Daniel S. Sitar

Drug-associated hospital admissions in older medical patients.

A survey of drug‐related admissions of patients aged 50 years and older was conducted at the Health Sciences Centre, Winnipeg to determine the interrelationship of risk factors, and isolate the effect of age. All nonelective medical admissions were prospectively assessed to determine the role of drug therapy as a contributory factor. Of the 863 eligible admissions, 162 exhibited at least one drug‐related adverse patient event (DRAPE) at the time of hospitalization. This accounted for 19% of the admissions (23% of 718 admissions that involved prescription drugs). Although adverse drug reactions were responsible for many DRAPEs (48%), intentional noncompliance (27%), treatment failure (19%), alcohol (14%), and medication error (10%) were also frequent contributing causes. Drugs commonly implicated in DRAPEs were systemic steroids, digoxin, nonsteroidal anti‐inflammatory agents, α‐methyldopa, calcium channel blockers, β‐blockers, theophylline, furosemide, sympathomimetics, thiazides, and benzodiazepines. The risk of a DRAPE was related to the number of diseases prior to admission (r = 0.81; P < .026) and the number of drugs used (r = 0.77; P < .001). Age was not correlated with the risk of a DRAPE. Females had significantly more adverse drug reactions, although sex was not a predictor for overall DRAPE risk.

Pill Count, Self-Report, and Pharmacy Claims Data to Measure Medication Adherence in the Elderly

OBJECTIVE: To compare medication adherence calculated from four different data sources including a pill count and self-report obtained during a home medication history, as well as calculations based on refill frequency derived from a provincial prescription claims database (manual and electronic). DESIGN: Baseline medication adherence was collected as part of a prospective, randomized, controlled study. Mean medication adherence results obtained from the four data sources were compared using repeated-measures ANOVA followed by a Tukeys multiple range test. SETTING: A pharmacy consultation service located at an interdisciplinary wellness center for noninstitutionalized elderly. PATIENTS: 65 years or older, noninstitutionalized, taking one or more prescribed or nonprescribed medications. Clients would either present to the wellness center or be referred by the Provincial Home Care program. RESULTS: When calculated from self-report or manual or electronic prescription claims data, mean percent adherence by drug was high and not statistically different (95.8% ± 17.1%, 107.6% ± 40.3%, and 94.6% ± 24.0%, respectively), whereas the pill count adherence was significantly lower at 74.0% ± 41.5% (p < 0.0001). CONCLUSIONS: An unexpected finding was that the pill count technique used in this study of elderly clients using chronic, repeat medications appeared to underestimate medication adherence. Numerous other limitations of pill count, self-report, and a province-wide prescription claims database in estimating medication adherence are presented. When using medication adherence as a process measure, the researcher and practitioner should be aware of the limitations unique to the data source they choose, and interpret data cautiously.

Safe use of the CXCR4 inhibitor ALX40-4C in humans

ALX40-4C is a small peptide inhibitor of the chemokine receptor CXCR4 that can inhibit X4 strains of HIV-1. Prior to the discovery of chemokine receptors as the HIV coreceptors, ALX40-4C was used in phase I/II clinical trials to evaluate its therapeutic potential against HIV-1, making ALX40-4C the first anticoreceptor inhibitor to be tested in humans against HIV-1. Patients in the highest dose groups achieved ALX40-4C levels above the effective concentration of the drug for nearly the entire 1-month treatment period. ALX40-4C was well tolerated by 39 of 40 asymptomatic HIV-infected patients, despite the critical role of CXCR4 in normal development and hematopoiesis. No significant or consistent reductions in viral load were observed, but only 12 of the enrolled patients harbored virus types that used CXCR4. We also found that ALX40-4C interacts with the second extracellular loop of CXCR4 and inhibits infection exclusively by blocking direct virus-CXCR4 interactions.

Age-related morphine kinetics

The kinetic disposition of morphine was compared in 13 young and 7 older healthy subjects after a single intravenous dose of 10 mg/70 kg morphine. The apparent volume of distribution at steady state in elderly subjects was only half of that in young subjects. This difference was derived from reductions in both central and peripheral kinetic compartment volumes in the older subjects. The β elimination phase for morphine was more rapid, but its plasma clearance was reduced in older subjects. Calculation of the peripheral compartment morphine concentration for these subjects indicated that drug concentration in this kinetic space was higher in older subjects for 1.5 hr after dosing.

Clinical Pharmacokinetics of Amantadine Hydrochloride

SummaryAmantadine is a drug with diverse uses ranging from prevention of influenza A illness to the treatment of patients with Parkinson’s disease. It is available only in oral formulations from which it is well absorbed and widely distributed, little drug being present in the circulation. Apparent volume of distribution is inversely related to dose over the therapeutic range and accounts in part for a noteworthy logarithmic increase in plasma concentration as a function of dose. Elimination is primarily by renal clearance by both glomerular filtration and tubular secretion.Amantadine accumulates in patients with renal dysfunction. Hence, doses must be reduced in such patients to avoid toxicity. Interactions with other drugs appear uncommon.Relationships have been demonstrated between amantadine therapeutic effects and plasma concentrations in different study cohorts, but not in individual patients. Dose schedules have been suggested for individuals in whom amantadine kinetics are different from healthy subjects. However, these schedules are controversial in their choice of target concentrations and in being untested as to predictive value.

