British journal of clinical pharmacology最新文献

Aims: The aim of this study was to assess differences between Chinese and White patients in pharmacokinetics (PK) of, and clinical response to, acalabrutinib and its pharmacologically active major metabolite, ACP-5862, to support recommended dosing in Chinese patients with B-cell malignancies.

Methods: A population pharmacokinetic (pop-PK) analysis was conducted to integrate data from a Chinese and a Japanese study into the existing model. The effect of race (East Asian vs. non-East Asian) on acalabrutinib and ACP-5862 PK parameters was assessed. The relationships between model-predicted exposures (e.g., acalabrutinib area under the plasma concentration-time curve for 24 h at steady-state [AUC_24h,ss]) and best overall response and safety outcomes were investigated in Chinese patients and the overall population.

Results: The pop-PK analysis included 686 patients with B-cell malignancies (Chinese, n = 105; Japanese, n = 6). A two-compartment model adequately described the PK profiles of acalabrutinib and ACP-5862 for Chinese patients. East Asian race was a statistically significant covariate on relative bioavailability and apparent volume of the peripheral compartment of acalabrutinib, showing 28% higher PK exposures in Chinese patients. The exposure-efficacy analysis showed that efficacy plateaued in Chinese patients with 100 mg twice-daily dosing while the exposure-safety analysis indicated a flat relationship of acalabrutinib AUC_24h,ss with grade ≥2 or ≥3 adverse events in both Chinese patients and the overall population with 100-400 mg daily doses.

Conclusions: Higher PK exposure was observed in Chinese patients vs. White patients but did not indicate a safety concern based on exposure-response relationships. The results supported using the 100 mg twice-daily dosing regimen in Chinese patients.

Direct oral anticoagulants (DOACs) are frequently used for the treatment and prevention of ischaemic stroke in patients with non-valvular atrial fibrillation. Compared to vitamin K antagonists, DOACs have significant advantages, although their drug-drug interaction (DDI) profile may complicate drug efficacy and safety. This narrative review addresses the clinical challenges posed by these DDIs and the potential pharmacological alternatives and monitoring strategies available. A PubMed search was conducted (1 January 2000-31 December 2023) including human DDI studies on DOAC use and CYP3A4/P-gp inducers in adult patients, evaluating patient outcome data and recommendations for DDI management. Twenty-two studies were included. Case reports (n = 6) indicated that antiepileptic drugs such as carbamazepine, phenobarbital and phenytoin may be associated with thromboembolic events. The nested case-control studies (n = 2) and cohort studies (n = 9) found that co-administration of DOACs and CYP3A4/P-gp inducers, particularly carbamazepine and phenytoin, increased the risk of thromboembolic events. Pharmacovigilance database analyses indicated a significant association between DOAC DDIs and increased reported stroke rates. Management recommendations in systematic reviews (n = 5) highlighted monitoring when DOACs were combined with inducers. Strategies included using alternative drugs with a weaker or preferentially absent inducing profile. Limited evidence suggests that edoxaban may be an acceptable option in case of DOAC and CYP3A4/P-gp inducer interactions; however, robust clinical data confirming safety are needed. Present literature indicates a higher thromboembolic risk in patients on DOAC treatment combining CYP3A4- and/or P-gp inducers. DOAC management should be tailored to the individual patient through collaboration between expert healthcare professionals.

Aims: The aim of this study was to determine if head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin chemoradiotherapy and short hydration (SH) experience less dose-limiting toxicity (DLT) and receive more cisplatin than those with medium hydration (MH) or long hydration (LH).

Methods: Baseline characteristics, cumulative cisplatin dose and toxicities were collected. Differences between LH, MH and SH were tested, with separate analyses for triweekly 100 mg/m² cisplatin and weekly 40 mg/m² cisplatin. Mixed models assessed the hydration schedule's effect on cumulative dose.

