Janice B. Schwartz

Gender Effects in Pharmacokinetics and Pharmacodynamics

SummaryThere are a number of examples of sex differences in drug pharmacokinetics and pharmacodynamics. Recent advances in the characterisation of specific isozymes involved in drug metabolism now allow for the preliminary identification of enzyme systems that are affected by sex. While current data are somewhat limited and not in complete agreement, the majority of studies show that apparent cytochrome P450 (CYP) 3A4 activity is higher in women than in men, whereas the activity of many other systems involved in drug metabolism may be higher in men than in women. Women and men also show different pharmacodynamic responses to a variety of drugs. While the clinical significance of these sex differences remains to be determined, we anticipate that they will be most important in the administration of drugs that have a narrow therapeutic range. In addition, sex differences in drug metabolism may be involved in the higher incidence of adverse reactions to drugs in women compared with men. Further research is needed to determine the scope and significance of these sex differences.Female-specific issues such as pregnancy, menopause, oral contraceptive use and menstruation may also have profound effects on drug metabolism. These effects can often be clinically important. Pregnancy may increase the elimination of antiepileptic agents, reducing their efficacy. Oral contraceptive use can interfere with the metabolism of many drugs and, conversely, certain drugs can impair contraceptive efficacy. More research is needed to determine the impact of menopause, hormone replacement and menstruation on drug therapy.

The influence of sex on pharmacokinetics

Biologic differences exist between men and women that can result in differences in responses to drugs. Both pharmacokinetic and pharmacodynamic differences between the sexes exist, with more data on pharmacokinetic differences. On average, men are larger than women. Body size differences results in larger distribution volumes and faster total clearance of most medications in men compared to women. Greater body fat in women (until older ages) may increase distribution volumes for lipophilic drugs in women. Total drug absorption does not appear to be significantly affected by sex although absorption rates may be slightly slower in women. Bioavailability after oral drug dosing, for CYP3A substrates in particular, may be somewhat higher in women compared to men. Bioavailability after transdermal drug administration does not appear to be significantly affected by gender; nor does protein binding. Renal processes of glomerular filtration, tubular secretion, and tubular reabsorption appear to be faster in men compared to women whether considered on a mg/kg basis or total body weight basis. Algorithms to estimate glomerular filtration rate incorporate sex as a factor; some also include weight. For hepatic processes, drugs metabolized by Phase I metabolism (oxidation, reduction, and hydrolysis via cytochrome P450’s 1A, 2D6, 2E1), Phase II conjugative metabolism (glucuronidation, conjugation, glucuronyltransferases, methyltransferases, dehydrogenases) and by combined oxidative and conjugation processes are usually cleared faster in men compared to women (mg/kg basis). Metabolism by CYP2C9, CYP2C19, and N-acetyltransferase, appear to be similar in men and women (mg/kg). Clearance of p-glycoprotein substrates appear to be similar in men and women. In contrast, total clearance of a number of CYP3A substrates appear to be mildly or moderately faster (mg/kg) in women compared to men. The clinical significance of reported differences warrants consideration. Clearance reported on a per kg basis directly addresses organ or enzyme clearance. The difference in size between men and women means translating these results to clinical dosage rates should include an adjustment for body size. Unfortunately, this is not standard. Reports of sex differences that persist after considering weight may warrant further dosage adjustments. In addition, investigations are often performed in healthy fasting individuals yet medications are prescribed to patients with confounding influences of disease, co-medications, diet, and social habits. The relative role of sex on pharmacokinetics as compared to genetics, age, disease, social habits and their potential interactions in the clinical setting is not yet fully known but should be routinely considered and further studied.

Sex Differences in Major Bleeding With Glycoprotein IIb/IIIa Inhibitors Results From the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Initiative

Background— Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS); their safe use in women, however, remains a concern. The contribution of dosing to the observed sex-related differences in bleeding is unknown. Methods and Results— We explored the relationship between patient sex, GP IIb/IIIa inhibitor use, dose, and bleeding in 32 601 patients with NSTE ACS across 400 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) hospitals, of whom 18 436 were treated. GP IIb/IIIa inhibitor dose was defined as excessive if not reduced when creatinine clearance was <50 mL/min for eptifibatide or <30 mL/min for tirofiban. Major bleeding was defined as a hematocrit drop ≥0.12, need for transfusion, or intracranial bleeding. Major bleeding was adjusted for clinical factors and antithrombotic dose. The risk for bleeding attributable to excess GP IIb/IIIa dose was determined by sex using prevalence and adjusted odds ratios (ORs). Women had higher rates of major bleeding than men among those treated with GP IIb/IIIa inhibitors (15.7% versus 7.3%, P<0.0001) and among those not treated (8.5% versus 5.4%, P<0.0001). Despite similar serum creatinine levels, creatinine clearance averaged 20 points lower among treated women than men. Treated women were also more likely to receive excess GP IIb/IIIa doses than men (46.4% versus 17.2%, P<0.0001; adjusted OR 3.81, 95% confidence interval [CI] 3.39 to 4.27). Excess dosing was associated with increased risk of bleeding in women (OR 1.72, 95% CI 1.30 to 2.28) and men (OR 1.27, 95% CI 0.97 to 1.66); however, bleeding risk attributable to dosing was much higher in women (25.0% versus 4.4%). Conclusions— Women experience more bleeding than men whether or not they are treated with GP IIb/IIIa inhibitors; however, because of frequent excessive dosing in women, up to one fourth of this sex-related risk difference in bleeding is avoidable. Appropriate dosing will improve care of all patients with NSTE ACS, with a particular benefit for women.