Validity of a prescription claims database to estimate medication adherence in older persons.

Background:Prescription claims data have been used to estimate refill medication adherence through calculations of cumulative medication acquisition (CMA) and cumulative medication gap (CMG) values. Few studies have assessed the validity of these calculated rates. Objectives:We sought to assess the validity of CMA and CMG calculated from the Manitoba prescription claims database (DPIN) against pill count medication adherence, targeting overall medications and angiotensin converting enzyme inhibitors (ACEIs). Methods:Using a survey of a convenience sample of subjects recruited through community pharmacies, subjects who were eligible for study (ie, 65 years or older, noninstitutionalized, taking 2 or more “discrete” prescribed medications, including an ACEI, and willing to provide informed consent) were studied. Pill counts were conducted on all prescribed medicines during 3 home interviews over the course of 4 months. Ten months of DPIN data also were collected on each subject. Results:The concordance between CMA and pill count for overall medications was 411/522 (79%) and for ACEIs was 89/101 (88%) with no systematic differences (McNemars P = 0.68 and P = 0.097, respectively). CMG and pill count showed even better concordance of 438/514 (85%) for overall medications and 96/101 (95%) for ACEIs, although systematic differences were noted for overall medications (McNemars P = 0.0012) but not for ACEIs (McNemars P = 0.500). Spearmans rank correlations were weak for all comparisons. Conclusions:The high concordance between prescription claims database and pill counts suggested that the rate with which patients refill their medications usually is consistent with the rate they consume them. DPIN is not accurate for nondiscrete dosage forms or medications prescribed for “as-required” use.

Pharmacokinetics and Pharmacodynamics of Meropenem in Febrile Neutropenic Patients with Bacteremia

BACKGROUND: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome. OBJECTIVE: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality. METHODS: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial. A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM. Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient. Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC50) for specific organisms. The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome. RESULTS: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients. Sixty patients with confirmed gram-positive or -negative bacteremia were studied. An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p = 0.04). An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p = 0.01). CONCLUSIONS: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

Efficacy of ipecac-induced emesis, orogastric lavage, and activated charcoal for acute drug overdose.

The efficacy of ipecac-induced emesis, large-bore orogastric lavage, and activated charcoal as gastrointestinal decontamination procedures after acute drug overdose is unknown. Using an ampicillin overdose model, these three procedures were compared with one another and to a control ingestion in ten human volunteers. Serial serum ampicillin levels were used to compute the areas under the concentration vs time curves (AUC) for each study. The reductions of ampicillin absorption compared to control were as follows: orogastric lavage 32% (NS), ipecac-induced emesis 38% (P less than .01), and activated charcoal 57% (P less than .01). This model examines each intervention in a mutually exclusive fashion. It supports activated charcoal administration as the primary gastrointestinal decontamination procedure after acute drug overdose.

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Background: Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza. Methods: We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain. Using tandem mass spectrometry, we assessed plasma levels of oseltamivir free base and its active metabolite carboxylate at baseline (before gastric administration of the drug) and at 2, 4, 6, 9 and 12 hours after the fourth or later dose. Results: Among the 36 patients who did not require dialysis, the median concentration of oseltamivir free base was 10.4 (interquartile range [IQR] 4.8–14.9) μg/L; the median concentration of the carboxylate metabolite was 404 (IQR 257–900) μg/L. The volume of distribution of the carboxylate metabolite did not increase with increasing body weight (R2 = 0.00, p = 0.87). The rate of elimination of oseltamivir carboxylate was modestly correlated with estimations of creatinine clearance (R2 = 0.27, p < 0.001). Drug clearance in the five patients who required continuous renal replacement therapy was about one-sixth that in the 36 patients with relatively normal renal function. Interpretation: Oseltamivir was well absorbed enterically in critically ill patients admitted to the ICU with suspected or confirmed pandemic (H1N1) influenza. The dosage of 75 mg twice daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. Adjustment of the dosage in patients with renal dysfunction requiring continuous renal replacement therapy is appropriate; adjustment for obesity does not appear to be necessary.

Whole‐bowel irrigation versus activated charcoal in sorbitol for the ingestion of modified‐release pharmaceuticals

Overdose with modified‐release pharmaceuticals is an increasing phenomenon. This study examines whole‐bowel irrigation as a potential decontamination strategy after overdose with enteric‐coated acetylsalicylic acid and compares it with administration of activated charcoal in sorbitol, which is currently the recommended intervention. A three‐phase randomized crossover protocol was used in 10 adult volunteers. Each volunteer ingested nine 325 mg doses of enteric‐coated acetylsalicylic acid on three occasions, with at least 1 week between each administration period. Serum samples were analyzed for salicylic acid concentration by HPLC. Both interventions decreased peak salicylic acid concentration, time‐to‐zero salicylic acid concentration, and AUC when compared with control (p < 0.01). Whole‐bowel irrigation was superior to activated charcoal in sorbitol by all three criteria (p < 0.05). Adverse effects were qualitatively and quantitatively greater during activated charcoal in sorbitol, and the volunteers preferred whole‐bowel irrigation over charcoal in sorbitol. Our data suggest that whole‐bowel irrigation should be considered for overdose of other modified‐release pharmaceuticals.