Results: A total of 389 patients were included. DLT occurrence was comparable between hydration groups (P = .060), but DLT type differed (P = .007). Nephrotoxicity was common with LH and MH (n = 11, 61% and n = 26, 45%, respectively), and ototoxicity with SH (n = 35, 36%). DLT occurrence in triweekly patients differed between LH and MH (n = 18, 64% vs n = 25, 32%, P = .004), but not between MH and SH (P = .171) or LH and SH (P = .055) patients. Cisplatin dose differed between LH and MH (median 200 vs 300, P = .008) as well as between LH and SH (median 200 vs 300, P = .024) but not between MH and SH (P = .429) patients. Hydration had no effect on dose (F = 2.09, P = .125).

Conclusions: DLT cause differed between hydration groups, with less nephrotoxicity but more ototoxicity in HNSCC patients with SH. Triweekly cisplatin LH patients had more DLT and lower cumulative dose compared to MH and SH, but no hydration effect in general on dose was found.

Aims: Daily broad-spectrum micronutrients are being used by the general public and formulations are receiving research interest in mental health settings. Despite concerns about combining medicines and broad-spectrum micronutrients in mental health care, there have not been any formal evaluations of potential interactions. Our objective was to evaluate a broad-spectrum micronutrient formula as a potential precipitant of pharmacokinetic drug-drug interactions through inhibition or induction of cytochrome P450 (CYP) enzymes.

Methods: This was a single-centre pharmacokinetic study. Twelve healthy participants received broad-spectrum micronutrients for 14 days (Days 1-14). Participants were administered a 'cocktail' of selective CYP probes midazolam 2 mg (CYP3A), dextromethorphan 30 mg (CYP2D6), losartan 25 mg (CYP2C9), omeprazole 20 mg (CYP2CI9) and caffeine 100 mg (CYP1A2) on Day 0 and Day 14, before taking and while taking broad-spectrum micronutrients. Plasma drug concentrations were measured at baseline and for 8 h following cocktail administration. AUC, C_max and T_max were compared before and after broad spectrum micronutrient administration using paired t-tests.

Results: Pre- and post-micronutrient geometric means (SD) for AUC_0-8h (μg*h/L) were: midazolam 25 (13) and 26 (14), P = 0.60; dextromethorphan 25 (99) and 19 (110), P = 0.46; losartan 219 (105) and 205 (76), P = 0.20; omeprazole 474 (394) and 402 (342), P = 016; and caffeine 13 800 (5400) and 12 800 (3500), P = 0.79. There were no statistically significant changes in geometric means of probe C_max, or T_max for any of the study drugs.

Conclusions: Broad-spectrum micronutrients are unlikely to be a major precipitant of pharmacokinetic drug-drug interactions.

Aims: The primary objective of this study was to determine the pharmacokinetics, mass balance and biotransformation of [¹⁴C]GT0918 in humans after the drug was administered to healthy Chinese male subjects.

Methods: The absorption, metabolism, and excretion (AME) of GT0918 was characterized via isotope labelling technology in six healthy Chinese male subjects after receiving a single 200 mg oral dose of [¹⁴C]GT0918 (80 μCi), and the phenotype, together with the metabolic mechanism of GT0918, was confirmed in vitro.

Results: The medium T_max of total radioactivity was 6.00 h (4.00-8.00 h) post-dose, and the mean C_max was 10.5 μg eq./mL (8.7-12.3 μg eq./mL) in plasma. Drug-related components in the plasma were eliminated slowly, with a mean t_1/2 of 67.7 h (54.4-90.7 h), and the radioactivity of the plasma samples from some subjects was above the below the quantization limit (BQL) until 17 days post-dose. After 19 days of dosing, the mean cumulative excreted radioactivity was 82.81% (79.07-86.07%) of the dose, including 29.47% (26.71-32.02%) in urine and 53.34% (52.01-55.62%) in faeces, indicating that the drug-related components of GT0918 were mainly excreted by faeces. Metabolite profiling revealed that the parent drug was detected in plasma, as well as in faeces and not in urine. In plasma, the most abundant metabolite was GT0955, a mono-oxidative metabolite of GT0918; in urine, the primary metabolite was GT0795, a metabolite of oxazole ring-opening followed by N-dealkylation; in faeces, the two main metabolites were M551 and the glucuronidation of GT0955. The majority of the metabolites were formed via an important aldehyde intermediate derived from the oxazole ring-opening, and the intermediate was trapped by methoxyamine hydrochloride in the in-vitro study. CYP3A4 is the main enzyme involved in the metabolism of GT0918.