The Current State of Knowledge on Age, Sex, and Their Interactions on Clinical Pharmacology

Pharmacokinetic and pharmacodynamic changes occur with increasing age. Sex differences in pharmacokinetics and pharmacodynamics exist and persist at older age. The issue for the clinician is how to best treat the older patient with currently available knowledge. This communication highlights age‐ and sex‐related differences in pharmacokinetics that should influence clinical practice and prescribing guidelines to optimize clinical responses. The most compelling data for sex‐specific medication dosing guidelines for older patients are related to volume of distribution differences, or size differences, between the sexes and to differences in glomerular filtration rates.

Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study

Proteins pathogenic in Alzheimers disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD.

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

Objective: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. Methods: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. Results: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p ≤ 0.0003). Conclusions: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

A Comparison of Measured and Calculated Free 25(OH) Vitamin D Levels in Clinical Populations

OBJECTIVE Our goal was to compare direct quantitation of circulating free 25-hydroxyvitamin D (25(OH)D)levels to calculated free 25(OH)D levels and their relationships to intact PTH (iPTH), a biomarker of 25(OH)D effect, in humans with a range of clinical conditions. PATIENTS AND METHODS Serum samples and clinical data were collected from 155 people: 111 without cirrhosis or pregnancy (comparison group), 24 cirrhotic patients with albumin <2.9 g/dL, and 20 pregnant women (second and third trimester). Total 25(OH)D (LC/MS/MS), free 25(OH)D (immunoassay), vitamin D binding protein (DBP) (immunoassay), albumin, and iPTH (immunoassay) were measured. RESULTS Total 25(OH)D, DBP, and albumin were lowest in patients with cirrhosis, but measured free 25(OH)D was highest in this group (P < .001). DBP was highest in pregnant women (P < .001), but measured free 25(OH)D did not differ from the comparison group. Calculated free 25(OH)D was positively correlated with measured free 25(OH)D (P < .0001) but explained only 13% of the variability with calculated values higher than measured. African Americans had lower DBP than other ethnic populations within all clinical groups (P < .03), and differences between measured and calculated free 25(OH)D were greatest in African Americans (P < .001). Measured free 25(OH)D was correlated with total 25(OH)D (P < .0001; r(2) = 0.51), but calculated free 25(OH)D was not. Similarly, both measured free 25(OH)D (P < .02) and total 25(OH)D (P < .05) were correlated with iPTH, but calculated free 25(OH)D was not. CONCLUSIONS Calculated free 25(OH)D levels varied considerably from direct measurements of free 25(OH)D with discrepancies greatest in the data for African Americans. Differences in DBP binding affinity likely contributed to estimation errors between the races. Directly measured free 25(OH)D concentrations were related to iPTH, but calculated estimates were not. Current algorithms to calculate free 25(OH)D may not be accurate. Further evaluation of directly measured free 25(OH)D levels to determine its role in research and clinical management of patients is needed.

Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimers disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)‐serine‐type 1 insulin receptor substrate (IRS‐1) and less P‐tyrosine‐IRS‐1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P‐serine 312‐IRS‐1 and P‐pan‐tyrosine‐IRS‐1 by ELISA and the ratio of P‐serine 312‐IRS‐1 to P‐pan‐tyrosine‐IRS‐1 (insulin resistance factor, R) for AD and DM2 and P‐serine 312‐IRS‐1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significandy higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P‐serine 312‐IRS‐1, P‐pan‐tyrosine‐IRS‐1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural‐derived blood exosomes of preclinical Alzheimers disease. FASEB J. 29, 589‐596 (2015). www.fasebj.org

Acute and Chronic Pharmacodynamic Interaction of Verapamil and Digoxin in Atrial Fibrillation

The safety, efficacy, and pharmacologic effect of combined verapamil and digoxin were studied in 10 patients with chronic atrial fibrillation. Heart rate recordings, treadmill exercise tests, physical examinations and serum digoxin concentrations during chronic digoxin therapy were compared with those after the acute administration of verapamil and 1, 2, 4, 6 and 10 weeks after the addition of oral verapamil to digoxin therapy. After both i.v. and chronic oral verapamil administration, resting and exercise heart rates were significantly lower. Increasing serum concentrations of verapamil correlated with increasing suppression of heart rate at rest and during exercise. The mean resting heart rate by 24-hour ambulatory ECG decreased from 87 ± 9 beats/min to 72 6 beats/min. The mean treadmill exercise heart rate decreased more markedly, from a mean of 151 26 beats/min to 106 ± 22 beats/min (both p < 0.001). During chronic therapy, heart rate reductions were seen 1 week after the addition of verapamil and were maintained without change for the duration of the trial. Blood pressures at rest and during exercise were unchanged. Cardiomegaly was present on the entry chest x-ray in six patients; after verapamil, heart size decreased in three and was unchanged in one; two patients had transient congestive heart failure that responded to diuretics. Serum digoxin levels increased from a mean of 1.6 ± 0.4 ng/ml to 2.7 + 0.9 ng/ml (p < 0.001) during verapamil. The increase was observed in hine of 10 patients but was not related to clinical signs of digitalis excess and no episodes of asystole were seen on the serial 24-hour ECGs. Chronic oral administration of verapamil, 320 mg/ day, resulted ih mean verapamil concentrations of 130–280 ng/ml (mean interdose concentration 140 ± 41 ng/ml) with great intersubject and intrasubject variability. We conclude that verapamil is effective in further suppressing the ventricular response rate in atrial fibrillation when given in combination with digitalis and can serve as an adjunct to digitalis therapy in the chronic management of patients with atrial fibrillation.

Age and Sex Variation In Prevalence Of Chronic Medical Conditions In Older Residents of U.S. Nursing Homes

To investigate patterns in prevalences of chronic medical conditions over the age span of long‐term stay nursing home residents and between the sexes with data from the 2004 National Nursing Home Survey (NNHS).