clinically significant portal hypertension. Absolute change in HVPG at week 6 was not different between groups (1.02 mmHg [90% CI -0.31, 2.35]). There was a trend towards decreased HVPG in patients with baseline HVPG ≥12 mmHg receiving zibo/dapa. Systolic and diastolic blood pressure were also reduced by zibo/dapa vs. placebo. Three mild adverse events (peripheral oedema) were reported (zibotentan/dapagliflozin, n = 2; placebo, n = 1). No serious adverse events or drug-induced liver injuries were observed.

Conclusions: Combined zibo/dapa was well tolerated and had a good safety profile in patients with compensated cirrhosis, but had no conclusive effect on HVPG.