Conclusions: Overall, all the dosed subjects completed the study, and GT0918 was found to be safe, with no grade II or above adverse events reported. A total dose of 82.81% was quantified in the urine (29.47%) and faeces (53.34%) of healthy adult male subjects after a single oral administration of 200 mg (80 μCi) GT0918 ([¹⁴C]GT0918). The metabolism of GT0918 is catalysed predominantly by CYP3A4, and an uncommon pathway of oxazole ring-opening to an aldehyde intermediate has also been proposed.

Aim: PREDICT-5FU aimed to document 5-fluorouracil (5FU) exposure in a cancer population and to evaluate the feasibility of 5FU and capecitabine therapeutic drug monitoring (TDM) in patients receiving standard doses and schedules.

Methods: Multicentre, prospective, observational single-arm study. Eligible adult patients received 5FU (infusional ≥24 h) or capecitabine. Patients were treated for gastrointestinal, breast and head-and-neck cancers at four Australian hospitals. TDM was performed in consecutive cycles until target area under the curve (AUC) was reached. Pharmacogenetic testing was performed for all patients.

Results: Fifty patients (24 males, 26 females) were recruited. Median age was 63 years; common diagnoses were lower gastrointestinal cancers 40% (20/50) and metastatic disease 80% (40/50). The majority received 5FU (38/50, 76%) over 46 h. Only 36% of 5FU patients achieved target AUC when dosed based on body surface area; 61% were below and 3% above target range. Post TDM-adjusted dosing, target AUC was achieved in 58% of patients (22% absolute increase vs. BSA dosing, p = 0.03), within median three cycles (range 1-5). DPYD variant allele carriers (3/4) had upfront reduced dosing due to heterozygosity; all were below the target AUC and one experienced Grade 3 toxicity. There was no correlation between dihydrouracil: uracil ratio [UH2/U] or uracilemia [U] and DPYD genotype. TDM results were reported with an average of 4 days from sampling.

Conclusion: TDM dosing is feasible and increases the proportion of patients reaching target AUC. Findings are relevant across all cancers treated with 5FU, and particularly for DPYD variant allele carriers receiving upfront dose reductions.

Aim: This study aims to conduct a hypothesis-generating screening for acute cardiovascular effects of prescription medications.

Methods: This Danish nationwide screening study was conducted among incident cases of cardiovascular diseases, including myocardial infarction (MI), ischemic stroke (IS), heart failure (HF), venous thromboembolism (VTE), myocarditis, and atrial fibrillation (AF), between January 2000 and December 2022. Using a case-crossover study design, we examined exposure to individual drugs on the date of the cardiovascular event (focal date) and three reference dates corresponding to days -180, -270 and -360 prior to index date. We calculated odds ratios (ORs) with 95% credible intervals (CIs) for associations between exposure drug and cardiovascular outcomes using the conditional logistic regression with a weak Bayesian shrinkage.

Results: After applying exclusion criteria, we identified 191,979 cases of AF, 145,148 cases of MI, 132,271 cases of IS, 71,821 cases of HF, 16,127 cases of VTE and 10,045 cases of myocarditis. Based on the threshold for the strength of associations (OR ≥ 1.5; lower limit of CI ≥ 1), we identified 222 associations for 104 individual drugs across all six outcomes. Some major drug classes, such as antibiotics, analgesics and corticosteroids, consistently demonstrated associations for most cardiovascular outcomes. Use of pantoprazole, in contrast to other PPIs, was associated with AF (OR 1.83; 95% CI 1.68-2.00) along with MI, HF, myocarditis and VTE. Similarly, oxazepam stood out among other benzodiazepines and demonstrated increased risk of VTE (OR 2.53; 95% CI 1.55-4.13) as well as MI, HF and AF.

Conclusions: The results highlight several potentially important associations across various pharmacological drug classes that warrant further investigation in tailored pharmacoepidemiological analyses.