Pharmacokinetic interaction after oral coadministration of clarithromycin and the tyrosine kinase inhibitor lapatinib in rats

Lapatinib is a tyrosine kinase inhibitor used to treat patients with locally advanced or metastatic breast cancer exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2 receptor, ErbB2). Preclinical and clinical studies suggest that lapatinib is mainly metabolized by CYP3A4, therefore the study in an animal model was designed to investigate the pharmacokinetic interaction of lapatinib and clarithromycin, a well-known CYP3A4 inhibitor. The rats were subjected to one of the two study groups: lapatinib + clarithromycin (ILap+Clar; n = 6), and lapatinib + placebo (IILap; n = 6). The animals were treated with lapatinib in the oral single dose of 100 mg/kg. The antibiotic was administered orally at a dose of 25 mg/kg. Blood sampling was performed until 30 hours after dosing for pharmacokinetic assays. Plasma concentrations of lapatinib were measured by liquid chromatography-mass spectrometry. The comparison of lapatinib maximum concentration and area under the concentration-time curve in the ILap+Clar with the control group IILap gave the ratios of 1.38 (90% confidence interval (CI)) (1.14; 1.68) and 1.16 (0.75; 1.79), respectively. A statistically significant difference between analyzed groups was revealed only for maximum concentration (p = 0.0107). Single oral administration of clarithromycin significantly increased the concentration of lapatinib in rats, therefore caution should be taken during concomitant treatment with this macrolide and the tyrosine kinase inhibitor in patients

The effect of total and partial nephrectomy on the pharmacokinetics of intravenous paracetamol in humans

Paracetamol is one of the most common analgesic and antipyretic drugs. Recently intravenous paracetamol has been widely used to treat moderate postoperative pain. Surgery is the main method of treatment of renal cancer. Total or partial nephrectomy can be performed, depending on the size and location of the tumor. Pharmacokinetics of drugs may depend on the type of surgery. The aim of the study was to compare the postinfusion pharmacokinetics of paracetamol in patients after total nephrectomy (TN) and nephron sparing surgery (NSS).The research was carried out on two groups of patients after nephrectomy: total (TN n = 37; mean [SD], age, 60.4 [10.9] years; BMI, 26.5 [3.8] kg/m2; creatinine clearance, Cl, 80.9 [37.1] mL/min) and nephron sparing surgery (NSS n = 17; 57.9 [16.5] years; BMI, 29.5 [5.3] kg/m2; Cl, 97.6 [27.8] mL/min). The patients were treated with paracetamol (PerfalganO Bristol-Myers Squibb) at an intravenous dose of 1.000 mg, which was infused for 15 minutes after surgery. The concentrations of paracetamol in the patients\u27 plasma were determined by the HPLC method with UV detection (X = 261 run). The main pharmacokinetic parameters of paracetamol in the TN vs. NSS group were as follows: C.. 29.08 [17.39] vs. 27.54 [15.70] pg/mL (p = 0.6692); AUC5, 29.24 [13.86] vs. 34.85 [14.28] pg.h/mL (p = 0.2896); AUMC5,,,, 47.58 [26.08] vs. 62.02 [27.64] pg-h/mL (p = 0.1345); to. 2.34 [0.96] vs. 1.93 [0.50] h (p = 0.1415), respectively. In both groups the exposure to paracetamol was comparable. The t1/2 after nephron sparing surgery was shorter than after total nephrectomy. Therefore, these patients may demand more frequent drug administration. In the NSS group the C. of the analgesic was considerably reduced in men

Pharmacokinetic interaction after oral coadministration of clarithromycin and the tyrosine kinase inhibitor lapatinib in rats

Lapatinib is a tyrosine kinase inhibitor used to treat patients with locally advanced or metastatic breast cancer exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2 receptor, ErbB2). Preclinical and clinical studies suggest that lapatinib is mainly metabolized by CYP3A4, therefore the study in an animal model was designed to investigate the pharmacokinetic interaction of lapatinib and clarithromycin, a well-known CYP3A4 inhibitor. The rats were subjected to one of the two study groups: lapatinib + clarithromycin (ILap+Clar; n = 6), and lapatinib + placebo (IILap; n = 6). The animals were treated with lapatinib in the oral single dose of 100 mg/kg. The antibiotic was administered orally at a dose of 25 mg/kg. Blood sampling was performed until 30 hours after dosing for pharmacokinetic assays. Plasma concentrations of lapatinib were measured by liquid chromatography-mass spectrometry. The comparison of lapatinib maximum concentration and area under the concentration-time curve in the ILap+Clar with the control group IILap gave the ratios of 1.38 (90% confidence interval (CI)) (1.14; 1.68) and 1.16 (0.75; 1.79), respectively. A statistically significant difference between analyzed groups was revealed only for maximum concentration (p = 0.0107). Single oral administration of clarithromycin significantly increased the concentration of lapatinib in rats, therefore caution should be taken during concomitant treatment with this macrolide and the tyrosine kinase inhibitor in patients.This article is published as Karbownik A., Porazka J, Luczak A., Tezyk A., Grabowski T., Wolc A., Grzeskowiak E., Szalek E. 2019. Pharmacokinetic interaction after oral coadministration of clarithromycin and the tyrosine kinase inhibitor lapatinib in rats. Acta Poloniae Pharmaceutica – Drug Research 76(4): 645-651.</p

The effect of total and partial nephrectomy on the pharmacokinetics of intravenous paracetamol in humans

Paracetamol is one of the most common analgesic and antipyretic drugs. Recently intravenous paracetamol has been widely used to treat moderate postoperative pain. Surgery is the main method of treatment of renal cancer. Total or partial nephrectomy can be performed, depending on the size and location of the tumor. Pharmacokinetics of drugs may depend on the type of surgery. The aim of the study was to compare the postinfusion pharmacokinetics of paracetamol in patients after total nephrectomy (TN) and nephron sparing surgery (NSS).The research was carried out on two groups of patients after nephrectomy: total (TN n = 37; mean [SD], age, 60.4 [10.9] years; BMI, 26.5 [3.8] kg/m2; creatinine clearance, Cl, 80.9 [37.1] mL/min) and nephron sparing surgery (NSS n = 17; 57.9 [16.5] years; BMI, 29.5 [5.3] kg/m2; Cl, 97.6 [27.8] mL/min). The patients were treated with paracetamol (PerfalganO Bristol-Myers Squibb) at an intravenous dose of 1.000 mg, which was infused for 15 minutes after surgery. The concentrations of paracetamol in the patients' plasma were determined by the HPLC method with UV detection (X = 261 run). The main pharmacokinetic parameters of paracetamol in the TN vs. NSS group were as follows: C.. 29.08 [17.39] vs. 27.54 [15.70] pg/mL (p = 0.6692); AUC5, 29.24 [13.86] vs. 34.85 [14.28] pg.h/mL (p = 0.2896); AUMC5,,,, 47.58 [26.08] vs. 62.02 [27.64] pg-h/mL (p = 0.1345); to. 2.34 [0.96] vs. 1.93 [0.50] h (p = 0.1415), respectively. In both groups the exposure to paracetamol was comparable. The t1/2 after nephron sparing surgery was shorter than after total nephrectomy. Therefore, these patients may demand more frequent drug administration. In the NSS group the C. of the analgesic was considerably reduced in men.This article is published as Karbownik A., Połom W., Porażka J., Szałek E., Grabowski T., Wolc A., Matuszewski M., Grześkowiak E. 2017. The effect of total and partial nephrectomy on the pharmacokinetics of intravenous paracetamol in humans. Acta Poloniae Pharmaceutica – Drug Research 74:929-935.</p

Identifying dementia using medical data linkage in a longitudinal cohort study: Lothian Birth Cohort 1936

Abstract Background The Lothian Birth Cohort 1936 (LBC1936) is a longitudinal study of ageing with well-characterised assessments, but until now, it has relied on self-report or proxies for dementia such as cognitive tests. Our aims were twofold: a) to describe a framework for identifying dementia in a cohort study. b) to report the age-specific incidence and prevalence of all-cause dementia and dementia subtypes in 865 individuals in the LBC1936. Methods Electronic Health Records (EHR) of all participants were reviewed, and relevant information was extracted to form case vignettes for everyone with any record of cognitive dysfunction. The EHR data sources include hospital and clinic letters, general practitioner and hospital referrals, prescribed medications, imaging and laboratory results. Death certificate data were obtained separately. Clinician assessments were performed when there was concern about a participant's cognition. A diagnosis of probable dementia, possible dementia, or no dementia was agreed upon by a consensus diagnostic review board, comprised of a multidisciplinary team of clinical dementia experts who reviewed case vignettes and clinician assessment letters. For those with probable dementia, a subtype was also determined, where possible. We compared the agreement between our newly ascertained dementia diagnoses with the existing self-reported dementia diagnoses. Results Self-reported dementia diagnoses were positive in only 17.8% of ascertained dementia diagnoses. The EHR review identified 163/865 (18.8%) individuals as having cognitive dysfunction. At the consensus diagnostic review board, 118/163 were diagnosed with probable all-cause dementia, a prevalence of 13.6%. Age-specific dementia prevalence increased with age from 0.8% (65–74.9 years) to 9.93% (85–89.9 years). Prevalence rates for women were higher in nearly all age groups. The most common subtype was dementia due to Alzheimer disease (49.2%), followed by mixed Alzheimer and cerebrovascular disease (17.0%), dementia of unknown or unspecified cause (16.1%), and dementia due to vascular disease (8.5%). Conclusions We present a robust systematic framework and guide for other cohort teams wanting to ascertain dementia diagnoses. The newly ascertained dementia diagnosis provides vital data for further analyses of LBC1936 to allow exploration of lifecourse predictors of dementia